肿瘤性骨软化症的临床和组织病理学特征
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摘要
第一部分肿瘤性骨软化症的临床资料分析
研究目的
肿瘤性骨软化症(Tumor induced osteomalacia, TIO)是一种由于肿瘤分泌调磷因子("phosphatonin")引起肾脏磷丢失增加造成的获得性代谢性骨病。肿瘤切除后,血磷恢复正常或较前有所上升。临床表现为乏力、骨痛,严重者出现骨折、骨骼畸形,严重影响患者生活质量。生化特点为高尿磷,低血磷,高碱性磷酸酶,血1,25(OH)2D3水平降低或正常,血钙水平基本正常。TIO肿瘤是来源于间叶组织的良性肿瘤,多位于骨或软组织内,位置隐匿,生长缓慢,肿瘤一般较小,不易被发现,造成诊断困难。本研究旨在探讨TIO的临床特点,诊断方法以及治疗手段。
研究方法
对2004年1月至2012年4月在北京协和医院明确诊断的89例肿瘤性低磷骨软化症患者进行研究。收集患者的病史、体格检查、骨代谢相关生化检查、骨密度、骨髂X线及骨扫描检查,对怀疑肿瘤相关低磷骨软化的患者进一步行锝-99m标记奥曲肽显像(99Tcm-OCT)检查。对奥曲肽显像阳性者再进一步行BUS、CT、MRI等明确肿瘤部位。奥曲肽显像阴性但高度怀疑TIO的患者行全身PET检查,积极寻找肿瘤部位。对定位明确的患者行手术治疗,监测术前及术后骨代谢指标及骨密度等。
研究结果
89例TIO患者(男：女=43/46),平均年龄42.9±12.3岁(范围18-71岁),病程中位数4.23年(范围1-27年)。所有患者均有不同程度的骨痛、乏力、活动障碍,77.0%(57/74)出现身高下降,63%(56/89)出现1次及1次以上的非暴力性骨折。其中40.4%(36/89)的人有肋骨骨折,30.3%(27/89)的人有股骨骨折,11.2%(10/89)的人有骨盆骨折,9.0%(8/89)的人有椎体骨折。59.6%(53/89)的人有不同程度的椎体变形,24.7%(22/89)的人有假骨折线。
TIO患者的平均血磷水平0.45±0.13mol/L,血ALP282±158U/L,血PTH70.1±56.3pg/ml,24小时尿磷为580.27±346.38mg,磷廓清指数(TmP/GFR)为0.38±0.15mmol/L,血清25(OH)D3为20.10±23.13pmol/1,血清1,25(OH)2D3为14.0±9.78pg/ml, β-CTX为0.80±0.83ng/ml。
99Tcm-OCT检查阳性者有73例,其中肿瘤位于软组织的有54例,骨组织中19例。对于99Tcm-OCT检查阳性者B超检查阳性率100%(41/41),CT阳性率91.7(33/36),MRI阳性率95.3%(41/43)。99Tcm-OCT检查阴性者16例,13例肿瘤位于软组织中,3例位于骨组织中。其中有10人行88Ga-DOTA PET检查均为阳性。
89例TIO患者中,有67例肿瘤位于软组织,22例位于骨组织。肿瘤可位于全身各处,下肢最常见,有48例(53.9%)；其次为头部,有26例(29.3%)。肿瘤的病理类型很多,其中78例病理类型为磷酸盐尿性间叶组织肿瘤(PMT),3例牙源性纤维瘤,神经纤维瘤、外周神经鞘瘤、血管外皮瘤、血管瘤、腱鞘巨细胞瘤、肌纤维母细胞瘤各1例,还有2例特殊的肿瘤包括1例肾透明细胞癌和1例胸腺类癌。大部分患者(81/89,91.0%)的肿瘤为良性,恶性8例(8/89,9.0%)。手术完整切除肿瘤后,大部分患者(76/89,85.4%)患者的血磷平均在术后5天左右恢复正常。但有些患者(4/89,4.5%)术后超过2周血磷才逐渐恢复正常。13例患者血磷最终未恢复正常。随访过程中有6例患者(6/76,7.9%)血磷再次下降到正常水平以下。血磷恢复正常的患者,术后6月骨痛明显缓解并逐渐恢复行走、工作能力,患者的骨密度也明显升高。
研究结论
1.89例TIO患者73例99Tcm-OCT检查有阳性发现(82.0%),表明99Tcm-OCT是发现TIO肿瘤的有效方法。99Tcm-OCT检查结合B超、CT、MRI有助于肿瘤定位。
2.99Tcm-OCT显像阴性的16例患者中有10例行68Ga-DOTA PET检查,均为阳性(100%,10/10)。表明68Ga-DOTA PET对于TIO肿瘤的敏感性更高,是一种更有效的方式。
3.TIO肿瘤为间叶组织来源的肿瘤,病理类型主要是磷酸盐尿性间叶组织肿瘤(PMT)。还有一些肿瘤可导致肿瘤性骨软化,如肾透明细胞癌和胸腺类癌等。
4.手术完整切除肿瘤是根治肿瘤的方法,完整切除肿瘤后有76例患者(76/89,82.0%)血磷在5天左右可上升到正常。
5.虽然大部分肿瘤为良性肿瘤,但是也可能为恶性,甚至发生转移。
6.随访过程中共有6例(6/89,6.7%)患者再次出现血磷下降,提示TIO患者术后可能复发。术后应注意随访观察。
第二部分肿瘤性骨软化的组织病理学研究
研究目的
肿瘤性骨软化是一种由于肿瘤分泌调磷因子FGF23导致的获得性骨软化症。现在已知的调磷因子有FGF23, MEPE, FGF7, sFRP4等。其中FGF23是研究最多的。FGF23主要是由骨组织中的成骨细胞和骨细胞分泌的,另外骨髓中包绕静脉窦的周细胞样细胞以及下丘脑腹外侧核,胸腺以及淋巴结也可少量产生。依据这个原理,我们推测T1O肿瘤中分泌FGF23的细胞是成骨细胞系某一阶段的细胞。为了验证我们的推理,本研究拟探讨T1O肿瘤中是否存在成骨细胞系的细胞。
研究方法
选取成骨细胞分化过程中各个阶段的分子作为标记分子,采用免疫组织化学的方法
检测46例T1O肿瘤组织中FGF23、MEPE、Cbfal、ALP、OC、DMP1的表达情况。
研究结果
1.T1O肿瘤的组织成分复杂。梭形肿瘤细胞是其主要成分,肿瘤组织中钙化现象多见。骨样结构在T1O肿瘤中不少见(30/46,65.2%),可为成熟骨样组织,也可为不成熟骨样组织。肿瘤中血管丰富,其中大量畸形血管存在。部分肿瘤组织中可见破骨样多核巨细胞。肿瘤细胞有丝分裂相少见,但往往边界不清,浸润周围组织。
2. FGF23在TIO肿瘤中的表达阳性率为100%(46/46)。FGF23主要是由成骨细胞机骨细胞分泌的,推测肿瘤中表达FGF23的细胞可能是源于成骨细胞系。
3. MEPE在TIO肿瘤中的表达阳性率为97.6%(45/46)。MEPE主要由位于矿化部位的骨细胞分泌,其表达提示肿瘤组织中有骨细胞。
4. Cbfal在TIO肿瘤中的表达阳性率为97.6%(45/46),作为间充质细胞向成骨细胞分化过程中最重要的因子,Cbfal的表达提示TIO肿瘤中有间充质干细胞向成骨细胞分化的趋势。
5.ALP在TIO肿瘤组织中的表达阳性率为97.6%(45/46)。ALP作为较为成熟成骨细胞的重要标记,其存在提示肿瘤中存在较为成熟的成骨细胞。
6.OC在TIO肿瘤中的表达阳性率为93.5%(43/46)。作为成熟成骨细胞非常特异的标记分子,OC的表达提示成熟成骨细胞的存在。
7. DMP1在TIO肿瘤中的表达阳性率58.7%(27/46)。DMP1主要是由位于矿化部位的骨细胞分泌的,其表达提示肿瘤中有相对较成熟的骨细胞存在。
8. Cbfal,ALP,OC,MEPE,DMP1,FGF23这些成骨细胞分化过程中依次表达的一系列蛋白在大部分TIO肿瘤中表达阳性,提示TIO肿瘤中存在成骨细胞的序列分化过程。
9.肿瘤中部分畸形血管内皮表达FGF23,ALP和OC,而正常血管内皮不表达,提示畸形血管内皮可能具有多向分化潜能,特别是向成骨细胞系列逆向分化的可能。
研究结论
1.本研究发现在TIO肿瘤中,FGF23和MEPE的表达阳性率很高,二者均为调磷因子,推测FGF23和MEPE可能与TIO患者低磷血症和骨软化密切相关.
2.TIO肿瘤组织中有各种分化程度的成骨细胞及骨细胞存在。提示TIO肿瘤中存在成骨细胞的序列分化过程。
3.肿瘤组织中畸形血管内皮表达成骨细胞特异的分子,提示畸形的血管内皮可能具有向成骨细胞系列逆向分化的可能。
Part I The clinical study of tumor induced osteomalacia
Object
Tumor induced osteomalacia (TIO) is a rare paraneoplastic syndrome induced by tumor produced phosphaturic factors, i. e. phosphatonins. The disorder is characterized by renal tubular phosphate loss, secondary to this process hypophosphatemia and defective production of active form of vitamin D. Clinical manifestations include bone pain, pathological fractures, muscle weakness and general fatigue. Osteomalacia-associated tumors are mesenchymal tumors that are usually benign. They are usually situated in the bones and in soft tissue. Most of them are small, slow-growing and difficult to locate. Their insignificant size and various locations coupled with rare occurrence of the disease and non-specificity of clinical symptoms lead to difficulties in reaching a diagnosis. The aim of this study is to discuss the pathophysiology of disease symptoms, diagnostic methods and treatment of oncogenic osteomalacia.
Method
We analyzed the clinical data of eighty nine patients who had been diagnosed as tumor induced osteomalacia from2004to2013in Peking Union Medical College Hospital. After taking their medical history, Physical examination was performed. Their bone turnover markers were measured and technetium-99m octreotide scintigraphy (99Tcm-OCT) was performed on every patient. If a tumor was suspected, BUS, CT or MRI was preceded on the patient. If99Tcm-OCT was negative but the patient was highly suspicious of TIO, the patient would get PET scan. After the tumor was located, it was resected in our hospital.
Result
There were forty three men (43/89,48.3%) and forty six (46/89,51.7%) women in our study. Their mean age was42.9±12.3years, the youngest was eighteen years old and the oldest was seventy one years old. The median value of their disease duration was four year long, the longest one was twenty seven year and the shortest one is about one year. All of these patients were presented with bone pain and fatigue. Fifty seven patients (57/89,77.0%) were shorter than before and fifty six patients(56/89,63.0%) had at least one fragile fracture. Thirty six patients (36/89,40.4%) had rib fracture, twenty seven (27/89,24.7%) had femur fracture, ten (10/89,11.2%) had pelvis fracture and eight (8/89,9.0%) had vertebrate fracture. Fifty three patients (53/89,59.6%) had biconcave or wedged vertebrate. Twenty two patients (22/89,24.7%) have pseudo-fracture.
The mean level of serum phosphate was0.45±0.13mmol/L, ALP was282±158U/L, PTH was70.1±56.3pg/ml,24h Up was580.27±346.38mg, TmP/GFR was0.38±0.15mmol/L,25(OH)D:3was20.10±23.13ng/ml,1,25(OH)2D:3was14.0±9.78pg/ml and β-CTX was0.80±0.83ng/ml。
Seventy three (73/89,82.0%) of all these patients had high99Tcm-OCT uptake. Fifty four of all these suspicious lesions were located in soft tissue while nineteen were in bone. Once the suspicious lesion was located by99Tcm-OCT, we proceeded to anatomic imaging such as BUS、CT and MRI to confirm the location of the tumor. The detection rate was one hundred percent (41/41,100%) for BUS, ninty two percent (33/36,91.7%) for CT and ninty five percent (41/43,95.3%) for MRI. Sixteen patients (16/89,18.0%) were99Tcm-OCT negative. Ten of these patients received68Ga-DOTA PET scan. ALL of them had found their suspicious lesions with68Ga-DOTA PET and they were proved to be the tumor location.
Sixty seven (67/89,75.3%) of these tumors occurred in soft tissue, twenty two (22/89,24.7%) occurred in bone. They were located form head to toe, but the most common place was lower limb (48/89,53.9%). Twenty six tumors (26/89,29.3%) were locatd in the head region, six (6/89,6.7%) in the upper limb, five (5/89,5.6%) in the thorax and abdominal region and four (4/89,4.5%) in the pelvis and groin region. Tumors associated with TIO had included a wide range of histopathological diagnoses, with seventy eight phosphaturic mesenchymal tumors and a few other tumors. While most of these tumors (81/89,91.0%) were benign, eight (8/89,9.0%) were malignant. Tumor resection was almost always curative, and following complete resection of the tumor, phosphate level returned to normal in senventy six patients (76/89,85.4%) by post-operative day five. Of these patients, twenty five recoverd in three days, twenty three recoverd in three to five days, seventeen recoverd in five to seven days, six recoverd in one to two weeks and five patients took more than two weeks to recover. While phosphate level was not recovered in thirteen patients (13/89,14.6%). During the followup, the symptoms relapsed in six patients. For the patiets who were cured completely, bone pain disappeared gradually in six months post operation and their bone mineral density increased gradually.
Conclusion
1.99Tcm-OCT was a very helpful method in our hospital for locating TIO tumors. The detection rate of99Tcm-PCT in our patients was82.0%. Once the suspicious lesion was located by99cm-OCT, we proceeded to BUS、CT and MRI to confirm the location of the tumor.
2.68Ga-DOTA PET was more specific than99Tcm-OCT in locating TIO tumors.
3. Tumors associated with TIO had included a wide range of histopathological diagnoses, including phosphaturic mesenchymal tumor, odontogenic fibroma, hemangioma, giant cell tumor of tendon sheath, neurofibroma. A few other tumor or carcinoma could also lead to osteomalacia, for example renal clear cell carcinoma, thymus carcinoid.
4. The treatment of choice for TIO was resection of the tumor with a wide margin to insure complete resection. The majority of patients demonstrated surgical cure, as evidenced by the return of serum phosphate to normal, by post-operative day5.
5. Although most of the tumors were benign, malignant presentation and metastases could occur.
6. Recurrences of these tumors could happen. All the patients should be followed up for as long as possible since recurrence could happen at any time.
Part II The histopathological study of tumor induced osteomalacia
Object
Tumor induced osteomalacia (TIO) is a rare paraneoplastic syndrome induced by tumor produced phosphaturic factors, i. e. phosphatonins. There is at least four phosphatonins, FGF23, MEPE, FGF7and sFRP4. FGF23is the widely recognized phosphaturic hormone that results in urine phosphate wasting and low levels of1,25(OH)2D3. FGF23is mainly secreted by osteocyte and osteoblast in bone tissue, with a little expression by pericyte like cells in bone marrow, hypothalamus. So we speculate that the tumor cells in TIO that secrete FGF23are osteogenic cells.The aim of this study is to discuss the histopathology of tumor induced osteomalacia and whether osteogenic cells are present in tumors associated with TIO.
Method
Utilizing immunohistochemical techniques, positive detection of protein that are sequencially expressed during different stages of osteoblast differentiation has been demonstrated for Cbfal, ALP, OC, DMP1, MEPE, FGF23.
Results
The phosphaturic mesenchymal tumor (PMT) contained neoplastic cells that were spindled in shape. Bone like structure was a frequent finding and steoclast-like giant cells could be seen. A prominent feature of these tumors was an elaborate intrinsic microvasculature with an admixture of vessel size and vascular pattern. The nuclear grade was low, and mitotic activity was usually absent or very low. But the tumors were poorly circumscribed and infiltration of surrounding tissues was common.
FGF23was positive in all of the46tumors associated with TIO. FGF23is primarily secreted by osteoblast and osteocyte. This may suggest that the tumor cells that secret FGF23are osteogenic cells.
MEPE was positive in97.6%of tumors associated with TIO. It is recognized that MEPE is secreted by osteocyte located in bone matrix. It is likely that the cells that express MEPE are osteocyte.
As a very important transcription factor in regulating the differentiation of mesenchymal stem cell to osteoblast, Cbfal was expressed in97.6%of tumors associated with TIO.The expression of Cbfal may indicate that the cells that are expressed are immature osteoblasts.
ALP was positive in97.6%of the tumors associated with TIO. ALP is mainly produced by osteoblast. Its expression could be recognized as a marker of osteoblast.
As the only and very specific marker of mature osteoblast, OC was positive in93.5%of the tumors. It is likely that there are mature osteoblasts in these tumor tissues.
DMP1was positive in58.7%of tumors associated with TIO. Secreted by osteocyte located in bone matrix, the expression of DMP1may indicate that the cells that it is secreted are osteocytes.
Cbfal, ALP, OC, MEPE, DMP1, FGF23are factors that are sequentially expressed during different stages of osteoblast differentiation. Tumors associated with TIO expressd almost all of this factors. This may indicate that osteogenic cells are present in these tumors.
In Our study we also found that ALP, OC and FGF23were also expressed by malformed endothelial cells in these tumors, while they were not expressed by normal endothelial cells.
Conclusion
Tumors associated with TIO expressd the phosphaturic factors FGF23and MEPE. These two factors are related to hypophosphatemia and osteomalacia.
A series of molecules that are sequentially expressed in different stages of osteoblast differentiation were also expressed in tumors associated with TIO. This may indicated that osteogenic cells are present in these tumors.
The malformaed endothelial cells are multipotential cells in tumors associated with TIO and they may have the potential of transdifferentiation to become osteogenic cells.
研究目的
肿瘤性骨软化症(Tumor induced osteomalacia, TIO)是一种由于肿瘤分泌调磷因子("phosphatonin")引起肾脏磷丢失增加造成的获得性代谢性骨病。肿瘤切除后,血磷恢复正常或较前有所上升。临床表现为乏力、骨痛,严重者出现骨折、骨骼畸形,严重影响患者生活质量。生化特点为高尿磷,低血磷,高碱性磷酸酶,血1,25(OH)2D3水平降低或正常,血钙水平基本正常。TIO肿瘤是来源于间叶组织的良性肿瘤,多位于骨或软组织内,位置隐匿,生长缓慢,肿瘤一般较小,不易被发现,造成诊断困难。本研究旨在探讨TIO的临床特点,诊断方法以及治疗手段。
研究方法
对2004年1月至2012年4月在北京协和医院明确诊断的89例肿瘤性低磷骨软化症患者进行研究。收集患者的病史、体格检查、骨代谢相关生化检查、骨密度、骨髂X线及骨扫描检查,对怀疑肿瘤相关低磷骨软化的患者进一步行锝-99m标记奥曲肽显像(99Tcm-OCT)检查。对奥曲肽显像阳性者再进一步行BUS、CT、MRI等明确肿瘤部位。奥曲肽显像阴性但高度怀疑TIO的患者行全身PET检查,积极寻找肿瘤部位。对定位明确的患者行手术治疗,监测术前及术后骨代谢指标及骨密度等。
研究结果
89例TIO患者(男：女=43/46),平均年龄42.9±12.3岁(范围18-71岁),病程中位数4.23年(范围1-27年)。所有患者均有不同程度的骨痛、乏力、活动障碍,77.0%(57/74)出现身高下降,63%(56/89)出现1次及1次以上的非暴力性骨折。其中40.4%(36/89)的人有肋骨骨折,30.3%(27/89)的人有股骨骨折,11.2%(10/89)的人有骨盆骨折,9.0%(8/89)的人有椎体骨折。59.6%(53/89)的人有不同程度的椎体变形,24.7%(22/89)的人有假骨折线。
TIO患者的平均血磷水平0.45±0.13mol/L,血ALP282±158U/L,血PTH70.1±56.3pg/ml,24小时尿磷为580.27±346.38mg,磷廓清指数(TmP/GFR)为0.38±0.15mmol/L,血清25(OH)D3为20.10±23.13pmol/1,血清1,25(OH)2D3为14.0±9.78pg/ml, β-CTX为0.80±0.83ng/ml。
99Tcm-OCT检查阳性者有73例,其中肿瘤位于软组织的有54例,骨组织中19例。对于99Tcm-OCT检查阳性者B超检查阳性率100%(41/41),CT阳性率91.7(33/36),MRI阳性率95.3%(41/43)。99Tcm-OCT检查阴性者16例,13例肿瘤位于软组织中,3例位于骨组织中。其中有10人行88Ga-DOTA PET检查均为阳性。
89例TIO患者中,有67例肿瘤位于软组织,22例位于骨组织。肿瘤可位于全身各处,下肢最常见,有48例(53.9%)；其次为头部,有26例(29.3%)。肿瘤的病理类型很多,其中78例病理类型为磷酸盐尿性间叶组织肿瘤(PMT),3例牙源性纤维瘤,神经纤维瘤、外周神经鞘瘤、血管外皮瘤、血管瘤、腱鞘巨细胞瘤、肌纤维母细胞瘤各1例,还有2例特殊的肿瘤包括1例肾透明细胞癌和1例胸腺类癌。大部分患者(81/89,91.0%)的肿瘤为良性,恶性8例(8/89,9.0%)。手术完整切除肿瘤后,大部分患者(76/89,85.4%)患者的血磷平均在术后5天左右恢复正常。但有些患者(4/89,4.5%)术后超过2周血磷才逐渐恢复正常。13例患者血磷最终未恢复正常。随访过程中有6例患者(6/76,7.9%)血磷再次下降到正常水平以下。血磷恢复正常的患者,术后6月骨痛明显缓解并逐渐恢复行走、工作能力,患者的骨密度也明显升高。
研究结论
1.89例TIO患者73例99Tcm-OCT检查有阳性发现(82.0%),表明99Tcm-OCT是发现TIO肿瘤的有效方法。99Tcm-OCT检查结合B超、CT、MRI有助于肿瘤定位。
2.99Tcm-OCT显像阴性的16例患者中有10例行68Ga-DOTA PET检查,均为阳性(100%,10/10)。表明68Ga-DOTA PET对于TIO肿瘤的敏感性更高,是一种更有效的方式。
3.TIO肿瘤为间叶组织来源的肿瘤,病理类型主要是磷酸盐尿性间叶组织肿瘤(PMT)。还有一些肿瘤可导致肿瘤性骨软化,如肾透明细胞癌和胸腺类癌等。
4.手术完整切除肿瘤是根治肿瘤的方法,完整切除肿瘤后有76例患者(76/89,82.0%)血磷在5天左右可上升到正常。
5.虽然大部分肿瘤为良性肿瘤,但是也可能为恶性,甚至发生转移。
6.随访过程中共有6例(6/89,6.7%)患者再次出现血磷下降,提示TIO患者术后可能复发。术后应注意随访观察。
第二部分肿瘤性骨软化的组织病理学研究
研究目的
肿瘤性骨软化是一种由于肿瘤分泌调磷因子FGF23导致的获得性骨软化症。现在已知的调磷因子有FGF23, MEPE, FGF7, sFRP4等。其中FGF23是研究最多的。FGF23主要是由骨组织中的成骨细胞和骨细胞分泌的,另外骨髓中包绕静脉窦的周细胞样细胞以及下丘脑腹外侧核,胸腺以及淋巴结也可少量产生。依据这个原理,我们推测T1O肿瘤中分泌FGF23的细胞是成骨细胞系某一阶段的细胞。为了验证我们的推理,本研究拟探讨T1O肿瘤中是否存在成骨细胞系的细胞。
研究方法
选取成骨细胞分化过程中各个阶段的分子作为标记分子,采用免疫组织化学的方法
检测46例T1O肿瘤组织中FGF23、MEPE、Cbfal、ALP、OC、DMP1的表达情况。
研究结果
1.T1O肿瘤的组织成分复杂。梭形肿瘤细胞是其主要成分,肿瘤组织中钙化现象多见。骨样结构在T1O肿瘤中不少见(30/46,65.2%),可为成熟骨样组织,也可为不成熟骨样组织。肿瘤中血管丰富,其中大量畸形血管存在。部分肿瘤组织中可见破骨样多核巨细胞。肿瘤细胞有丝分裂相少见,但往往边界不清,浸润周围组织。
2. FGF23在TIO肿瘤中的表达阳性率为100%(46/46)。FGF23主要是由成骨细胞机骨细胞分泌的,推测肿瘤中表达FGF23的细胞可能是源于成骨细胞系。
3. MEPE在TIO肿瘤中的表达阳性率为97.6%(45/46)。MEPE主要由位于矿化部位的骨细胞分泌,其表达提示肿瘤组织中有骨细胞。
4. Cbfal在TIO肿瘤中的表达阳性率为97.6%(45/46),作为间充质细胞向成骨细胞分化过程中最重要的因子,Cbfal的表达提示TIO肿瘤中有间充质干细胞向成骨细胞分化的趋势。
5.ALP在TIO肿瘤组织中的表达阳性率为97.6%(45/46)。ALP作为较为成熟成骨细胞的重要标记,其存在提示肿瘤中存在较为成熟的成骨细胞。
6.OC在TIO肿瘤中的表达阳性率为93.5%(43/46)。作为成熟成骨细胞非常特异的标记分子,OC的表达提示成熟成骨细胞的存在。
7. DMP1在TIO肿瘤中的表达阳性率58.7%(27/46)。DMP1主要是由位于矿化部位的骨细胞分泌的,其表达提示肿瘤中有相对较成熟的骨细胞存在。
8. Cbfal,ALP,OC,MEPE,DMP1,FGF23这些成骨细胞分化过程中依次表达的一系列蛋白在大部分TIO肿瘤中表达阳性,提示TIO肿瘤中存在成骨细胞的序列分化过程。
9.肿瘤中部分畸形血管内皮表达FGF23,ALP和OC,而正常血管内皮不表达,提示畸形血管内皮可能具有多向分化潜能,特别是向成骨细胞系列逆向分化的可能。
研究结论
1.本研究发现在TIO肿瘤中,FGF23和MEPE的表达阳性率很高,二者均为调磷因子,推测FGF23和MEPE可能与TIO患者低磷血症和骨软化密切相关.
2.TIO肿瘤组织中有各种分化程度的成骨细胞及骨细胞存在。提示TIO肿瘤中存在成骨细胞的序列分化过程。
3.肿瘤组织中畸形血管内皮表达成骨细胞特异的分子,提示畸形的血管内皮可能具有向成骨细胞系列逆向分化的可能。
Part I The clinical study of tumor induced osteomalacia
Object
Tumor induced osteomalacia (TIO) is a rare paraneoplastic syndrome induced by tumor produced phosphaturic factors, i. e. phosphatonins. The disorder is characterized by renal tubular phosphate loss, secondary to this process hypophosphatemia and defective production of active form of vitamin D. Clinical manifestations include bone pain, pathological fractures, muscle weakness and general fatigue. Osteomalacia-associated tumors are mesenchymal tumors that are usually benign. They are usually situated in the bones and in soft tissue. Most of them are small, slow-growing and difficult to locate. Their insignificant size and various locations coupled with rare occurrence of the disease and non-specificity of clinical symptoms lead to difficulties in reaching a diagnosis. The aim of this study is to discuss the pathophysiology of disease symptoms, diagnostic methods and treatment of oncogenic osteomalacia.
Method
We analyzed the clinical data of eighty nine patients who had been diagnosed as tumor induced osteomalacia from2004to2013in Peking Union Medical College Hospital. After taking their medical history, Physical examination was performed. Their bone turnover markers were measured and technetium-99m octreotide scintigraphy (99Tcm-OCT) was performed on every patient. If a tumor was suspected, BUS, CT or MRI was preceded on the patient. If99Tcm-OCT was negative but the patient was highly suspicious of TIO, the patient would get PET scan. After the tumor was located, it was resected in our hospital.
Result
There were forty three men (43/89,48.3%) and forty six (46/89,51.7%) women in our study. Their mean age was42.9±12.3years, the youngest was eighteen years old and the oldest was seventy one years old. The median value of their disease duration was four year long, the longest one was twenty seven year and the shortest one is about one year. All of these patients were presented with bone pain and fatigue. Fifty seven patients (57/89,77.0%) were shorter than before and fifty six patients(56/89,63.0%) had at least one fragile fracture. Thirty six patients (36/89,40.4%) had rib fracture, twenty seven (27/89,24.7%) had femur fracture, ten (10/89,11.2%) had pelvis fracture and eight (8/89,9.0%) had vertebrate fracture. Fifty three patients (53/89,59.6%) had biconcave or wedged vertebrate. Twenty two patients (22/89,24.7%) have pseudo-fracture.
The mean level of serum phosphate was0.45±0.13mmol/L, ALP was282±158U/L, PTH was70.1±56.3pg/ml,24h Up was580.27±346.38mg, TmP/GFR was0.38±0.15mmol/L,25(OH)D:3was20.10±23.13ng/ml,1,25(OH)2D:3was14.0±9.78pg/ml and β-CTX was0.80±0.83ng/ml。
Seventy three (73/89,82.0%) of all these patients had high99Tcm-OCT uptake. Fifty four of all these suspicious lesions were located in soft tissue while nineteen were in bone. Once the suspicious lesion was located by99Tcm-OCT, we proceeded to anatomic imaging such as BUS、CT and MRI to confirm the location of the tumor. The detection rate was one hundred percent (41/41,100%) for BUS, ninty two percent (33/36,91.7%) for CT and ninty five percent (41/43,95.3%) for MRI. Sixteen patients (16/89,18.0%) were99Tcm-OCT negative. Ten of these patients received68Ga-DOTA PET scan. ALL of them had found their suspicious lesions with68Ga-DOTA PET and they were proved to be the tumor location.
Sixty seven (67/89,75.3%) of these tumors occurred in soft tissue, twenty two (22/89,24.7%) occurred in bone. They were located form head to toe, but the most common place was lower limb (48/89,53.9%). Twenty six tumors (26/89,29.3%) were locatd in the head region, six (6/89,6.7%) in the upper limb, five (5/89,5.6%) in the thorax and abdominal region and four (4/89,4.5%) in the pelvis and groin region. Tumors associated with TIO had included a wide range of histopathological diagnoses, with seventy eight phosphaturic mesenchymal tumors and a few other tumors. While most of these tumors (81/89,91.0%) were benign, eight (8/89,9.0%) were malignant. Tumor resection was almost always curative, and following complete resection of the tumor, phosphate level returned to normal in senventy six patients (76/89,85.4%) by post-operative day five. Of these patients, twenty five recoverd in three days, twenty three recoverd in three to five days, seventeen recoverd in five to seven days, six recoverd in one to two weeks and five patients took more than two weeks to recover. While phosphate level was not recovered in thirteen patients (13/89,14.6%). During the followup, the symptoms relapsed in six patients. For the patiets who were cured completely, bone pain disappeared gradually in six months post operation and their bone mineral density increased gradually.
Conclusion
1.99Tcm-OCT was a very helpful method in our hospital for locating TIO tumors. The detection rate of99Tcm-PCT in our patients was82.0%. Once the suspicious lesion was located by99cm-OCT, we proceeded to BUS、CT and MRI to confirm the location of the tumor.
2.68Ga-DOTA PET was more specific than99Tcm-OCT in locating TIO tumors.
3. Tumors associated with TIO had included a wide range of histopathological diagnoses, including phosphaturic mesenchymal tumor, odontogenic fibroma, hemangioma, giant cell tumor of tendon sheath, neurofibroma. A few other tumor or carcinoma could also lead to osteomalacia, for example renal clear cell carcinoma, thymus carcinoid.
4. The treatment of choice for TIO was resection of the tumor with a wide margin to insure complete resection. The majority of patients demonstrated surgical cure, as evidenced by the return of serum phosphate to normal, by post-operative day5.
5. Although most of the tumors were benign, malignant presentation and metastases could occur.
6. Recurrences of these tumors could happen. All the patients should be followed up for as long as possible since recurrence could happen at any time.
Part II The histopathological study of tumor induced osteomalacia
Object
Tumor induced osteomalacia (TIO) is a rare paraneoplastic syndrome induced by tumor produced phosphaturic factors, i. e. phosphatonins. There is at least four phosphatonins, FGF23, MEPE, FGF7and sFRP4. FGF23is the widely recognized phosphaturic hormone that results in urine phosphate wasting and low levels of1,25(OH)2D3. FGF23is mainly secreted by osteocyte and osteoblast in bone tissue, with a little expression by pericyte like cells in bone marrow, hypothalamus. So we speculate that the tumor cells in TIO that secrete FGF23are osteogenic cells.The aim of this study is to discuss the histopathology of tumor induced osteomalacia and whether osteogenic cells are present in tumors associated with TIO.
Method
Utilizing immunohistochemical techniques, positive detection of protein that are sequencially expressed during different stages of osteoblast differentiation has been demonstrated for Cbfal, ALP, OC, DMP1, MEPE, FGF23.
Results
The phosphaturic mesenchymal tumor (PMT) contained neoplastic cells that were spindled in shape. Bone like structure was a frequent finding and steoclast-like giant cells could be seen. A prominent feature of these tumors was an elaborate intrinsic microvasculature with an admixture of vessel size and vascular pattern. The nuclear grade was low, and mitotic activity was usually absent or very low. But the tumors were poorly circumscribed and infiltration of surrounding tissues was common.
FGF23was positive in all of the46tumors associated with TIO. FGF23is primarily secreted by osteoblast and osteocyte. This may suggest that the tumor cells that secret FGF23are osteogenic cells.
MEPE was positive in97.6%of tumors associated with TIO. It is recognized that MEPE is secreted by osteocyte located in bone matrix. It is likely that the cells that express MEPE are osteocyte.
As a very important transcription factor in regulating the differentiation of mesenchymal stem cell to osteoblast, Cbfal was expressed in97.6%of tumors associated with TIO.The expression of Cbfal may indicate that the cells that are expressed are immature osteoblasts.
ALP was positive in97.6%of the tumors associated with TIO. ALP is mainly produced by osteoblast. Its expression could be recognized as a marker of osteoblast.
As the only and very specific marker of mature osteoblast, OC was positive in93.5%of the tumors. It is likely that there are mature osteoblasts in these tumor tissues.
DMP1was positive in58.7%of tumors associated with TIO. Secreted by osteocyte located in bone matrix, the expression of DMP1may indicate that the cells that it is secreted are osteocytes.
Cbfal, ALP, OC, MEPE, DMP1, FGF23are factors that are sequentially expressed during different stages of osteoblast differentiation. Tumors associated with TIO expressd almost all of this factors. This may indicate that osteogenic cells are present in these tumors.
In Our study we also found that ALP, OC and FGF23were also expressed by malformed endothelial cells in these tumors, while they were not expressed by normal endothelial cells.
Conclusion
Tumors associated with TIO expressd the phosphaturic factors FGF23and MEPE. These two factors are related to hypophosphatemia and osteomalacia.
A series of molecules that are sequentially expressed in different stages of osteoblast differentiation were also expressed in tumors associated with TIO. This may indicated that osteogenic cells are present in these tumors.
The malformaed endothelial cells are multipotential cells in tumors associated with TIO and they may have the potential of transdifferentiation to become osteogenic cells.
引文
[1]Folpe AL, Fanburg-Smith JC, Billings SD, Bisceglia M, Bertoni F, Cho JY, Econs MJ, Inwards CY, Jan de Beur SM, Mentzel T, et al.Most osteomalacia-associated mesenchymal tumors are a single histopathologic entity:an analysis of 32 cases and a comprehensive review of the literature[J]. Am J Surg Pathol,2004,28(1):1-30.
[2]Carpenter TO, Ellis BK, Insogna KL, Philbrick WM, Sterpka J, Shimkets R.Fibroblast growth factor 7: an inhibitor of phosphate transport derived from oncogenic osteomalacia-causing tumors[J]. J Clin Endocrinol Metab,2005,90(2):1012-1020.
[3]Shimada T, Mizutani S, Muto T, Yoneya T, Hino R, Takeda S, Takeuchi Y, Fujita T, Fukumoto S, Yamashita T.Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia[J]. Proc Natl Acad Sci U S A,2001,98(11):6500-6505.
[4]Schiavi SC, Kumar R.The phosphatonin pathway:new insights in phosphate homeostasis[J]. Kidney Int,2004,65(1):1-14.
[5]Drake TG, Albright F, Castleman B.PARATHYROID HYPERPLASIA IN RABBITS PRODUCED BY PARENTERAL PHOSPHATE ADMINISTRATION[J]. J Clin Invest,1937,16(2):203-206.
[6]Prader A, Illig R, Uehlinger E, Stalder G.[Rickets following bone tumor][J]. Helv Paediatr Acta,1959, 14(554-565.
[7]Nuovo MA, Dorfman HD, Sun CC, Chalew SA.Tumor-induced osteomalacia and rickets[J]. Am J Surg Pathol,1989,13(7):588-599.
[8]Econs MJ, Drezner MK.Tumor-induced osteomalacia--unveiling a new hormone[J]. N Engl J Med,1994, 330(23):1679-1681.
[9]Tenenhouse HS, Sabbagh Y.Novel phosphate-regulating genes in the pathogenesis of renal phosphate wasting disorders[J]. Pflugers Arch,2002,444(3):317-326.
[10]Saito H, Kusano K, Kinosaki M, Ito H, Hirata M, Segawa H, Miyamoto K, Fukushima N.Human fibroblast growth factor-23 mutants suppress Na+-dependent phosphate co-transport activity and lalpha,25-dihydroxyvitamin D3 production[J]. J Biol Chem,2003,278(4):2206-2211.
[11]Weidner N.Review and update:oncogenic osteomalacia-rickets[J]. Ultrastruct Pathol,1991, 15(4-5):317-333.
[12]Silve C, Beck L.Is FGF23 the long sought after phosphaturic factor phosphatonin?[J]. Nephrol Dial Transplant,2002,17(6):958-961.
[13]Furco A, Roger M, Mouchet B, Richard O, Martinache X, Fur A.Osteomalacia cured by surgery[J]. Eur J Intern Med,2002,13(1):67-69.
[14]Larsson T, Zahradnik R, Lavigne J, Ljunggren O, Juppner H, Jonsson KB.Immunohistochemical detection of FGF-23 protein in tumors that cause oncogenic osteomalacia[J]. Eur J Endocrinol,2003, 148(2):269-276.
[15]Dupond JL, Magy N, Mahammedi M, Prie D, Gil H, Meaux-Ruault N, Kantelip B.[Oncogenic osteomalacia:the role of the phosphatonins. Diagnostic usefulness of the Fibroblast Growth Factor 23 measurement in one patient][J]. Rev Med Interne,2005,26(3):238-241.
[16]Liu S, Zhou J, Tang W, Jiang X, Rowe DW, Quarles LD.Pathogenic role of Fgf23 in Hyp mice[J]. Am J Physiol Endocrinol Metab,2006,291(1):E38-49.
[17]Haeusler G, Freilinger M, Dominkus M, Egerbacher M, Amann G, Kolb A, Schlegel W, Raimann A, Staudenherz A.Tumor-induced hypophosphatemic rickets in an adolescent boy-clinical presentation, diagnosis, and histological findings in growth plate and muscle tissue[J]. J Clin Endocrinol Metab,2010, 95(10):4511-4517.
[18]Ludwig GD, Kyle CG, de Blanco M."Tertiary" hyperparathyroidism induced by osteomalacia resulting from phosphorus depletion[J]. Am J Med,1967,43(1):136-140.
[19]Huang QL, Feig DS, Blackstein ME.Development of tertiary hyperparathyroidism after phosphate supplementation in oncogenic osteomalacia[J]. J Endocrinol Invest,2000,23(4):263-267.
[20]Nguyen BD, Wang EA.Indium-Ⅲ pentetreotide scintigraphy of mesenchymal tumor with oncogenic osteomalacia[J]. Clin Nucl Med,1999,24(2):130-131.
[21]Rhee Y, Lee JD, Shin KH, Lee HC, Huh KB, Lim SK.Oncogenic osteomalacia associated with mesenchymal tumour detected by indium-Ⅲ octreotide scintigraphy[J]. Clin Endocrinol (Oxf),2001, 54(4):551-554.
[22]Garcia CA, Spencer RP.Bone and In-Ⅲ octreotide imaging in oncogenic osteomalacia:a case report[J]. Clin Nucl Med,2002,27(8):582-583.
[23]Paglia F, Dionisi S, Minisola S.Octreotide for tumor-induced osteomalacia[J]. N Engl J Med,2002, 346(22):1748-1749; author reply 1748-1749.
[24]Seufert J, Ebert K, Muller J, Eulert J, Hendrich C, Werner E, Schuuze N, Schulz G, Kenn W, Richtmann H, et al.Octreotide therapy for tumor-induced osteomalacia [J]. N Engl J Med,2001, 345(26):1883-1888.
[25]Roarke MC, Nguyen BD.PET/CT localization of phosphaturic mesenchymal neoplasm causing tumor-induced osteomalacia[J]. Clin Nucl Med,2007,32(4):300-301.
[26]Khadgawat R, Singh Y, Kansara S, Tandon N, Bal C, Seith A, Kotwal P.PET/CT localisation of a scapular haemangiopericytoma with tumour-induced osteomalacia[J]. Singapore Med J,2009, 50(2):e55-57.
[27]Leaf DE, Pereira RC, Bazari H, Juppner H.Oncogenic osteomalacia due to FGF23-expressing colon adenocarcinoma[J]. J Clin Endocrinol Metab,2013,98(3):887-891.
[28]Stone E, Bernier V, Rabinovich S, From GL.Oncogenic osteomalacia associated with a mesenchymal chondrosarcoma[J]. Clin Invest Med,1984,7(3):179-185.
[29]Lustman F, Parmentier R, Dustin P.Oncogenic osteomalacia and renal adenomatoid dysplasia[J]. Ann Intern Med,1985,102(6):869-870.
[30]McMurtry CT, Godschalk M, Malluche HH, Geng Z, Adler RA.Oncogenic osteomalacia associated with metastatic prostate carcinoma:case report and review of the literature[J]. J Am Geriatr Soc,1993, 41(9):983-985.
[31]Weidner N, Santa Cruz D.Phosphaturic mesenchymal tumors. A polymorphous group causing osteomalacia or rickets[J]. Cancer,1987,59(8):1442-1454.
[32]!!! INVALID CITATION!!!
[33]Xia WB, Jiang Y, Li M, Xing XP, Wang O, Hu YY, Zhang HB, Liu HC, Meng XW, Zhou XY.Levels and dynamic changes of serum fibroblast growth factor 23 in hypophosphatemic rickets/osteomalacia[J]. Chin Med J (Engl),2010,123(9):1158-1162.
[34]Rowe PS, de Zoysa PA, Dong R, Wang HR, White KE, Econs MJ, Oudet CL.MEPE, a new gene expressed in bone marrow and tumors causing osteomalacia[J]. Genomics,2000,67(1):54-68.
[35]Toyosawa S, Tomita Y, Kishino M, Hashimoto J, Ueda T, Tsujimura T, Aozasa K, Ijuhin N, Komori T.Expression of dentin matrix protein 1 in tumors causing oncogenic osteomalacia[J]. Mod Pathol,2004, 17(5):573-578.
[36]Komori T, Yagi H, Nomura S, Yamaguchi A, Sasaki K, Deguchi K, Shimizu Y, Bronson RT, Gao YH, Inada M, et al.Targeted disruption of Cbfal results in a complete lack of bone formation owing to maturational arrest of osteoblasts[J]. Cell,1997,89(5):755-764.
[37]Bonewald LF.The amazing osteocyte[J]. J Bone Miner Res,2011,26(2):229-238.
[38]Gattineni J, Bates C, Twombley K, Dwarakanath V, Robinson ML, Goetz R, Mohammadi M, Baum M.FGF23 decreases renal NaPi-2a and NaPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1 [J]. Am J Physiol Renal Physiol,2009,297(2):F282-291.
[39]Kuro-o M.Klotho as a regulator of fibroblast growth factor signaling and phosphate/calcium metabolism[J]. Curr Opin Nephrol Hypertens,2006,15(4):437-441.
[40]Jiang Y, Xia WB, Xing XP, Silva BC, Li M, Wang O, Zhang HB, Li F, Jing HL, Zhong DR, et al.Tumor-induced osteomalacia:an important cause of adult-onset hypophosphatemic osteomalacia in China:Report of 39 cases and review of the literature[J]. J Bone Miner Res,2012,27(9):1967-1975.
[41]Strewler GJ.FGF23, hypophosphatemia, and rickets:has phosphatonin been found?[J]. Proc Natl Acad Sci U S A.2001,98(11):5945-5946.
[42]Fukumoto S, Yamashita T.Fibroblast growth factor-23 is the phosphaturic factor in tumor-induced osteomalacia and may be phosphatonin[J]. Curr Opin Nephrol Hypertens,2002,11(4):385-389.
[43]Hu FK, Yuan F, Jiang CY, Lv DW, Mao BB, Zhang Q, Yuan ZQ, Wang Y.Tumor-induced osteomalacia with elevated fibroblast growth factor 23:a case of phosphaturic mesenchymal tumor mixed with connective tissue variants and review of the literature[J]. Chin J Cancer,2011,30(11):794-804.
[44]Argiro L, Desbarats M, Glorieux FH, Ecarot B.Mepe, the gene encoding a tumor-secreted protein in oncogenic hypophosphatemic osteomalacia, is expressed in bone[J]. Genomics,2001,74(3):342-351.
[45]Addison WN, Nakano Y, Loisel T, Crine P, McKee MD.MEPE-ASARM peptides control extracellular matrix mineralization by binding to hydroxyapatite:an inhibition regulated by PHEX cleavage of ASARM[J]. J Bone Miner Res,2008,23(10):1638-1649.
[46]Lu C, Huang S, Miclau T, Helms JA, Colnot C.Mepe is expressed during skeletal development and regeneration[J]. Histochem Cell Biol,2004,121(6):493-499.
[47]Nampei A, Hashimoto J, Hayashida K, Tsuboi H, Shi K, Tsuji I, Miyashita H, Yamada T, Matsukawa N, Matsumoto M, et al.Matrix extracellular phosphoglycoprotein (MEPE) is highly expressed in osteocytes in human bone[J]. J Bone Miner Metab,2004,22(3):176-184.
[48]Qin C, Baba O, Butler WT.Post-translational modifications of sibling proteins and their roles in osteogenesis and dentinogenesis[J]. Crit Rev Oral Biol Med,2004,15(3):126-136.
[49]Boskey AL, Chiang P, Fermanis A, Brown J, Taleb H, David V, Rowe PS.MEPE's diverse effects on mineralization[J]. Calcif Tissue Int,2010,86(1):42-46.
[50]Bacic D, Wagner CA, Hernando N, Kaissling B, Biber J, Murer H.Novel aspects in regulated expression of the renal type IIa Na/Pi-cotransporter[J]. Kidney Int Suppl,200491):S5-S12.
[51]Rowe PS.The wrickkened pathways of FGF23, MEPE and PHEX[J]. Crit Rev Oral Biol Med,2004, 15(5):264-281.
[52]Karsenty G, Ducy P, Starbuck M, Priemel M, Shen J, Geoffroy V, Amling M.Cbfal as a regulator of osteoblast differentiation and function[J]. Bone,1999,25(1):107-108.
[53]Ducy P, Zhang R, Geoffroy V, Ridall AL, Karsenty G.Osf2/Cbfal:a transcriptional activator of osteoblast differentiation[J]. Cell,1997,89(5):747-754.
[54]Sugawara M, Kato N, Tsuchiya T, Motoyama T.RUNX2 expression in developing human bones and various bone tumors[J]. Pathol Int,2011,61(10):565-571.
[55]Lucero CM, Vega OA, Osorio MM, Tapia JC, Antonelli M, Stein GS, van Wijnen AJ, Galindo MA.The cancer-related transcription factor Runx2 modulates cell proliferation in human osteosarcoma cell lines[J]. J Cell Physiol,2013,228(4):714-723.
[56]Li H, Zhou RJ, Zhang GQ, Xu JP.Clinical significance of RUNX2 expression in patients with nonsmall cell lung cancer:a 5-year follow-up study[J]. Tumour Biol,2013,34(3):1807-1812.
[57]Ferrari N, McDonald L, Morris JS, Cameron ER, Blyth K.RUNX2 in mammary gland development and breast cancer[J]. J Cell Physiol,2013,228(6):1137-1142.
[58]Yun SJ, Yoon HY, Bae SC, Lee OJ, Choi YH, Moon SK, Kim IY, Kim WJ.Transcriptional repression of RUNX2 is associated with aggressive clinicopathological outcomes, whereas nuclear location of the protein is related to metastasis in prostate cancer[J]. Prostate Cancer Prostatic Dis,2012,15(4):369-373.
[59]Sancisi V, Borettini G, Maramotti S, Ragazzi M, Tamagnini I, Nicoli D, Piana S, Ciarrocchi A.Runx2 isoform I controls a panel of proinvasive genes driving aggressiveness of papillary thyroid carcinomas[J). J Clin Endocrinol Metab,2012,97(10):E2006-2015.
[60]Li W, Xu S, Lin S, Zhao W.Overexpression of runt-related transcription factor-2 is associated with advanced tumor progression and poor prognosis in epithelial ovarian cancer[J]. J Biomed Biotechnol,2012, 2012(456534.
[61]Vermeulen AH, Vermeer C, Bosman FT.Histochemical detection of osteocalcin in normal and pathological human bone[J]. J Histochem Cytochem,1989,37(10):1503-1508.
[62]Glowacki J, Rey C, Glimcher MJ, Cox KA, Lian J.A role for osteocalcin in osteoclast differentiation[J]. J Cell Biochem,1991,45(3):292-302.
[63]Yu Q, Xiao MZ, Wu BL, Zhu QL, Guo T, Li F.[Cbfal induces the expression of the mineral-related proteins in human dental papilla cells][J]. Zhonghua Kou Qiang Yi Xue Za Zhi,2003,38(4):271-274.
[64]Butler WT, Ritchie HH, Bronckers AL.Extracellular matrix proteins of dentine[J]. Ciba Found Symp,1997,205(107-115; discussion 115-107.
[65]Fen JQ, Zhang J, Dallas SL, Lu Y, Chen S, Tan X, Owen M, Harris SE, MacDougall M.Dentin matrix protein 1, a target molecule for Cbfal in bone, is a unique bone marker gene[J]. J Bone Miner Res,2002, 17(10):1822-1831.
[66]Feng JQ, Huang H, Lu Y, Ye L, Xie Y, Tsutsui TW, Kunieda T, Castranio T, Scott G, Bonewald LB, Mishina Y.The Dentin matrix protein 1 (Dmp1) is specifically expressed in mineralized, but not soft, tissues during development[J]. J Dent Res,2003,82(10):776-780.
[67]Toyosawa S, Shintani S, Fujiwara T, Ooshima T, Sato A, Ijuhin N, Komori T.Dentin matrix protein 1 is predominantly expressed in chicken and rat osteocytes but not in osteoblasts[J]. J Bone Miner Res,2001, 16(11):2017-2026.
[68]George A, Sabsay B, Simonian PA, Veis A.Characterization of a novel dentin matrix acidic phosphoprotein. Implications for induction of biomineralization[J]. J Biol Chem,1993, 268(17):12624-12630.
[69]Sun Y, Chen L, Ma S, Zhou J, Zhang H, Feng JQ, Qin C.Roles of DMP1 processing in osteogenesis, dentinogenesis and chondrogenesis[J]. Cells Tissues Organs,2011,194(2-4):199-204.
[70]Lu Y, Qin C, Xie Y, Bonewald LF, Feng JQ.Studies of the DMP157-kDa functional domain both in vivo and in vitro[J]. Cells Tissues Organs,2009,189(1-4):175-185.
[71]Lu Y, Yuan B, Qin C, Cao Z, Xie Y, Dallas SL, McKee MD, Drezner MK, Bonewald LF, Feng JQ.The biological function of DMP-I in osteocyte maturation is mediated by its 57-kDa C-terminal fragment[J]. J Bone Miner Res,2011,26(2):331-340.
[72][J].
[73]He J, Xu Y, Koya D, Kanasaki K.Role of the endothelial-to-mesenchymal transition in renal fibrosis of chronic kidney disease[J]. Clin Exp Nephrol,2013.
[74]Kanasaki K, Taduri G, Koya D.Diabetic nephropathy. the role of inflammation in fibroblast activation and kidney fibrosis[J]. Front Endocrinol (Lausanne),2013,4(7.
[75]Piera-Velazquez S, Jimenez SA.Molecular mechanisms of endothelial to mesenchymal cell transition (EndoMT) in experimentally induced fibrotic diseases[J]. Fibrogenesis Tissue Repair,2012,5 Suppl 1(S7.
[76]Medici D, Olsen BR.The role of endothelial-mesenchymal transition in heterotopic ossification[J]. J Bone Miner Res,2012,27(8):1619-1622.
[77]Lin F, Wang N, Zhang TC.The role of endothelial-mesenchymal transition in development and pathological process[J]. IUBMB Life,2012,64(9):717-723.
[1]KE W, WE E, JLH OR.Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23[J]. Nat Genet,2000,26(3):345-348.
[2]Shimada T, Kakitani M, Yamazaki Y, Hasegawa H, Takeuchi Y, Fujita T, Fukumoto S, Tomizuka K, Yamashita T.Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism[J]. J Clin Invest,2004,113(4):561-568.
[3]Feng JQ, Ward LM, Liu S, Lu Y, Xie Y, Yuan B, Yu X, Rauch F, Davis SI, Zhang S, et al.Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism[J]. Nat Genet,2006,38(11):1310-1315.
[4]Pettifor JM, Thandrayen K.Hypophosphatemic rickets:unraveling the role of FGF23[J]. Calcif Tissue Int,2012,91(5):297-306.
[5]Carpenter EAlaTO.Rickets:The Skeletal Disorders of Impaired Calcium or Phosphate Availability[J]. 2013.
[6]Tenenhouse HS, Beck L.Renal Na(+)-phosphate cotransporter gene expression in X-linked Hyp and Gy mice[J]. Kidney Int,1996,49(4):1027-1032.
[7]Hruska KA, Rifas L, Cheng SL, Gupta A, Halstead L, Avioli L.X-1 inked hypophosphatemic rickets and the murine Hyp homologue[J]. Am J Physiol,1995,268(3 Pt 2):F357-362.
[8]Rector FC, Jr.Sodium, bicarbonate, and chloride absorption by the proximal tubule[J]. Am J Physiol,1983,244(5):F461-471.
[9]Forster IC, Hernando N, Biber J, Murer H.Proximal tubular handling of phosphate:A molecular perspective[J]. Kidney Int,2006,70(9):1548-1559.
[10]Tenenhouse HS.Phosphate transport:molecular basis, regulation and pathophysiology[J]. J Steroid Biochem Mol Biol,2007,103(3-5):572-577.
[11]Miyamoto K, Ito M, Tatsumi S, Kuwahata M, Segawa H.New aspect of renal phosphate reabsorption: the type IIc sodium-dependent phosphate transporter[J]. Am J Nephrol,2007,27(5):503-515.
[12]Biber J, Hernando N, Traebert M, Volkl H, Murer H.Parathyroid hormone-mediated regulation of renal phosphate reabsorption[J]. Nephrol Dial Transplant,2000,15 Suppl 6(29-30.
[13]Quarles LD.Endocrine functions of bone in mineral metabolism regulation[J]. J Clin Invest,2008, 118(12):3820-3828.
[14]Quarles LD.FGF23, PHEX, and MEPE regulation of phosphate homeostasis and skeletal mineralization[J]. Am J Physiol Endocrinol Metab,2003,285(1):E1-9.
[15]Liu S, Tang W, Zhou J, Stubbs JR, Luo Q, Pi M, Quarles LD.Fibroblast growth factor 23 is a counter-regulatory phosphaturic hormone for vitamin D[J]. J Am Soc Nephrol,2006,17(5):1305-1315.
[16]Liu S, Gupta A, Quarles LD.Emerging role of fibroblast growth factor 23 in a bone-kidney axis regulating systemic phosphate homeostasis and extracellular matrix mineralization[J]. Curr Opin Nephrol Hypertens,2007,16(4):329-335.
[17]Tiosano D, Hochberg Z.Hypophosphatemia:the common denominator of all rickets[J]. J Bone Miner Metab,2009,27(4):392-401.
[18]Prader A, Illig R, Uehlinger E, Stalder G.[Rickets following bone tumor][J]. Helv Paediatr Acta,1959, 14(554-565.
[19]Meyer RA, Jr., Meyer MH, Gray RW.Parabiosis suggests a humoral factor is involved in X-linked hypophosphatemia in mice[J]. J Bone Miner Res,1989,4(4):493-500.
[20]Nesbitt T, Coffman TM, Griffiths R, Drezner MK.Crosstransplantation of kidneys in normal and Hyp mice. Evidence that the Hyp mouse phenotype is unrelated to an intrinsic renal defect[J]. J Clin Invest,1992, 89(5):1453-1459.
[21]Miyauchi A, Fukase M, Tsutsumi M, Fujita T.HEMANGIOPERICYTOMA-INDUCED OSTEOMALACIA-TUMOR-TRANSPLANTATION IN NUDE-MICE CAUSES HYPOPHOSPHATEMIA AND TUMOR EXTRACTS INHIBIT RENAL 25-HYDROXYVITAMIN-D 1-HYDROXYLASE ACTIVITY[J]. Journal of Clinical Endocrinology & Metabolism,1988,67(1):46-53.
[22]Econs MJ, Drezner MK.Tumor-induced osteomalacia--unveiling a new hormone[J]. N Engl J Med,1994,330(23):1679-1681.
[23]Bai XY, Miao D, Goltzman D, Karaplis AC.The autosomal dominant hypophosphatemic rickets R176Q mutation in fibroblast growth factor 23 resists proteolytic cleavage and enhances in vivo biological potency[J]. J Biol Chem,2003,278(11):9843-9849.
[24]Ubaidus S, Li M, Sultana S, de Freitas PH, Oda K, Maeda T, Takagi R, Amizuka N.FGF23 is mainly synthesized by osteocytes in the regularly distributed osteocytic lacunar canalicular system established after physiological bone remodeling[J]. J Electron Microsc (Tokyo),2009,58(6):381-392.
[25]Jonsson KB, Zahradnik R, Larsson T, White KE, Sugimoto T, Imanishi Y, Yamamoto T, Hampson G, Koshiyama H, Ljunggren O, et al.Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia[J]. N Engl J Med.2003,348(17):1656-1663.
[26]Riminucci M, Collins MT, Fedarko NS, Cherman N, Corsi A, White KE, Waguespack S, Gupta A, Hannon T, Econs MJ, et al.FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting[J]. J Clin Invest,2003,112(5):683-692.
[27]Fukumoto S, Shimizu Y.Fibroblast growth factor 23 as a phosphotropic hormone and beyond[J]. J Bone Miner Metab,2011,29(5):507-514.
[28]Alon US.Clinical practice. Fibroblast growth factor (FGF)23:a new hormone[J]. Eur J Pediatr,2011, 170(5):545-554.
[29]Gattineni J, Baum M.Genetic disorders of phosphate regulation[J]. Pediatr Nephrol,2012, 27(9):1477-1487.
[30]Carpenter TO.The expanding family of hypophosphatemic syndromes[J]. J Bone Miner Metab,2012, 30(1):1-9.
[31]Baroncelli GI, Toschi B, Bertelloni S.Hypophosphatemic rickets[J]. Curr Opin Endocrinol Diabetes Obes,2012,19(6):460-467.
[32]Penido MG, Alon US.Phosphate homeostasis and its role in bone health[J]. Pediatr Nephrol,2012, 27(11):2039-2048.
[33]Martin A, David V, Li H, Dai B, Feng JQ, Quarles LD.Overexpression of the DMP1 C-terminal fragment stimulates FGF23 and exacerbates the hypophosphatemic rickets phenotype in Hyp mice[J]. Mol Endocrinol,2012,26(11):1883-1895.
[34]Onishi T, Umemura S, Shintani S, Ooshima T.Phex mutation causes overexpression of FGF23 in teeth[J]. Arch Oral Biol,2008,53(2):99-104.
[35]Lorenz-Depiereux B, Bastepe M, Benet-Pages A, Amyere M, Wagenstaller J, Muller-Barth U, Badenhoop K, Kaiser SM, Rittmaster RS, Shlossberg AH, et al.DMPl mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis[J]. Nat Genet,2006,38(11):1248-1250.
[36]Kuro-o M.Klotho as a regulator of fibroblast growth factor signaling and phosphate/calcium metabolism[J]. Curr Opin Nephrol Hypertens,2006,15(4):437-441.
[37]Kurosu H, Ogawa Y, Miyoshi M, Yamamoto M, Nandi A, Rosenblatt KP, Baum MG, Schiavi S, Hu MC, Moe OW, Kuro-o M.Regulation of fibroblast growth factor-23 signaling by klotho[J]. J Biol Chem,2006,281 (10):6120-6123.
[38]Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, Fujita T, Fukumoto S, Yamashita T.Klotho converts canonical FGF receptor into a specific receptor for FGF23[J]. Nature,2006, 444(7120):770-774.
[39]Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, et al.Mutation of the mouse klotho gene leads to a syndrome resembling ageing[J]. Nature,1997,390(6655):45-51.
[40]Ben-Dov IZ, Galitzer H, Lavi-Moshayoff V, Goetz R, Kuro-o M, Mohammadi M, Sirkis R, Naveh-Many T, Silver J.The parathyroid is a target organ for FGF23 in rats[J]. J Clin Invest,2007, 117(12):4003-4008.
[41]Segawa H, Kawakami E, Kaneko I, Kuwahata M, Ito M, Kusano K, Saito H, Fukushima N, Miyamoto K.Effect of hydrolysis-resistant FGF23-R179Q on dietary phosphate regulation of the renal type-11 Na/Pi transporter[J]. Pflugers Arch,2003,446(5):585-592.
[42]Segawa H, Yamanaka S, Ohno Y, Onitsuka A, Shiozawa K, Aranami F, Furutani J, Tomoe Y, Ito M, Kuwahata M, et al.Correlation between hyperphosphatemia and type Ⅱ Na-Pi cotransporter activity in klotho mice[J]. Am J Physiol Renal Physiol,2007,292(2):F769-779.
[43]Shimada T, Urakawa I, Yamazaki Y, Hasegawa H, Hino R, Yoneya T, Takeuchi Y, Fujita T, Fukumoto S, Yamashita T.FGF-23 transgenic mice demonstrate hypophosphatemic rickets with reduced expression of sodium phosphate cotransporter type Ⅱa[J]. Biochem Biophys Res Commun,2004,314(2):409-414.
[44]Farrow EG, Davis SI, Summers LJ, White KE.Initial FGF23-mediated signaling occurs in the distal convoluted tubule[J]. J Am Soc Nephrol,2009,20(5):955-960.
[45]Hu MC, Shi M, Zhang J, Pastor J, Nakatani T, Lanske B, Razzaque MS, Rosenblatt KP, Baum MG, Kuro-o M, Moe OW.Klotho:a novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule[J]. FASEB J,2010,24(9):3438-3450.
[46]Gattineni J, Bates C, Twombley K, Dwarakanath V, Robinson ML, Goetz R, Mohammadi M, Baum M.FGF23 decreases renal NaPi-2a and NaPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1 [J]. Am J Physiol Renal Physiol,2009,297(2):F282-291.
[47]Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R, Takeuchi Y, Fujita T, Nakahara K, Fukumoto S, Yamashita T.FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis[J]. J Bone Miner Res,2004,19(3):429-435.
[48]Shalhoub V, Ward SC, Sun B, Stevens J, Renshaw L, Hawkins N, Richards WG.Fibroblast growth factor 23 (FGF23) and alpha-klotho stimulate osteoblastic MC3T3.E1 cell proliferation and inhibit mineralization[J]. Calcif Tissue Int,2011,89(2):140-150.
[49]Wang H, Yoshiko Y, Yamamoto R, Minamizaki T, Kozai K, Tanne K, Aubin JE, Maeda N.Overexpression of fibroblast growth factor 23 suppresses osteoblast differentiation and matrix mineralization in vitro[J]. J Bone Miner Res,2008,23(6):939-948.
[50]Lorenz-Depiereux B, Schnabel D, Tiosano D, Hausler G, Strom TM.Loss-of-function ENPP1 mutations cause both generalized arterial calcification of infancy and autosomal-recessive hypophosphatemic rickets[J]. Am J Hum Genet,2010,86(2):267-272.
[51]Levy-Litan V, Hershkovitz E, Avizov L, Leventhal N, Bercovich D, Chalifa-Caspi V, Manor E, Buriakovsky S, Hadad Y, Goding J, Parvari R.Autosomal-recessive hypophosphatemic rickets is associated with an inactivation mutation in the ENPP1 gene[J]. Am J Hum Genet,2010,86(2):273-278.
[52]Ryan WG, Nibbe AF, Schwartz TB, Ray RD.Fibrous dysplasia of bone with vitamin D resistant rickets: a case study [J]. Metabolism,1968,17(11):988-998.
[53]Dent CE, Gertner JM.Hypophosphataemic osteomalacia in fibrous dysplasia[J]. Q J Med,1976, 45(179):411-420.
[54]Dachille RD, Goldberg JS, Wexler ID, Shons AR.Fibrous dysplasia-induced hypocalcemia/rickets[J]. J Oral Maxillofac Surg,1990,48(12):1319-1322.
[55]Zutt M, Strutz F, Happle R, Habenicht EM, Emmert S, Haenssle HA, Kretschmer L, Neumann C.Schimmelpenning-Feuerstein-Mims syndrome with hypophosphatemic rickets[J]. Dermatology,2003, 207(1):72-76.
[56]Hoffman WH, Jueppner HW, Deyoung BR, O'Dorisio M S, Given KS.Elevated fibroblast growth factor-23 in hypophosphatemic linear nevus sebaceous syndrome[J]. Am J Med Genet A,2005, 134(3):233-236.
[57]Srinivas UM, Tourani KL.Epidermal nevus syndrome with hypophosphatemic renal rickets with hypercalciuria:a bonemarrow diagnosis[J]. Int J Hematol,2008,88(2):125-126.
[58]Bianchine JW, Stambler AA, Harrison HE.Familial hypophosphatemic rickets showing autosomal dominant inheritance[J]. Birth Defects Orig Artie Ser,1971,7(6):287-295.
[59]Pettifor JM.What's new in hypophosphataemic rickets?[J]. Eur J Pediatr,2008,167(5):493-499.
[60]Xia W, Meng X, Jiang Y, Li M, Xing X, Pang L, Wang O, Pei Y, Yu LY, Sun Y, et al.Three novel mutations of the PHEX gene in three Chinese families with X-linked dominant hypophosphatemic rickets[J]. Calcif Tissue Int,2007,81(6):415-420.
[61]A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. The HYP Consortium[J]. Nat Genet,1995,11(2):130-136.
[62]Beck L, Soumounou Y, Martel J, Krishnamurthy G, Gauthier C, Goodyer CG, Tenenhouse HS.Pex/PEX tissue distribution and evidence for a deletion in the 3'region of the Pex gene in X-linked hypophosphatemic mice[J]. J Clin Invest,1997,99(6):1200-1209.
[63]Xia WB, Jiang Y, Li M, Xing XP, Wang O, Hu YY, Zhang HB, Liu HC, Meng XW, Zhou XY.Levels and dynamic changes of serum fibroblast growth factor 23 in hypophosphatemic rickets/osteomalacia[J]. Chin Med J (Engl),2010,123(9):1158-1162.
[64]Liu S, Zhou J, Tang W, Jiang X, Rowe DW, Quarles LD.Pathogenic role of Fgf23 in Hyp mice[J]. Am J Physiol Endocrinol Metab,2006,291(1):E38-49.
[65]Liu S, Guo R, Simpson LG, Xiao ZS, Burnham CE, Quarles LD.Regulation of fibroblastic growth factor 23 expression but not degradation by PHEX[J]. J Biol Chem,2003,278(39):37419-37426.
[66]David V, Martin A, Hedge AM, Drezner MK, Rowe PS.ASARM peptides:PHEX-dependent and-independent regulation of serum phosphate[J]. Am J Physiol Renal Physiol,2011,300(3):F783-791.
[67]Econs MJ, McEnery PT.Autosomal dominant hypophosphatemic rickets/osteomalacia:clinical characterization of a novel renal phosphate-wasting disorder[J]. J Clin Endocrinol Metab,1997, 82(2):674-681.
[68]Imel EA, Peacock M, Gray AK, Padgett LR, Hui SL, Econs MJ.Iron modifies plasma FGF23 differently in autosomal dominant hypophosphatemic rickets and healthy humans[J]. J Clin Endocrinol Metab,2011,96(11):3541-3549.
[69]Kruse K, Woelfel D, Strom TM.Loss of renal phosphate wasting in a child with autosomal dominant hypophosphatemic rickets caused by a FGF23 mutation[J]. Horm Res,2001,55(6):305-308.
[70]White KE, Cam G, Lorenz-Depiereux B, Benet-Pages A, Strom TM, Econs MJ.Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23[J]. Kidney Int,2001,60(6):2079-2086.
[71]Sun Y, Wang O, Xia W, Jiang Y, Li M, Xing X, Hu Y, Liu H, Meng X, Zhou X.FGF23 analysis of a Chinese family with autosomal dominant hypophosphatemic rickets[J]. J Bone Miner Metab,2012, 30(1):78-84.
[72]Imel EA, Econs MJ.Fibroblast growth factor 23:roles in health and disease[J]. J Am Soc Nephrol,2005, 16(9):2565-2575.
[73]Perry W, Stamp TC.Hereditary hypophosphataemic rickets with autosomal recessive inheritance and severe osteosclerosis. A report of two cases[J]. J Bone Joint Surg Br,1978,60-B(3):430-434.
[74]Scriver CR, Reade T, Halal F, Costa T, Cole DE.Autosomal hypophosphataemic bone disease responds to 1,25-(OH)2D3[J]. Arch Dis Child,1981,56(3):203-207.
[75]Gattineni J, Baum M.Regulation of phosphate transport by fibroblast growth factor 23 (FGF23): implications for disorders of phosphate metabolism[J]. Pediatr Nephrol,2010,25(4):591-601.
[76]Farrow EG, White KE.Recent advances in renal phosphate handling[J]. Nat Rev Nephrol,2010, 6(4):207-217.
[77]Saito T, Shimizu Y, Hori M, Taguchi M, Igarashi T, Fukumoto S, Fujitab T.A patient with hypophosphatemic rickets and ossification of posterior longitudinal ligament caused by a novel homozygous mutation in ENPP1 gene[J]. Bone,2011,49(4):913-916.
[78]Carpenter TO, Imel EA, Holm IA, Jan de Beur SM, Insogna KL.A clinician's guide to X-linked hypophosphatemia[J]. J Bone Miner Res,2011,26(7):1381-1388.
[79]Quinlan C, Guegan K, Offiah A, Neill RO, Hiorns MP, Ellard S, Bockenhauer D, Hoff WV, Waters AM.Growth in PHEX-associated X-linked hypophosphatemic rickets:the importance of early treatment[J]. Pediatr Nephrol,2012,27(4):581-588.
[80]Makitie O.Early Treatment Improves Growth and Biochemical and Radiographic Outcome in X-Linked Hypophosphatemic Rickets[J]. Journal of Clinical Endocrinology & Metabolism,2003, 88(8):3591-3597.
[81]Zivicnjak M, Schnabel D, Staude H, Even G, Marx M, Beetz R, Holder M, Billing H, Fischer DC, Rabl W, et al.Three-year growth hormone treatment in short children with X-linked hypophosphatemic rickets: effects on linear growth and body disproportion[J]. J Clin Endocrinol Metab,2011,96(12):E2097-2105.
[82]Liu ES, Carpenter TO, Gundberg CM, Simpson CA, Insogna KL.Calcitonin administration in X-linked hypophosphatemia[J]. N EngI J Med,2011,364(17):1678-1680.
[83]Aono Y, Hasegawa H, Yamazaki Y, Shimada T, Fujita T, Yamashita T, Fukumoto S.Anti-FGF-23 neutralizing antibodies ameliorate muscle weakness and decreased spontaneous movement of Hyp mice[J]. J Bone Miner Res,2011,26(4):803-810.
[84]Shimada T, Fukumoto S.FGF23 as a novel therapeutic target[J]. Adv Exp Med Biol,2012, 728(158-170.
[85]Wyman AL, Paradinas FJ, Daly JR.Hypophosphataemic osteomalacia associated with a malignant tumour of the tibia:report of a case[J]. J Clin Pathol,1977,30(4):328-335.
[86]Rico H, Fernandez-Miranda E, Sanz J, Gomez-Castresana F, Escriba A, Hernandez ER, Krsnik I.Oncogenous osteomalacia:a new case secondary to a malignant tumor[J]. Bone,1986,7(5):325-329.
[87]Harvey JN, Gray C, Belchetz PE.Oncogenous osteomalacia and malignancy[J]. Clin Endocrinol (Oxf),1992,37(4):379-382.
[88]Ogose A, Hotta T, Emura I, Hatano H, Inoue Y, Umezu H, Endo N.Recurrent malignant variant of phosphaturic mesenchymal tumor with oncogenic osteomalacia[J]. Skeletal Radiol,2001,30(2):99-103.
[89]Uramoto N, Furukawa M, Yoshizaki T.Malignant phosphaturic mesenchymal tumor, mixed connective tissue variant of the tongue[J]. Auris Nasus Larynx,2009,36(1):104-105.
[90]Cai Q, Hodgson SF, Kao PC, Lennon VA, Klee GG, Zinsmiester AR, Kumar R.Brief report:inhibition of renal phosphate transport by a tumor product in a patient with oncogenic osteomalacia[J]. N Engl J Med,1994,330(23):1645-1649.
[91]Yamazaki Y, Okazaki R, Shibata M, Hasegawa Y, Satoh K, Tajima T, Takeuchi Y, Fujita T, Nakahara K, Yamashita T, Fukumoto S.Increased circulatory level of biologically active full-length FGF-23 in patients with hypophosphatemic rickets/osteomalacia[J]. J Clin Endocrinol Metab,2002,87(11):4957-4960.
[92]Takeuchi Y, Suzuki H, Ogura S, Imai R, Yamazaki Y, Yamashita T, Miyamoto Y, Okazaki H, Nakamura K, Nakahara K, et al.Venous sampling for fibroblast growth factor-23 confirms preoperative diagnosis of tumor-induced osteomalacia[J]. J Clin Endocrinol Metab,2004,89(8):3979-3982.
[93]Jiang Y, Xia WB, Xing XP, Silva BC, Li M, Wang O, Zhang HB, Li F, Jing HL, Zhong DR, et al.Tumor-induced osteomalacia:an important cause of adult-onset hypophosphatemic osteomalacia in China:Report of 39 cases and review of the literature[J]. J Bone Miner Res,2012,27(9):1967-1975.
[94]White KE, Jonsson KB, Cam G, Hampson G, Spector TD, Mannstadt M, Lorenz-Depiereux B, Miyauchi A, Yang IM, Ljunggren O, et al.The autosomal dominant hypophosphatemic rickets (ADHR) gene is a secreted polypeptide overexpressed by tumors that cause phosphate wasting[J]. J Clin Endocrinol Metab,2001,86(2):497-500.
[95]Farrow EG, White KE.Tumor-induced osteomalacia[J]. Expert Rev Endocrinol Metab,2009, 4(5):435-442.
[96]Hesse E, Moessinger E, Rosenthal H, Laenger F, Brabant G, Petrich T, Gratz KF, Bastian L.Oncogenic osteomalacia:exact tumor localization by co-registration of positron emission and computed tomography [J]. J Bone Miner Res,2007,22(1):158-162.
[97]Clunie GP, Fox PE, Stamp TC.Four cases of acquired hypophosphataemic ('oncogenic') osteomalacia. Problems of diagnosis, treatment and long-term management[J]. Rheumatology (Oxford),2000, 39(12):1415-1421.
[98]Khosravi A, Cutler CM, Kelly MH, Chang R, Royal RE, Sherry RM, Wodajo FM, Fedarko NS, Collins MT.Determination of the elimination half-life of fibroblast growth factor-23 [J]. Journal of Clinical Endocrinology & Metabolism,2007,92(6):2374-2377.
[99]Spiegel AM, Shenker A, Weinstein LS.Receptor-effector coupling by G proteins:implications for normal and abnormal signal transduction[J]. Endocr Rev,1992,13(3):536-565.
[100]Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Spiegel AM.Activating mutations of the stimulatory G protein in the McCune-Albright syndrome[J]. N Engl J Med,1991,325(24):1688-1695.
[101]Schwindinger WF, Francomano CA, Levine MA.Identification of a mutation in the gene encoding the alpha subunit of the stimulatory G protein of adenylyl cyclase in McCune-Albright syndrome[J]. Proc Natl Acad Sci U S A,1992,89(11):5152-5156.
[102]Lee PA, Van Dop C, Migeon CJ.McCune-Albright syndrome. Long-term follow-up[J]. JAMA,1986, 256(21):2980-2984.
[103]Collins MT, Chebli C, Jones J, Kushner H, Consugar M, Rinaldo P, Wientroub S, Bianco P, Robey PGRenal phosphate wasting in fibrous dysplasia of bone is part of a generalized renal tubular dysfunction similar to that seen in tumor-induced osteomalacia[J]. J Bone Miner Res,2001,16(5):806-813.
[104]Yamamoto T, Miyamoto KI, Ozono K, Taketani Y, Katai K, Miyauchi A, Shima M, Yoshikawa H, Yoh K, Takeda E, Okada S.Hypophosphatemic rickets accompanying McCune-Albright syndrome: evidence that a humoral factor causes hypophosphatemia[J]. J Bone Miner Metab,2001,19(5):287-295.
[105]Chadha M, Singh AP, Singh AP.Hypophosphataemic osteomalacia in neurofibromatosis[J]. Acta Orthop Belg,2009,75(6):847-850.
[106]Lambert J, Lips P.Adult hypophosphataemic osteomalacia with Fanconi syndrome presenting in a patient with neurofibromatosis[J]. Neth J Med,1989,35(5-6):309-316.
[107]Konishi K, Nakamura M, Yamakawa H, Suzuki H, Saruta T, Hanaoka H, Davatchi F.Hypophosphatemic osteomalacia in von Recklinghausen neurofibromatosis[J]. Am J Med Sci,1991, 301(5):322-328.
[108]Retnam VJ, Rangnekar DM, Bhandarkar SD.Neurofibromatosis with hypophosphatemic osteomalacia (Von Recklinghausen-Hernberg-Edgren-Swann syndrome) (a case report)[J]. J Assoc Physicians India,1980,28(9):319-322.
[109]Abdel-Wanis M, Kawahara N.Hypophosphatemic osteomalacia in neurofibromatosis 1:hypotheses for pathogenesis and higher incidence of spinal deformity[J]. Med Hypotheses,2002,59(2):183-185.
[110]Solomon LM, Esterly NB.Epidermal and other congenital organoid nevi[J]. Curr Probl Pediatr,1975, 6(1):1-56.
[111]Grebe TA, Rimsza ME, Richter SF, Hansen RC, Hoy me HE.Further delineation of the epidermal nevus syndrome:two cases with new findings and literature review[J]. Am J Med Genet,1993,47(1):24-30.
[112]Aschinberg LC, Solomon LM, Zeis PM, Justice P, Rosenthal IM.Vitamin D-resistant rickets associated with epidermal nevus syndrome:demonstration of a phosphaturic substance in the dermal lesions[J]. J Pediatr,1977,91(1):56-60.
[113]Carey DE, Drezner MK, Hamdan JA, Mange M, Ahmad MS, Mubarak S, Nyhan WL.Hypophosphatemic rickets/osteomalacia in linear sebaceous nevus syndrome:a variant of tumor-induced osteomalacia[J]. J Pediatr,1986,109(6):994-1000.
[114]Goldblum JR, Headington JT.Hypophosphatemic vitamin D-resistant rickets and multiple spindle and epithelioid nevi associated with linear nevus sebaceus syndrome[J]. J Am Acad Dermatol,1993, 29(1):109-111.
[115]Skovby F, Svejgaard E, Moller J.Hypophosphatemic rickets in linear sebaceous nevus sequence[J]. J Pediatr,1987, 111(6Pt 1):855-857.
[116]Eyskens B, Proesmans W, Van Damme B, Lateur L, Bouillon R, Hoogmartens M.Tumour-induced rickets:a case report and review of the literature[J]. Eur J Pediatr,1995,154(6):462-468.
[117]Oranje AP, Przyrembel H, Meradji M, Loonen MC, de Klerk JB.Solomon's epidermal nevus syndrome (type:linear nevus sebaceus) and hypophosphatemic vitamin D-resistant rickets[J]. Arch Dermatol,1994,130(9):1167-1171.
[118]Narazaki R, Ihara K, Namba N, Matsuzaki H, Ozono K, Hara T.Linear nevus sebaceous syndrome with hypophosphatemic rickets with elevated FGF-23[J]. Pediatr Nephrol,2012,27(5):861-863.
[119]Sethi SK, Hari P, Bagga A.Elevated FGF-23 and parathormone in linear nevus sebaceous syndrome with resistant rickets[J]. Pediatr Nephrol,2010,25(8):1577-1578.
[120]White KE, Cabral JM, Davis SI, Fishburn T, Evans WE, Ichikawa S, Fields J, Yu X, Shaw NJ, McLellan NJ, et al.Mutations that cause osteoglophonic dysplasia define novel roles for FGFR1 in bone elongation[J]. Am J Hum Genet,2005,76(2):361-367.
[121]Farrow EG, Davis SI, Mooney SD, Beighton P, Mascarenhas L, Gutierrez YR, Pitukcheewanont P, White KE.Extended mutational analyses of FGFR1 in osteoglophonic dysplasia[J]. Am J Med Genet A.2006,140(5):537-539.
[122]Roberts TS, Stephen L, Beighton P.Osteoglophonic dysplasia:dental and orthodontic implications[J]. Orthod Craniofac Res,2006,9(3):153-156.
[123]Beighton P, Cremin BJ, Kozlowski K.Osteoglophonic dwarfism[J]. Pediatr Radiol,1980,10(1):46-50.
[124]Beighton P.Osteoglophonic dysplasia[J]. J Med Genet,1989,26(9):572-576.
[125]Brownstein CA, Adler F, Nelson-Williams C, Iijima J, Li P, Imura A, Nabeshima Y, Reyes-Mugica M, Carpenter TO, Lifton RP.A translocation causing increased alpha-klotho level results in hypophosphatemic rickets and hyperparathyroidism[J]. Proc Natl Acad Sci U S A,2008,105(9):3455-3460.
[2]Carpenter TO, Ellis BK, Insogna KL, Philbrick WM, Sterpka J, Shimkets R.Fibroblast growth factor 7: an inhibitor of phosphate transport derived from oncogenic osteomalacia-causing tumors[J]. J Clin Endocrinol Metab,2005,90(2):1012-1020.
[3]Shimada T, Mizutani S, Muto T, Yoneya T, Hino R, Takeda S, Takeuchi Y, Fujita T, Fukumoto S, Yamashita T.Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia[J]. Proc Natl Acad Sci U S A,2001,98(11):6500-6505.
[4]Schiavi SC, Kumar R.The phosphatonin pathway:new insights in phosphate homeostasis[J]. Kidney Int,2004,65(1):1-14.
[5]Drake TG, Albright F, Castleman B.PARATHYROID HYPERPLASIA IN RABBITS PRODUCED BY PARENTERAL PHOSPHATE ADMINISTRATION[J]. J Clin Invest,1937,16(2):203-206.
[6]Prader A, Illig R, Uehlinger E, Stalder G.[Rickets following bone tumor][J]. Helv Paediatr Acta,1959, 14(554-565.
[7]Nuovo MA, Dorfman HD, Sun CC, Chalew SA.Tumor-induced osteomalacia and rickets[J]. Am J Surg Pathol,1989,13(7):588-599.
[8]Econs MJ, Drezner MK.Tumor-induced osteomalacia--unveiling a new hormone[J]. N Engl J Med,1994, 330(23):1679-1681.
[9]Tenenhouse HS, Sabbagh Y.Novel phosphate-regulating genes in the pathogenesis of renal phosphate wasting disorders[J]. Pflugers Arch,2002,444(3):317-326.
[10]Saito H, Kusano K, Kinosaki M, Ito H, Hirata M, Segawa H, Miyamoto K, Fukushima N.Human fibroblast growth factor-23 mutants suppress Na+-dependent phosphate co-transport activity and lalpha,25-dihydroxyvitamin D3 production[J]. J Biol Chem,2003,278(4):2206-2211.
[11]Weidner N.Review and update:oncogenic osteomalacia-rickets[J]. Ultrastruct Pathol,1991, 15(4-5):317-333.
[12]Silve C, Beck L.Is FGF23 the long sought after phosphaturic factor phosphatonin?[J]. Nephrol Dial Transplant,2002,17(6):958-961.
[13]Furco A, Roger M, Mouchet B, Richard O, Martinache X, Fur A.Osteomalacia cured by surgery[J]. Eur J Intern Med,2002,13(1):67-69.
[14]Larsson T, Zahradnik R, Lavigne J, Ljunggren O, Juppner H, Jonsson KB.Immunohistochemical detection of FGF-23 protein in tumors that cause oncogenic osteomalacia[J]. Eur J Endocrinol,2003, 148(2):269-276.
[15]Dupond JL, Magy N, Mahammedi M, Prie D, Gil H, Meaux-Ruault N, Kantelip B.[Oncogenic osteomalacia:the role of the phosphatonins. Diagnostic usefulness of the Fibroblast Growth Factor 23 measurement in one patient][J]. Rev Med Interne,2005,26(3):238-241.
[16]Liu S, Zhou J, Tang W, Jiang X, Rowe DW, Quarles LD.Pathogenic role of Fgf23 in Hyp mice[J]. Am J Physiol Endocrinol Metab,2006,291(1):E38-49.
[17]Haeusler G, Freilinger M, Dominkus M, Egerbacher M, Amann G, Kolb A, Schlegel W, Raimann A, Staudenherz A.Tumor-induced hypophosphatemic rickets in an adolescent boy-clinical presentation, diagnosis, and histological findings in growth plate and muscle tissue[J]. J Clin Endocrinol Metab,2010, 95(10):4511-4517.
[18]Ludwig GD, Kyle CG, de Blanco M."Tertiary" hyperparathyroidism induced by osteomalacia resulting from phosphorus depletion[J]. Am J Med,1967,43(1):136-140.
[19]Huang QL, Feig DS, Blackstein ME.Development of tertiary hyperparathyroidism after phosphate supplementation in oncogenic osteomalacia[J]. J Endocrinol Invest,2000,23(4):263-267.
[20]Nguyen BD, Wang EA.Indium-Ⅲ pentetreotide scintigraphy of mesenchymal tumor with oncogenic osteomalacia[J]. Clin Nucl Med,1999,24(2):130-131.
[21]Rhee Y, Lee JD, Shin KH, Lee HC, Huh KB, Lim SK.Oncogenic osteomalacia associated with mesenchymal tumour detected by indium-Ⅲ octreotide scintigraphy[J]. Clin Endocrinol (Oxf),2001, 54(4):551-554.
[22]Garcia CA, Spencer RP.Bone and In-Ⅲ octreotide imaging in oncogenic osteomalacia:a case report[J]. Clin Nucl Med,2002,27(8):582-583.
[23]Paglia F, Dionisi S, Minisola S.Octreotide for tumor-induced osteomalacia[J]. N Engl J Med,2002, 346(22):1748-1749; author reply 1748-1749.
[24]Seufert J, Ebert K, Muller J, Eulert J, Hendrich C, Werner E, Schuuze N, Schulz G, Kenn W, Richtmann H, et al.Octreotide therapy for tumor-induced osteomalacia [J]. N Engl J Med,2001, 345(26):1883-1888.
[25]Roarke MC, Nguyen BD.PET/CT localization of phosphaturic mesenchymal neoplasm causing tumor-induced osteomalacia[J]. Clin Nucl Med,2007,32(4):300-301.
[26]Khadgawat R, Singh Y, Kansara S, Tandon N, Bal C, Seith A, Kotwal P.PET/CT localisation of a scapular haemangiopericytoma with tumour-induced osteomalacia[J]. Singapore Med J,2009, 50(2):e55-57.
[27]Leaf DE, Pereira RC, Bazari H, Juppner H.Oncogenic osteomalacia due to FGF23-expressing colon adenocarcinoma[J]. J Clin Endocrinol Metab,2013,98(3):887-891.
[28]Stone E, Bernier V, Rabinovich S, From GL.Oncogenic osteomalacia associated with a mesenchymal chondrosarcoma[J]. Clin Invest Med,1984,7(3):179-185.
[29]Lustman F, Parmentier R, Dustin P.Oncogenic osteomalacia and renal adenomatoid dysplasia[J]. Ann Intern Med,1985,102(6):869-870.
[30]McMurtry CT, Godschalk M, Malluche HH, Geng Z, Adler RA.Oncogenic osteomalacia associated with metastatic prostate carcinoma:case report and review of the literature[J]. J Am Geriatr Soc,1993, 41(9):983-985.
[31]Weidner N, Santa Cruz D.Phosphaturic mesenchymal tumors. A polymorphous group causing osteomalacia or rickets[J]. Cancer,1987,59(8):1442-1454.
[32]!!! INVALID CITATION!!!
[33]Xia WB, Jiang Y, Li M, Xing XP, Wang O, Hu YY, Zhang HB, Liu HC, Meng XW, Zhou XY.Levels and dynamic changes of serum fibroblast growth factor 23 in hypophosphatemic rickets/osteomalacia[J]. Chin Med J (Engl),2010,123(9):1158-1162.
[34]Rowe PS, de Zoysa PA, Dong R, Wang HR, White KE, Econs MJ, Oudet CL.MEPE, a new gene expressed in bone marrow and tumors causing osteomalacia[J]. Genomics,2000,67(1):54-68.
[35]Toyosawa S, Tomita Y, Kishino M, Hashimoto J, Ueda T, Tsujimura T, Aozasa K, Ijuhin N, Komori T.Expression of dentin matrix protein 1 in tumors causing oncogenic osteomalacia[J]. Mod Pathol,2004, 17(5):573-578.
[36]Komori T, Yagi H, Nomura S, Yamaguchi A, Sasaki K, Deguchi K, Shimizu Y, Bronson RT, Gao YH, Inada M, et al.Targeted disruption of Cbfal results in a complete lack of bone formation owing to maturational arrest of osteoblasts[J]. Cell,1997,89(5):755-764.
[37]Bonewald LF.The amazing osteocyte[J]. J Bone Miner Res,2011,26(2):229-238.
[38]Gattineni J, Bates C, Twombley K, Dwarakanath V, Robinson ML, Goetz R, Mohammadi M, Baum M.FGF23 decreases renal NaPi-2a and NaPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1 [J]. Am J Physiol Renal Physiol,2009,297(2):F282-291.
[39]Kuro-o M.Klotho as a regulator of fibroblast growth factor signaling and phosphate/calcium metabolism[J]. Curr Opin Nephrol Hypertens,2006,15(4):437-441.
[40]Jiang Y, Xia WB, Xing XP, Silva BC, Li M, Wang O, Zhang HB, Li F, Jing HL, Zhong DR, et al.Tumor-induced osteomalacia:an important cause of adult-onset hypophosphatemic osteomalacia in China:Report of 39 cases and review of the literature[J]. J Bone Miner Res,2012,27(9):1967-1975.
[41]Strewler GJ.FGF23, hypophosphatemia, and rickets:has phosphatonin been found?[J]. Proc Natl Acad Sci U S A.2001,98(11):5945-5946.
[42]Fukumoto S, Yamashita T.Fibroblast growth factor-23 is the phosphaturic factor in tumor-induced osteomalacia and may be phosphatonin[J]. Curr Opin Nephrol Hypertens,2002,11(4):385-389.
[43]Hu FK, Yuan F, Jiang CY, Lv DW, Mao BB, Zhang Q, Yuan ZQ, Wang Y.Tumor-induced osteomalacia with elevated fibroblast growth factor 23:a case of phosphaturic mesenchymal tumor mixed with connective tissue variants and review of the literature[J]. Chin J Cancer,2011,30(11):794-804.
[44]Argiro L, Desbarats M, Glorieux FH, Ecarot B.Mepe, the gene encoding a tumor-secreted protein in oncogenic hypophosphatemic osteomalacia, is expressed in bone[J]. Genomics,2001,74(3):342-351.
[45]Addison WN, Nakano Y, Loisel T, Crine P, McKee MD.MEPE-ASARM peptides control extracellular matrix mineralization by binding to hydroxyapatite:an inhibition regulated by PHEX cleavage of ASARM[J]. J Bone Miner Res,2008,23(10):1638-1649.
[46]Lu C, Huang S, Miclau T, Helms JA, Colnot C.Mepe is expressed during skeletal development and regeneration[J]. Histochem Cell Biol,2004,121(6):493-499.
[47]Nampei A, Hashimoto J, Hayashida K, Tsuboi H, Shi K, Tsuji I, Miyashita H, Yamada T, Matsukawa N, Matsumoto M, et al.Matrix extracellular phosphoglycoprotein (MEPE) is highly expressed in osteocytes in human bone[J]. J Bone Miner Metab,2004,22(3):176-184.
[48]Qin C, Baba O, Butler WT.Post-translational modifications of sibling proteins and their roles in osteogenesis and dentinogenesis[J]. Crit Rev Oral Biol Med,2004,15(3):126-136.
[49]Boskey AL, Chiang P, Fermanis A, Brown J, Taleb H, David V, Rowe PS.MEPE's diverse effects on mineralization[J]. Calcif Tissue Int,2010,86(1):42-46.
[50]Bacic D, Wagner CA, Hernando N, Kaissling B, Biber J, Murer H.Novel aspects in regulated expression of the renal type IIa Na/Pi-cotransporter[J]. Kidney Int Suppl,200491):S5-S12.
[51]Rowe PS.The wrickkened pathways of FGF23, MEPE and PHEX[J]. Crit Rev Oral Biol Med,2004, 15(5):264-281.
[52]Karsenty G, Ducy P, Starbuck M, Priemel M, Shen J, Geoffroy V, Amling M.Cbfal as a regulator of osteoblast differentiation and function[J]. Bone,1999,25(1):107-108.
[53]Ducy P, Zhang R, Geoffroy V, Ridall AL, Karsenty G.Osf2/Cbfal:a transcriptional activator of osteoblast differentiation[J]. Cell,1997,89(5):747-754.
[54]Sugawara M, Kato N, Tsuchiya T, Motoyama T.RUNX2 expression in developing human bones and various bone tumors[J]. Pathol Int,2011,61(10):565-571.
[55]Lucero CM, Vega OA, Osorio MM, Tapia JC, Antonelli M, Stein GS, van Wijnen AJ, Galindo MA.The cancer-related transcription factor Runx2 modulates cell proliferation in human osteosarcoma cell lines[J]. J Cell Physiol,2013,228(4):714-723.
[56]Li H, Zhou RJ, Zhang GQ, Xu JP.Clinical significance of RUNX2 expression in patients with nonsmall cell lung cancer:a 5-year follow-up study[J]. Tumour Biol,2013,34(3):1807-1812.
[57]Ferrari N, McDonald L, Morris JS, Cameron ER, Blyth K.RUNX2 in mammary gland development and breast cancer[J]. J Cell Physiol,2013,228(6):1137-1142.
[58]Yun SJ, Yoon HY, Bae SC, Lee OJ, Choi YH, Moon SK, Kim IY, Kim WJ.Transcriptional repression of RUNX2 is associated with aggressive clinicopathological outcomes, whereas nuclear location of the protein is related to metastasis in prostate cancer[J]. Prostate Cancer Prostatic Dis,2012,15(4):369-373.
[59]Sancisi V, Borettini G, Maramotti S, Ragazzi M, Tamagnini I, Nicoli D, Piana S, Ciarrocchi A.Runx2 isoform I controls a panel of proinvasive genes driving aggressiveness of papillary thyroid carcinomas[J). J Clin Endocrinol Metab,2012,97(10):E2006-2015.
[60]Li W, Xu S, Lin S, Zhao W.Overexpression of runt-related transcription factor-2 is associated with advanced tumor progression and poor prognosis in epithelial ovarian cancer[J]. J Biomed Biotechnol,2012, 2012(456534.
[61]Vermeulen AH, Vermeer C, Bosman FT.Histochemical detection of osteocalcin in normal and pathological human bone[J]. J Histochem Cytochem,1989,37(10):1503-1508.
[62]Glowacki J, Rey C, Glimcher MJ, Cox KA, Lian J.A role for osteocalcin in osteoclast differentiation[J]. J Cell Biochem,1991,45(3):292-302.
[63]Yu Q, Xiao MZ, Wu BL, Zhu QL, Guo T, Li F.[Cbfal induces the expression of the mineral-related proteins in human dental papilla cells][J]. Zhonghua Kou Qiang Yi Xue Za Zhi,2003,38(4):271-274.
[64]Butler WT, Ritchie HH, Bronckers AL.Extracellular matrix proteins of dentine[J]. Ciba Found Symp,1997,205(107-115; discussion 115-107.
[65]Fen JQ, Zhang J, Dallas SL, Lu Y, Chen S, Tan X, Owen M, Harris SE, MacDougall M.Dentin matrix protein 1, a target molecule for Cbfal in bone, is a unique bone marker gene[J]. J Bone Miner Res,2002, 17(10):1822-1831.
[66]Feng JQ, Huang H, Lu Y, Ye L, Xie Y, Tsutsui TW, Kunieda T, Castranio T, Scott G, Bonewald LB, Mishina Y.The Dentin matrix protein 1 (Dmp1) is specifically expressed in mineralized, but not soft, tissues during development[J]. J Dent Res,2003,82(10):776-780.
[67]Toyosawa S, Shintani S, Fujiwara T, Ooshima T, Sato A, Ijuhin N, Komori T.Dentin matrix protein 1 is predominantly expressed in chicken and rat osteocytes but not in osteoblasts[J]. J Bone Miner Res,2001, 16(11):2017-2026.
[68]George A, Sabsay B, Simonian PA, Veis A.Characterization of a novel dentin matrix acidic phosphoprotein. Implications for induction of biomineralization[J]. J Biol Chem,1993, 268(17):12624-12630.
[69]Sun Y, Chen L, Ma S, Zhou J, Zhang H, Feng JQ, Qin C.Roles of DMP1 processing in osteogenesis, dentinogenesis and chondrogenesis[J]. Cells Tissues Organs,2011,194(2-4):199-204.
[70]Lu Y, Qin C, Xie Y, Bonewald LF, Feng JQ.Studies of the DMP157-kDa functional domain both in vivo and in vitro[J]. Cells Tissues Organs,2009,189(1-4):175-185.
[71]Lu Y, Yuan B, Qin C, Cao Z, Xie Y, Dallas SL, McKee MD, Drezner MK, Bonewald LF, Feng JQ.The biological function of DMP-I in osteocyte maturation is mediated by its 57-kDa C-terminal fragment[J]. J Bone Miner Res,2011,26(2):331-340.
[72]
[73]He J, Xu Y, Koya D, Kanasaki K.Role of the endothelial-to-mesenchymal transition in renal fibrosis of chronic kidney disease[J]. Clin Exp Nephrol,2013.
[74]Kanasaki K, Taduri G, Koya D.Diabetic nephropathy. the role of inflammation in fibroblast activation and kidney fibrosis[J]. Front Endocrinol (Lausanne),2013,4(7.
[75]Piera-Velazquez S, Jimenez SA.Molecular mechanisms of endothelial to mesenchymal cell transition (EndoMT) in experimentally induced fibrotic diseases[J]. Fibrogenesis Tissue Repair,2012,5 Suppl 1(S7.
[76]Medici D, Olsen BR.The role of endothelial-mesenchymal transition in heterotopic ossification[J]. J Bone Miner Res,2012,27(8):1619-1622.
[77]Lin F, Wang N, Zhang TC.The role of endothelial-mesenchymal transition in development and pathological process[J]. IUBMB Life,2012,64(9):717-723.
[1]KE W, WE E, JLH OR.Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23[J]. Nat Genet,2000,26(3):345-348.
[2]Shimada T, Kakitani M, Yamazaki Y, Hasegawa H, Takeuchi Y, Fujita T, Fukumoto S, Tomizuka K, Yamashita T.Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism[J]. J Clin Invest,2004,113(4):561-568.
[3]Feng JQ, Ward LM, Liu S, Lu Y, Xie Y, Yuan B, Yu X, Rauch F, Davis SI, Zhang S, et al.Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism[J]. Nat Genet,2006,38(11):1310-1315.
[4]Pettifor JM, Thandrayen K.Hypophosphatemic rickets:unraveling the role of FGF23[J]. Calcif Tissue Int,2012,91(5):297-306.
[5]Carpenter EAlaTO.Rickets:The Skeletal Disorders of Impaired Calcium or Phosphate Availability[J]. 2013.
[6]Tenenhouse HS, Beck L.Renal Na(+)-phosphate cotransporter gene expression in X-linked Hyp and Gy mice[J]. Kidney Int,1996,49(4):1027-1032.
[7]Hruska KA, Rifas L, Cheng SL, Gupta A, Halstead L, Avioli L.X-1 inked hypophosphatemic rickets and the murine Hyp homologue[J]. Am J Physiol,1995,268(3 Pt 2):F357-362.
[8]Rector FC, Jr.Sodium, bicarbonate, and chloride absorption by the proximal tubule[J]. Am J Physiol,1983,244(5):F461-471.
[9]Forster IC, Hernando N, Biber J, Murer H.Proximal tubular handling of phosphate:A molecular perspective[J]. Kidney Int,2006,70(9):1548-1559.
[10]Tenenhouse HS.Phosphate transport:molecular basis, regulation and pathophysiology[J]. J Steroid Biochem Mol Biol,2007,103(3-5):572-577.
[11]Miyamoto K, Ito M, Tatsumi S, Kuwahata M, Segawa H.New aspect of renal phosphate reabsorption: the type IIc sodium-dependent phosphate transporter[J]. Am J Nephrol,2007,27(5):503-515.
[12]Biber J, Hernando N, Traebert M, Volkl H, Murer H.Parathyroid hormone-mediated regulation of renal phosphate reabsorption[J]. Nephrol Dial Transplant,2000,15 Suppl 6(29-30.
[13]Quarles LD.Endocrine functions of bone in mineral metabolism regulation[J]. J Clin Invest,2008, 118(12):3820-3828.
[14]Quarles LD.FGF23, PHEX, and MEPE regulation of phosphate homeostasis and skeletal mineralization[J]. Am J Physiol Endocrinol Metab,2003,285(1):E1-9.
[15]Liu S, Tang W, Zhou J, Stubbs JR, Luo Q, Pi M, Quarles LD.Fibroblast growth factor 23 is a counter-regulatory phosphaturic hormone for vitamin D[J]. J Am Soc Nephrol,2006,17(5):1305-1315.
[16]Liu S, Gupta A, Quarles LD.Emerging role of fibroblast growth factor 23 in a bone-kidney axis regulating systemic phosphate homeostasis and extracellular matrix mineralization[J]. Curr Opin Nephrol Hypertens,2007,16(4):329-335.
[17]Tiosano D, Hochberg Z.Hypophosphatemia:the common denominator of all rickets[J]. J Bone Miner Metab,2009,27(4):392-401.
[18]Prader A, Illig R, Uehlinger E, Stalder G.[Rickets following bone tumor][J]. Helv Paediatr Acta,1959, 14(554-565.
[19]Meyer RA, Jr., Meyer MH, Gray RW.Parabiosis suggests a humoral factor is involved in X-linked hypophosphatemia in mice[J]. J Bone Miner Res,1989,4(4):493-500.
[20]Nesbitt T, Coffman TM, Griffiths R, Drezner MK.Crosstransplantation of kidneys in normal and Hyp mice. Evidence that the Hyp mouse phenotype is unrelated to an intrinsic renal defect[J]. J Clin Invest,1992, 89(5):1453-1459.
[21]Miyauchi A, Fukase M, Tsutsumi M, Fujita T.HEMANGIOPERICYTOMA-INDUCED OSTEOMALACIA-TUMOR-TRANSPLANTATION IN NUDE-MICE CAUSES HYPOPHOSPHATEMIA AND TUMOR EXTRACTS INHIBIT RENAL 25-HYDROXYVITAMIN-D 1-HYDROXYLASE ACTIVITY[J]. Journal of Clinical Endocrinology & Metabolism,1988,67(1):46-53.
[22]Econs MJ, Drezner MK.Tumor-induced osteomalacia--unveiling a new hormone[J]. N Engl J Med,1994,330(23):1679-1681.
[23]Bai XY, Miao D, Goltzman D, Karaplis AC.The autosomal dominant hypophosphatemic rickets R176Q mutation in fibroblast growth factor 23 resists proteolytic cleavage and enhances in vivo biological potency[J]. J Biol Chem,2003,278(11):9843-9849.
[24]Ubaidus S, Li M, Sultana S, de Freitas PH, Oda K, Maeda T, Takagi R, Amizuka N.FGF23 is mainly synthesized by osteocytes in the regularly distributed osteocytic lacunar canalicular system established after physiological bone remodeling[J]. J Electron Microsc (Tokyo),2009,58(6):381-392.
[25]Jonsson KB, Zahradnik R, Larsson T, White KE, Sugimoto T, Imanishi Y, Yamamoto T, Hampson G, Koshiyama H, Ljunggren O, et al.Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia[J]. N Engl J Med.2003,348(17):1656-1663.
[26]Riminucci M, Collins MT, Fedarko NS, Cherman N, Corsi A, White KE, Waguespack S, Gupta A, Hannon T, Econs MJ, et al.FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting[J]. J Clin Invest,2003,112(5):683-692.
[27]Fukumoto S, Shimizu Y.Fibroblast growth factor 23 as a phosphotropic hormone and beyond[J]. J Bone Miner Metab,2011,29(5):507-514.
[28]Alon US.Clinical practice. Fibroblast growth factor (FGF)23:a new hormone[J]. Eur J Pediatr,2011, 170(5):545-554.
[29]Gattineni J, Baum M.Genetic disorders of phosphate regulation[J]. Pediatr Nephrol,2012, 27(9):1477-1487.
[30]Carpenter TO.The expanding family of hypophosphatemic syndromes[J]. J Bone Miner Metab,2012, 30(1):1-9.
[31]Baroncelli GI, Toschi B, Bertelloni S.Hypophosphatemic rickets[J]. Curr Opin Endocrinol Diabetes Obes,2012,19(6):460-467.
[32]Penido MG, Alon US.Phosphate homeostasis and its role in bone health[J]. Pediatr Nephrol,2012, 27(11):2039-2048.
[33]Martin A, David V, Li H, Dai B, Feng JQ, Quarles LD.Overexpression of the DMP1 C-terminal fragment stimulates FGF23 and exacerbates the hypophosphatemic rickets phenotype in Hyp mice[J]. Mol Endocrinol,2012,26(11):1883-1895.
[34]Onishi T, Umemura S, Shintani S, Ooshima T.Phex mutation causes overexpression of FGF23 in teeth[J]. Arch Oral Biol,2008,53(2):99-104.
[35]Lorenz-Depiereux B, Bastepe M, Benet-Pages A, Amyere M, Wagenstaller J, Muller-Barth U, Badenhoop K, Kaiser SM, Rittmaster RS, Shlossberg AH, et al.DMPl mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis[J]. Nat Genet,2006,38(11):1248-1250.
[36]Kuro-o M.Klotho as a regulator of fibroblast growth factor signaling and phosphate/calcium metabolism[J]. Curr Opin Nephrol Hypertens,2006,15(4):437-441.
[37]Kurosu H, Ogawa Y, Miyoshi M, Yamamoto M, Nandi A, Rosenblatt KP, Baum MG, Schiavi S, Hu MC, Moe OW, Kuro-o M.Regulation of fibroblast growth factor-23 signaling by klotho[J]. J Biol Chem,2006,281 (10):6120-6123.
[38]Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, Fujita T, Fukumoto S, Yamashita T.Klotho converts canonical FGF receptor into a specific receptor for FGF23[J]. Nature,2006, 444(7120):770-774.
[39]Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, et al.Mutation of the mouse klotho gene leads to a syndrome resembling ageing[J]. Nature,1997,390(6655):45-51.
[40]Ben-Dov IZ, Galitzer H, Lavi-Moshayoff V, Goetz R, Kuro-o M, Mohammadi M, Sirkis R, Naveh-Many T, Silver J.The parathyroid is a target organ for FGF23 in rats[J]. J Clin Invest,2007, 117(12):4003-4008.
[41]Segawa H, Kawakami E, Kaneko I, Kuwahata M, Ito M, Kusano K, Saito H, Fukushima N, Miyamoto K.Effect of hydrolysis-resistant FGF23-R179Q on dietary phosphate regulation of the renal type-11 Na/Pi transporter[J]. Pflugers Arch,2003,446(5):585-592.
[42]Segawa H, Yamanaka S, Ohno Y, Onitsuka A, Shiozawa K, Aranami F, Furutani J, Tomoe Y, Ito M, Kuwahata M, et al.Correlation between hyperphosphatemia and type Ⅱ Na-Pi cotransporter activity in klotho mice[J]. Am J Physiol Renal Physiol,2007,292(2):F769-779.
[43]Shimada T, Urakawa I, Yamazaki Y, Hasegawa H, Hino R, Yoneya T, Takeuchi Y, Fujita T, Fukumoto S, Yamashita T.FGF-23 transgenic mice demonstrate hypophosphatemic rickets with reduced expression of sodium phosphate cotransporter type Ⅱa[J]. Biochem Biophys Res Commun,2004,314(2):409-414.
[44]Farrow EG, Davis SI, Summers LJ, White KE.Initial FGF23-mediated signaling occurs in the distal convoluted tubule[J]. J Am Soc Nephrol,2009,20(5):955-960.
[45]Hu MC, Shi M, Zhang J, Pastor J, Nakatani T, Lanske B, Razzaque MS, Rosenblatt KP, Baum MG, Kuro-o M, Moe OW.Klotho:a novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule[J]. FASEB J,2010,24(9):3438-3450.
[46]Gattineni J, Bates C, Twombley K, Dwarakanath V, Robinson ML, Goetz R, Mohammadi M, Baum M.FGF23 decreases renal NaPi-2a and NaPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1 [J]. Am J Physiol Renal Physiol,2009,297(2):F282-291.
[47]Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R, Takeuchi Y, Fujita T, Nakahara K, Fukumoto S, Yamashita T.FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis[J]. J Bone Miner Res,2004,19(3):429-435.
[48]Shalhoub V, Ward SC, Sun B, Stevens J, Renshaw L, Hawkins N, Richards WG.Fibroblast growth factor 23 (FGF23) and alpha-klotho stimulate osteoblastic MC3T3.E1 cell proliferation and inhibit mineralization[J]. Calcif Tissue Int,2011,89(2):140-150.
[49]Wang H, Yoshiko Y, Yamamoto R, Minamizaki T, Kozai K, Tanne K, Aubin JE, Maeda N.Overexpression of fibroblast growth factor 23 suppresses osteoblast differentiation and matrix mineralization in vitro[J]. J Bone Miner Res,2008,23(6):939-948.
[50]Lorenz-Depiereux B, Schnabel D, Tiosano D, Hausler G, Strom TM.Loss-of-function ENPP1 mutations cause both generalized arterial calcification of infancy and autosomal-recessive hypophosphatemic rickets[J]. Am J Hum Genet,2010,86(2):267-272.
[51]Levy-Litan V, Hershkovitz E, Avizov L, Leventhal N, Bercovich D, Chalifa-Caspi V, Manor E, Buriakovsky S, Hadad Y, Goding J, Parvari R.Autosomal-recessive hypophosphatemic rickets is associated with an inactivation mutation in the ENPP1 gene[J]. Am J Hum Genet,2010,86(2):273-278.
[52]Ryan WG, Nibbe AF, Schwartz TB, Ray RD.Fibrous dysplasia of bone with vitamin D resistant rickets: a case study [J]. Metabolism,1968,17(11):988-998.
[53]Dent CE, Gertner JM.Hypophosphataemic osteomalacia in fibrous dysplasia[J]. Q J Med,1976, 45(179):411-420.
[54]Dachille RD, Goldberg JS, Wexler ID, Shons AR.Fibrous dysplasia-induced hypocalcemia/rickets[J]. J Oral Maxillofac Surg,1990,48(12):1319-1322.
[55]Zutt M, Strutz F, Happle R, Habenicht EM, Emmert S, Haenssle HA, Kretschmer L, Neumann C.Schimmelpenning-Feuerstein-Mims syndrome with hypophosphatemic rickets[J]. Dermatology,2003, 207(1):72-76.
[56]Hoffman WH, Jueppner HW, Deyoung BR, O'Dorisio M S, Given KS.Elevated fibroblast growth factor-23 in hypophosphatemic linear nevus sebaceous syndrome[J]. Am J Med Genet A,2005, 134(3):233-236.
[57]Srinivas UM, Tourani KL.Epidermal nevus syndrome with hypophosphatemic renal rickets with hypercalciuria:a bonemarrow diagnosis[J]. Int J Hematol,2008,88(2):125-126.
[58]Bianchine JW, Stambler AA, Harrison HE.Familial hypophosphatemic rickets showing autosomal dominant inheritance[J]. Birth Defects Orig Artie Ser,1971,7(6):287-295.
[59]Pettifor JM.What's new in hypophosphataemic rickets?[J]. Eur J Pediatr,2008,167(5):493-499.
[60]Xia W, Meng X, Jiang Y, Li M, Xing X, Pang L, Wang O, Pei Y, Yu LY, Sun Y, et al.Three novel mutations of the PHEX gene in three Chinese families with X-linked dominant hypophosphatemic rickets[J]. Calcif Tissue Int,2007,81(6):415-420.
[61]A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. The HYP Consortium[J]. Nat Genet,1995,11(2):130-136.
[62]Beck L, Soumounou Y, Martel J, Krishnamurthy G, Gauthier C, Goodyer CG, Tenenhouse HS.Pex/PEX tissue distribution and evidence for a deletion in the 3'region of the Pex gene in X-linked hypophosphatemic mice[J]. J Clin Invest,1997,99(6):1200-1209.
[63]Xia WB, Jiang Y, Li M, Xing XP, Wang O, Hu YY, Zhang HB, Liu HC, Meng XW, Zhou XY.Levels and dynamic changes of serum fibroblast growth factor 23 in hypophosphatemic rickets/osteomalacia[J]. Chin Med J (Engl),2010,123(9):1158-1162.
[64]Liu S, Zhou J, Tang W, Jiang X, Rowe DW, Quarles LD.Pathogenic role of Fgf23 in Hyp mice[J]. Am J Physiol Endocrinol Metab,2006,291(1):E38-49.
[65]Liu S, Guo R, Simpson LG, Xiao ZS, Burnham CE, Quarles LD.Regulation of fibroblastic growth factor 23 expression but not degradation by PHEX[J]. J Biol Chem,2003,278(39):37419-37426.
[66]David V, Martin A, Hedge AM, Drezner MK, Rowe PS.ASARM peptides:PHEX-dependent and-independent regulation of serum phosphate[J]. Am J Physiol Renal Physiol,2011,300(3):F783-791.
[67]Econs MJ, McEnery PT.Autosomal dominant hypophosphatemic rickets/osteomalacia:clinical characterization of a novel renal phosphate-wasting disorder[J]. J Clin Endocrinol Metab,1997, 82(2):674-681.
[68]Imel EA, Peacock M, Gray AK, Padgett LR, Hui SL, Econs MJ.Iron modifies plasma FGF23 differently in autosomal dominant hypophosphatemic rickets and healthy humans[J]. J Clin Endocrinol Metab,2011,96(11):3541-3549.
[69]Kruse K, Woelfel D, Strom TM.Loss of renal phosphate wasting in a child with autosomal dominant hypophosphatemic rickets caused by a FGF23 mutation[J]. Horm Res,2001,55(6):305-308.
[70]White KE, Cam G, Lorenz-Depiereux B, Benet-Pages A, Strom TM, Econs MJ.Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23[J]. Kidney Int,2001,60(6):2079-2086.
[71]Sun Y, Wang O, Xia W, Jiang Y, Li M, Xing X, Hu Y, Liu H, Meng X, Zhou X.FGF23 analysis of a Chinese family with autosomal dominant hypophosphatemic rickets[J]. J Bone Miner Metab,2012, 30(1):78-84.
[72]Imel EA, Econs MJ.Fibroblast growth factor 23:roles in health and disease[J]. J Am Soc Nephrol,2005, 16(9):2565-2575.
[73]Perry W, Stamp TC.Hereditary hypophosphataemic rickets with autosomal recessive inheritance and severe osteosclerosis. A report of two cases[J]. J Bone Joint Surg Br,1978,60-B(3):430-434.
[74]Scriver CR, Reade T, Halal F, Costa T, Cole DE.Autosomal hypophosphataemic bone disease responds to 1,25-(OH)2D3[J]. Arch Dis Child,1981,56(3):203-207.
[75]Gattineni J, Baum M.Regulation of phosphate transport by fibroblast growth factor 23 (FGF23): implications for disorders of phosphate metabolism[J]. Pediatr Nephrol,2010,25(4):591-601.
[76]Farrow EG, White KE.Recent advances in renal phosphate handling[J]. Nat Rev Nephrol,2010, 6(4):207-217.
[77]Saito T, Shimizu Y, Hori M, Taguchi M, Igarashi T, Fukumoto S, Fujitab T.A patient with hypophosphatemic rickets and ossification of posterior longitudinal ligament caused by a novel homozygous mutation in ENPP1 gene[J]. Bone,2011,49(4):913-916.
[78]Carpenter TO, Imel EA, Holm IA, Jan de Beur SM, Insogna KL.A clinician's guide to X-linked hypophosphatemia[J]. J Bone Miner Res,2011,26(7):1381-1388.
[79]Quinlan C, Guegan K, Offiah A, Neill RO, Hiorns MP, Ellard S, Bockenhauer D, Hoff WV, Waters AM.Growth in PHEX-associated X-linked hypophosphatemic rickets:the importance of early treatment[J]. Pediatr Nephrol,2012,27(4):581-588.
[80]Makitie O.Early Treatment Improves Growth and Biochemical and Radiographic Outcome in X-Linked Hypophosphatemic Rickets[J]. Journal of Clinical Endocrinology & Metabolism,2003, 88(8):3591-3597.
[81]Zivicnjak M, Schnabel D, Staude H, Even G, Marx M, Beetz R, Holder M, Billing H, Fischer DC, Rabl W, et al.Three-year growth hormone treatment in short children with X-linked hypophosphatemic rickets: effects on linear growth and body disproportion[J]. J Clin Endocrinol Metab,2011,96(12):E2097-2105.
[82]Liu ES, Carpenter TO, Gundberg CM, Simpson CA, Insogna KL.Calcitonin administration in X-linked hypophosphatemia[J]. N EngI J Med,2011,364(17):1678-1680.
[83]Aono Y, Hasegawa H, Yamazaki Y, Shimada T, Fujita T, Yamashita T, Fukumoto S.Anti-FGF-23 neutralizing antibodies ameliorate muscle weakness and decreased spontaneous movement of Hyp mice[J]. J Bone Miner Res,2011,26(4):803-810.
[84]Shimada T, Fukumoto S.FGF23 as a novel therapeutic target[J]. Adv Exp Med Biol,2012, 728(158-170.
[85]Wyman AL, Paradinas FJ, Daly JR.Hypophosphataemic osteomalacia associated with a malignant tumour of the tibia:report of a case[J]. J Clin Pathol,1977,30(4):328-335.
[86]Rico H, Fernandez-Miranda E, Sanz J, Gomez-Castresana F, Escriba A, Hernandez ER, Krsnik I.Oncogenous osteomalacia:a new case secondary to a malignant tumor[J]. Bone,1986,7(5):325-329.
[87]Harvey JN, Gray C, Belchetz PE.Oncogenous osteomalacia and malignancy[J]. Clin Endocrinol (Oxf),1992,37(4):379-382.
[88]Ogose A, Hotta T, Emura I, Hatano H, Inoue Y, Umezu H, Endo N.Recurrent malignant variant of phosphaturic mesenchymal tumor with oncogenic osteomalacia[J]. Skeletal Radiol,2001,30(2):99-103.
[89]Uramoto N, Furukawa M, Yoshizaki T.Malignant phosphaturic mesenchymal tumor, mixed connective tissue variant of the tongue[J]. Auris Nasus Larynx,2009,36(1):104-105.
[90]Cai Q, Hodgson SF, Kao PC, Lennon VA, Klee GG, Zinsmiester AR, Kumar R.Brief report:inhibition of renal phosphate transport by a tumor product in a patient with oncogenic osteomalacia[J]. N Engl J Med,1994,330(23):1645-1649.
[91]Yamazaki Y, Okazaki R, Shibata M, Hasegawa Y, Satoh K, Tajima T, Takeuchi Y, Fujita T, Nakahara K, Yamashita T, Fukumoto S.Increased circulatory level of biologically active full-length FGF-23 in patients with hypophosphatemic rickets/osteomalacia[J]. J Clin Endocrinol Metab,2002,87(11):4957-4960.
[92]Takeuchi Y, Suzuki H, Ogura S, Imai R, Yamazaki Y, Yamashita T, Miyamoto Y, Okazaki H, Nakamura K, Nakahara K, et al.Venous sampling for fibroblast growth factor-23 confirms preoperative diagnosis of tumor-induced osteomalacia[J]. J Clin Endocrinol Metab,2004,89(8):3979-3982.
[93]Jiang Y, Xia WB, Xing XP, Silva BC, Li M, Wang O, Zhang HB, Li F, Jing HL, Zhong DR, et al.Tumor-induced osteomalacia:an important cause of adult-onset hypophosphatemic osteomalacia in China:Report of 39 cases and review of the literature[J]. J Bone Miner Res,2012,27(9):1967-1975.
[94]White KE, Jonsson KB, Cam G, Hampson G, Spector TD, Mannstadt M, Lorenz-Depiereux B, Miyauchi A, Yang IM, Ljunggren O, et al.The autosomal dominant hypophosphatemic rickets (ADHR) gene is a secreted polypeptide overexpressed by tumors that cause phosphate wasting[J]. J Clin Endocrinol Metab,2001,86(2):497-500.
[95]Farrow EG, White KE.Tumor-induced osteomalacia[J]. Expert Rev Endocrinol Metab,2009, 4(5):435-442.
[96]Hesse E, Moessinger E, Rosenthal H, Laenger F, Brabant G, Petrich T, Gratz KF, Bastian L.Oncogenic osteomalacia:exact tumor localization by co-registration of positron emission and computed tomography [J]. J Bone Miner Res,2007,22(1):158-162.
[97]Clunie GP, Fox PE, Stamp TC.Four cases of acquired hypophosphataemic ('oncogenic') osteomalacia. Problems of diagnosis, treatment and long-term management[J]. Rheumatology (Oxford),2000, 39(12):1415-1421.
[98]Khosravi A, Cutler CM, Kelly MH, Chang R, Royal RE, Sherry RM, Wodajo FM, Fedarko NS, Collins MT.Determination of the elimination half-life of fibroblast growth factor-23 [J]. Journal of Clinical Endocrinology & Metabolism,2007,92(6):2374-2377.
[99]Spiegel AM, Shenker A, Weinstein LS.Receptor-effector coupling by G proteins:implications for normal and abnormal signal transduction[J]. Endocr Rev,1992,13(3):536-565.
[100]Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Spiegel AM.Activating mutations of the stimulatory G protein in the McCune-Albright syndrome[J]. N Engl J Med,1991,325(24):1688-1695.
[101]Schwindinger WF, Francomano CA, Levine MA.Identification of a mutation in the gene encoding the alpha subunit of the stimulatory G protein of adenylyl cyclase in McCune-Albright syndrome[J]. Proc Natl Acad Sci U S A,1992,89(11):5152-5156.
[102]Lee PA, Van Dop C, Migeon CJ.McCune-Albright syndrome. Long-term follow-up[J]. JAMA,1986, 256(21):2980-2984.
[103]Collins MT, Chebli C, Jones J, Kushner H, Consugar M, Rinaldo P, Wientroub S, Bianco P, Robey PGRenal phosphate wasting in fibrous dysplasia of bone is part of a generalized renal tubular dysfunction similar to that seen in tumor-induced osteomalacia[J]. J Bone Miner Res,2001,16(5):806-813.
[104]Yamamoto T, Miyamoto KI, Ozono K, Taketani Y, Katai K, Miyauchi A, Shima M, Yoshikawa H, Yoh K, Takeda E, Okada S.Hypophosphatemic rickets accompanying McCune-Albright syndrome: evidence that a humoral factor causes hypophosphatemia[J]. J Bone Miner Metab,2001,19(5):287-295.
[105]Chadha M, Singh AP, Singh AP.Hypophosphataemic osteomalacia in neurofibromatosis[J]. Acta Orthop Belg,2009,75(6):847-850.
[106]Lambert J, Lips P.Adult hypophosphataemic osteomalacia with Fanconi syndrome presenting in a patient with neurofibromatosis[J]. Neth J Med,1989,35(5-6):309-316.
[107]Konishi K, Nakamura M, Yamakawa H, Suzuki H, Saruta T, Hanaoka H, Davatchi F.Hypophosphatemic osteomalacia in von Recklinghausen neurofibromatosis[J]. Am J Med Sci,1991, 301(5):322-328.
[108]Retnam VJ, Rangnekar DM, Bhandarkar SD.Neurofibromatosis with hypophosphatemic osteomalacia (Von Recklinghausen-Hernberg-Edgren-Swann syndrome) (a case report)[J]. J Assoc Physicians India,1980,28(9):319-322.
[109]Abdel-Wanis M, Kawahara N.Hypophosphatemic osteomalacia in neurofibromatosis 1:hypotheses for pathogenesis and higher incidence of spinal deformity[J]. Med Hypotheses,2002,59(2):183-185.
[110]Solomon LM, Esterly NB.Epidermal and other congenital organoid nevi[J]. Curr Probl Pediatr,1975, 6(1):1-56.
[111]Grebe TA, Rimsza ME, Richter SF, Hansen RC, Hoy me HE.Further delineation of the epidermal nevus syndrome:two cases with new findings and literature review[J]. Am J Med Genet,1993,47(1):24-30.
[112]Aschinberg LC, Solomon LM, Zeis PM, Justice P, Rosenthal IM.Vitamin D-resistant rickets associated with epidermal nevus syndrome:demonstration of a phosphaturic substance in the dermal lesions[J]. J Pediatr,1977,91(1):56-60.
[113]Carey DE, Drezner MK, Hamdan JA, Mange M, Ahmad MS, Mubarak S, Nyhan WL.Hypophosphatemic rickets/osteomalacia in linear sebaceous nevus syndrome:a variant of tumor-induced osteomalacia[J]. J Pediatr,1986,109(6):994-1000.
[114]Goldblum JR, Headington JT.Hypophosphatemic vitamin D-resistant rickets and multiple spindle and epithelioid nevi associated with linear nevus sebaceus syndrome[J]. J Am Acad Dermatol,1993, 29(1):109-111.
[115]Skovby F, Svejgaard E, Moller J.Hypophosphatemic rickets in linear sebaceous nevus sequence[J]. J Pediatr,1987, 111(6Pt 1):855-857.
[116]Eyskens B, Proesmans W, Van Damme B, Lateur L, Bouillon R, Hoogmartens M.Tumour-induced rickets:a case report and review of the literature[J]. Eur J Pediatr,1995,154(6):462-468.
[117]Oranje AP, Przyrembel H, Meradji M, Loonen MC, de Klerk JB.Solomon's epidermal nevus syndrome (type:linear nevus sebaceus) and hypophosphatemic vitamin D-resistant rickets[J]. Arch Dermatol,1994,130(9):1167-1171.
[118]Narazaki R, Ihara K, Namba N, Matsuzaki H, Ozono K, Hara T.Linear nevus sebaceous syndrome with hypophosphatemic rickets with elevated FGF-23[J]. Pediatr Nephrol,2012,27(5):861-863.
[119]Sethi SK, Hari P, Bagga A.Elevated FGF-23 and parathormone in linear nevus sebaceous syndrome with resistant rickets[J]. Pediatr Nephrol,2010,25(8):1577-1578.
[120]White KE, Cabral JM, Davis SI, Fishburn T, Evans WE, Ichikawa S, Fields J, Yu X, Shaw NJ, McLellan NJ, et al.Mutations that cause osteoglophonic dysplasia define novel roles for FGFR1 in bone elongation[J]. Am J Hum Genet,2005,76(2):361-367.
[121]Farrow EG, Davis SI, Mooney SD, Beighton P, Mascarenhas L, Gutierrez YR, Pitukcheewanont P, White KE.Extended mutational analyses of FGFR1 in osteoglophonic dysplasia[J]. Am J Med Genet A.2006,140(5):537-539.
[122]Roberts TS, Stephen L, Beighton P.Osteoglophonic dysplasia:dental and orthodontic implications[J]. Orthod Craniofac Res,2006,9(3):153-156.
[123]Beighton P, Cremin BJ, Kozlowski K.Osteoglophonic dwarfism[J]. Pediatr Radiol,1980,10(1):46-50.
[124]Beighton P.Osteoglophonic dysplasia[J]. J Med Genet,1989,26(9):572-576.
[125]Brownstein CA, Adler F, Nelson-Williams C, Iijima J, Li P, Imura A, Nabeshima Y, Reyes-Mugica M, Carpenter TO, Lifton RP.A translocation causing increased alpha-klotho level results in hypophosphatemic rickets and hyperparathyroidism[J]. Proc Natl Acad Sci U S A,2008,105(9):3455-3460.