DMP1 C末端突变小鼠模型的建立和表型分析
摘要
低血磷性佝偻病(hypophosphatemic rickets, HR)是由于肾小管对磷的重吸收降低而造成的以骨骼矿化不良、骨软化和佝偻病为主要特征的一组疾病,其主要临床表现为血磷减少、尿磷增多、佝偻病和骨软化症等,在新生儿中的发病率约为两万分之一。遗传性低血磷性佝偻病具有明显遗传异质性,根据遗传方式可以分为以下几种：1)X连锁低血磷性佝偻病(X-linked hypophosphatemic rickets, XLHR, MIM 307800),其致病基因是PHEX(phosphate regulating endopeptidase homolog, X-linked); 2)常染色体显性低血磷性佝偻病(autosomal dominant hypophosphatemic rickets, ADHR, MIM193100),其致病基因是FGF23 (Fibroblast Growth Factor 23); 3)常染色体隐性低血磷性佝偻病(autosomal recessive hypophosphatemic rickets, ARHR,MIM 241520和613312),其致病基因是DMP1 (Dentin Matrix Protein 1)或ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1);4)伴有高尿钙症的遗传性低血磷性佝偻病(hereditary hypophosphatemic rickets with hypercalciuria, HHRH, MIM 241530),其致病基因是SLC34A3 (solute carrier family 34, member 3)
DMPl基因的编码产物是一种酸性非胶原细胞外基质蛋白,属于SIBLING (Small Integrin-Binding LIgand N-linked Glycoprotein)家族成员。该家族成员不仅具有相似的生物学特性,而且在染色体上成簇排列。DMP1基因在人类染色体上位于4q21-22,在小鼠染色体上位于5q21。DMP1在骨骼和牙齿中表达较高,在多个非矿化的组织中也有表达,但表达水平较低。DMP1蛋白在翻译后被水解成两个片段：N末端的37 kDa大小的片段和C末端的57 kDa大小的片段,然而目前并不清楚哪一个片段在骨骼和牙齿发育过程中发挥更重要的作用。
Dmp1基因敲除小鼠在胚胎期和刚出生时没有明显的异常表型,提示Dmp1基因不是小鼠早期骨骼和牙齿发育所必需的。在出生后,Dmp1基因敲除小鼠表现出明显的牙齿发育异常,具体表现为前牙本质向牙本质成熟过程缺陷、牙髓腔和牙根管变大、前牙本质变宽、牙本质变窄并且矿化不全。Dmp1基因敲除小鼠还表现出第3磨牙的缺损或发育迟缓,以及牙周缺陷,包括牙槽骨疏松和牙骨质缺陷等。Dmp1基因敲除小鼠在骨骼方面表现出矿化程度降低、骨软化症和佝偻病等症状,具体表现为椎骨和长骨长度变短、直径变大、次级骨化中心发育迟缓和畸形、生长板变宽并且不规则(由于增殖区细胞增殖活性升高和肥大软骨细胞区细胞凋亡降低引起)和骨骺区变大(由于血管侵入受损引起)。Dmp1基因敲除小鼠同时伴有肾磷代谢异常和Fgf23含量升高,但是尿钙含量正常。本课题组曾在一个ARHR家系的患者中检测到DMP1基因第1484-1490位核苷酸纯合缺失,这7个碱基的缺失引起移码突变,使该蛋白C末端最后18个氨基酸残基被33个新的氨基酸残基取代,且被替代的18个氨基酸残基在种属间高度保守。本课题分析了该家系ARHR患者的牙齿表型,并分析了突变蛋白的体外功能。为进一步研究该DMP1突变的分子和病理生理学机制,我们制作了含有该突变的小鼠模型并对其进行了表型分析。
第一,分析DMP1 C末端缺失患者牙齿表型发现,患者具有明显的牙齿发育异常：对该家系患者的口腔X光片分析结果发现,患者的乳牙和恒牙都表现出明显的异常,包括牙髓腔和牙根管变大,牙本质变薄,牙釉质的缺损等。
第二,体外分析提示突变蛋白保留DMP1蛋白的部分功能：对比分析由DMP1基因突变导致的ARHR患者和Dmp1基因敲除小鼠表型特点发现,两者具有一些类似表型,如低血磷症等；但也存在一些差异。这些差异可能是由于人和小鼠之间的种属特异性造成的,也可能是由于突变的DMP1蛋白仍保留有部分功能。为明确C末端缺失突变对DMP1功能的影响及其致病机制,本课题首先在体外分析了该缺失突变对DMP1蛋白水解和分泌的影响,并分析了该突变对ERK磷酸化活性的影响。结果发现DMP1蛋白的C末端突变不影响该蛋白的正常分泌和水解,C末端突变的DMP1蛋白仍保留有部分的激活ERK信号通路的功能,表明突变蛋白没有完全丧失功能。
第三,构建了具有与ARHR患者相同突变的Dmp1突变小鼠模型：为分析DMP1C末端突变的致病机制,我们首先采用转基因方法构建了一种转基因小鼠,该转基因小鼠在3.6 kb Collal启动子的启动下表达含有与ARHR患者相同突变的全长Dmp1基因。我们成功得到了11只founder小鼠,并选取了其中3个独立的品系,用RT-PCR和原位杂交的方法对其进行了表达分析,转基因在骨骼和牙齿中的表达模式与内源性的Dmp1基因基本一致,表达量高于内源性的Dmp1基因。X光片结果显示,与对照小鼠相比,表达突变型Dmp1基因的转基因小鼠没有明显的骨骼和牙齿表型。在此基础上,我们将该转基因小鼠与Dmp1基因敲除小鼠杂交,获得了仅表达外源性突变型Dmp1基因而不表达内源性野生型Dmp1基因的小鼠,即Dmp1基因突变小鼠模型。
第四,Dmp1基因突变小鼠模型从骨骼、牙齿和生化指标等多方面再现了人类突变患者的表型特征：我们利用组织学、X光片、Micro-CT、扫描电子显微镜、双荧光标记和血清生化分析等技术系统全面地分析了Dmp1基因突变小鼠的表型,并与ARHR患者的症状和Dmp1基因敲除小鼠的表型进行比较。
1)骨骼表型：小鼠全身X光片和后肢X光片显示,Dmp1基因突变小鼠表现出佝偻病表型,包括股骨和胫骨长度变短,干垢端变大、生长板变宽和骨骼形态改变。定量分析结果显示,Dmp1基因突变小鼠的胫骨长度与正常对照相比变短,但是变短程度不如Dmp1基因敲除小鼠明显。骨骼石蜡切片的Safranin-O染色也进一步验证了佝偻病特征,生长板明显变宽,其中肥大软骨细胞层的变宽程度最大,静止层和增殖层也有一定程度的变宽。Goldner染色结果显示Dmp1基因突变小鼠骨皮质中含有非常多的类骨质,表现出骨骼矿化不全和骨软化症。双荧光标记实验显示骨骼矿化速率降低、矿化过程紊乱。扫描电子显微镜结果显示Dmp1基因突变小鼠的骨细胞lacuna-canalicular系统异常,骨细胞体积变大,表面粗糙,突触变短并且变少。这些异常的骨骼表型严重程度明显低于Dmp1基因敲除小鼠,但是与ARHR患者骨骼异常一致,表明Dmp1基因突变小鼠模型较好地模拟了人类突变的骨骼方面表型。
2)牙齿表型：小鼠牙齿的X光片和Micro-CT分析结果显示,Dmp1基因突变小鼠牙本质变薄,牙髓腔和牙根管体积变大,但是表型程度比Dmp1基因敲除小鼠要轻。牙齿切片的H&E染色结果也进一步验证了X光片和Micro-CT的分析结果,Dmp1基因突变小鼠的前牙本质变宽,而牙本质变窄。双荧光标记实验显示Dmp1基因突变小鼠牙本质矿化形成的速度明显变慢、牙本质矿化过程出现异常。此外,Dmp1基因突变小鼠还表现出下颌骨节发育异常。然而以上实验结果以及反向散射扫描电子显微镜结果都没有发现Dmp1基因突变小鼠中有任何的牙釉质缺陷,这一结果与ARHR患者的牙釉质缺陷症状不同。这些结果提示Dmp1基因突变小鼠模型较好地模拟了人类突变的牙本质方面表型,而ARHR患者中发现的牙釉质缺陷可能是由于DMP1基因突变之外的其他原因导致。
3)血清生化指标分析：Dmp1基因突变小鼠血清中Fgf23分子含量升高,磷的含量降低,但是改变程度较小；血清中钙的含量没有明显变化。这一结果与ARHR患者非常一致,但改变程度比Dmp1基因敲除小鼠的改变程度小很多。
综上所述,Dmp1基因突变小鼠在以上三方面再现了人类突变表型特征,但是与Dmp1基因敲除小鼠相比,该突变所引起的表型效应较轻,也提示该突变蛋白仍保留了部分功能。
Dmp1基因突变小鼠模型的成功构建不仅为研究该突变的致病机制及寻找该疾病治疗手段奠定了基础,而且也为研究DMP1基因的其它突变提供了重要参考。
Hypophosphatemic rickets (HR) is characterized by hypomineralization of bone, rickets and osteomalacia due to abnormal Pi reabsorption in renal tubules. The clinical features of HR include hypophosphatemia, phosphaturia, rickets and osteomalacia, with an incidence of 1 in 20,000 newborns. Hypophosphatemic rickets can be inherited in autosomal dominant, autosomal recessive, or X-linked pattern. X-linked hypophosphatemic rickets (XLHR, MIM 307800) is caused by mutation in the PHEX gene (phosphate regulating endopeptidase homolog, X-linked). Autosomal dominant hypophosphatemic rickets (ADHR, MIM 193100) is caused by mutation in the FGF23 gene (Fibroblast Growth Factor 23). Autosomal recessive hypophosphatemic rickets (ARHR, MIM 241520 and 613312) is caused by mutation in the DMP1 gene (Dentin Matrix Protein 1) or in the ENPP1 gene (ectonucleotide pyrophosphatase/phosphodiesterase 1). Hereditary hypophosphatemic rickets with hypercalciuria (HHRH, MIM 241530) is caused by mutation in the SLC34A3 gene (solute carrier family 34, member 3).
DMP1 gene encodes an acidic non-collagen extracellular matrix protein, a member of the SIBLING (Small Integrin-Binding LIgand N-linked Glycoprotein) family whose members share similar features in both biological properties and genomic structure. DMP1 gene was mapped to human chromosome 4q21-22 and mouse chromosome 5q21, respectively. DMP1 is highly expressed in bone and dentin, and lower expressed in non-mineralized tissues. DMP1 is cleaved into the 37 kDa N-terminal and the 57 kDa C-terminal fragments, but it is not clear which fragment is functionally critical for bone and tooth formation both in vivo and in vitro.
Dmpl null embryos and newborns display no apparent gross abnormal phenotype, suggesting that Dmpl is not essential for early mouse skeletal or dental development. Dmpl null mice postnatally developed a profound tooth phenotype characterized by partial failure of maturation of predentin into dentin, enlarged pulp chambers and root canals, increased width of predentin zone with reduced dentin wall, and hypomineralization. Dmpl null mice also showed absence or delayed development of the third molar and periodontal breakdown, including porous alveolar and defective cementum. Dmpl null mice manifested decreased bone mineralization and osteomalacia, as well as rickets, which was characterized by shorter and wider vertebrae and long bones, delayed and malformed secondary ossification centers, irregular and highly expanded growth plate (due to increased cell proliferation in proliferating zone and reduced apoptosis in the hypertrophic zone) and increased epiphyses area (due to impaired blood vessel invasion). The rickets and osteomalacia phenotypes of Dmpl null mice were associated with isolated renal phosphate-wasting, elevated Fgf23 levels and normal calciuria.
In the patients of one of our previously reported ARHR kindreds, a homozygous deletion of nucleotides 1484-1490 in DMP1 gene was detected. The deletion of the 7 nucleotides resulted in a frameshift that replaced the conserved C-terminal 18 residues with 33 novel residues. In the present study, we characterized the tooth phenotypes of the patients, and analyzed the function of mutant protein in vitro. To further understand the molecular and pathophysiologic mechanism of this DMP1 mutation, we generated and characterized a mouse model with this specific mutation.
Firstly, we examined the tooth phenotype of the patients with DMP1 C-terminal mutation, and found that the patients displayed obvious abnormalities during tooth development:the radiographs from the patient teeth (both primary and permanent teeth) showed significantly enlarged pulps and root canals with extremely thin dentin and loss of enamel.
Secondly, in vitro function assays suggested that the mutant protein maintained partial function of DMP1:ARHR patients with DMP1 mutation and Dmpl null mice share some common features, such as hypophosphatemia. However, minor differences exist between the mouse model and the human ARHR patients. These differences could be due to species-specificity of human versus mouse, or that the mutant DMP1 in human may maintain partial function of DMP1. To determine the function of the C-terminal mutant DMP1 and the mechanism in which it causes ARHR, we examined the cleavage and secretion of the C-terminal mutant DMP1, and its function on ERK phosphorylation. The C-terminal mutant DMP1 can be secreted and cleaved normally and maintained partial function on ERK phosphorylation. These data suggested that the mutant protein did not completely lose its function.
Thirdly, we genetated a mouse model harboring the human DMP1 1481-1490 deletion mutation. To study the mechanism in which DMP1 C-terminal mutation cause ARHR, we generated transgenic mice harboring the full-length Dmpl cDNA with the same deletion mutation as observed in ARHR patients under control of the 3.6 kb Collal promoter. Eleven founder mice were got and 3 independent lines were used for expression analyses by RT-PCR and in situ hybridization. The expression pattern of the transgene in bone and teeth is the same as endogenous Dmpl gene, and the expression level is higher than endogenous Dmpl gene. Radiographs showed that the transgenic mice expressing the mutant Dmpl gene did not show an apparent bone and teeth phenotype compared to the WT control mice. Then, these transgenic lines were crossed to Dmpl null mice, and the homozygous mice with Dmpl mutation but without endogenous Dmpl gene were obtained.
Fourthly, the Dmpl mutant mice recaptured the human ARHR patients' phenotypes, including bone, tooth and serum markers:The phenotypes of Dmpl mutant mice were characterized and compared with those of ARHR patients and Dmpl null mice using several assays including histology, radiography, Micro-CT, SEM, calcein/alizarin red double labeling, and serum biochemistry.
1) Bone phenotype:As showed in radiographs of the whole bodies and hind limbs, Dmpl mutant mice displayed rickets phenotype, including shorter femur and tibia, expanded metaphyses, enlarged growth plates and malformed bone shape. Quantitative analyses of tibia length confirmed that the long bones in Dmpl mutant mice are shorter compared to the control mice, but are not as severe as Dmpl null mice. Histological data of Safranin-O staining further confirmed the rickets phenotype such as striking expansion of the growth plate, including resting zone, proliferation zone and hypertrophic zone with the last one expanded most. Goldner assay showed abundant osteoid in the mineral of cortical bone in Dmpl mutant mice, a significant sign of hypo-mineralization and osteomalacia phenotype. Double fluorochrome labeling assay showed slow rate and disruption of bone mineralization in Dmpl mutant mice. Dmpl mutant mice also showed abnormalities in the osteocyte lacuna-canalicular system by SEM, such as enlarged size and buckled surface of the osteocytes, and fewer and shorter synapses. These phenotypes of Dmpl mutant mice were consistent with observations in samples from ARHR patients, but milder than those in Dmpl null mice, suggesting that the Dmpl mutant mice can recapture the human ARHR bone phenotype.
2) Tooth phenotype:Dmpl mutant mice showed thin dentin and enlarged pulp cavities and root canals with radiograph and Micro-CT analyses, but the phenotype is milder than that in Dmpl null mice. Histological data of H&E staining further confirmed the dentin phenotype in Dmpl mutant mice:the expanded predentin and the thin dentin. The double labeling assay also showed reduction of the dentin formation rate and diffused labeling lines in Dmpl mutant mice. Dmpl mutant mice also showed defects in condyle formation. However, all these analyses as well as backscattered SEM results did not show any enamel defects in Dmpl mutant mice, which is different from the enamel defects in ARHR patients. These data suggested that the Dmpl mutant mice can recapture the human ARHR tooth phenotype, and the enamel defects in ARHR patients may be due to reasons other than DMP1 mutation.
3) Serum biochemistry:we also showed a mild increase of serum Fgf23 in the Dmpl mutant mice compared to the control. Similarly, the decrease in serum Pi level was also mild in all three age groups tested. The serum calcium level is largely unchanged in the Dmpl mutant mice. These data of Dmpl mutant mice were consistent with those in ARHR patients, but milder than those of Dmpl null mice.
In summary, Dmpl mutant mice recaptured the phenotype of the human ARHR patients in all 3 aspects mentioned above. However, the phenotype of Dmpl mutant mice is milder that that of Dmpl null mice, suggesting that the mutant DMP1 molecule maintained a partial function of this protein.
Successful generation and characterization of the DMP1 C-terminal mutant mice model will provide a foundation for studies on the mechanism in which DMP1 mutation causes ARHR, a powerful tool for studies of clinical therapy of this disease, and an important clue for the studies on other mutations of DMP1 gene.
DMPl基因的编码产物是一种酸性非胶原细胞外基质蛋白,属于SIBLING (Small Integrin-Binding LIgand N-linked Glycoprotein)家族成员。该家族成员不仅具有相似的生物学特性,而且在染色体上成簇排列。DMP1基因在人类染色体上位于4q21-22,在小鼠染色体上位于5q21。DMP1在骨骼和牙齿中表达较高,在多个非矿化的组织中也有表达,但表达水平较低。DMP1蛋白在翻译后被水解成两个片段：N末端的37 kDa大小的片段和C末端的57 kDa大小的片段,然而目前并不清楚哪一个片段在骨骼和牙齿发育过程中发挥更重要的作用。
Dmp1基因敲除小鼠在胚胎期和刚出生时没有明显的异常表型,提示Dmp1基因不是小鼠早期骨骼和牙齿发育所必需的。在出生后,Dmp1基因敲除小鼠表现出明显的牙齿发育异常,具体表现为前牙本质向牙本质成熟过程缺陷、牙髓腔和牙根管变大、前牙本质变宽、牙本质变窄并且矿化不全。Dmp1基因敲除小鼠还表现出第3磨牙的缺损或发育迟缓,以及牙周缺陷,包括牙槽骨疏松和牙骨质缺陷等。Dmp1基因敲除小鼠在骨骼方面表现出矿化程度降低、骨软化症和佝偻病等症状,具体表现为椎骨和长骨长度变短、直径变大、次级骨化中心发育迟缓和畸形、生长板变宽并且不规则(由于增殖区细胞增殖活性升高和肥大软骨细胞区细胞凋亡降低引起)和骨骺区变大(由于血管侵入受损引起)。Dmp1基因敲除小鼠同时伴有肾磷代谢异常和Fgf23含量升高,但是尿钙含量正常。本课题组曾在一个ARHR家系的患者中检测到DMP1基因第1484-1490位核苷酸纯合缺失,这7个碱基的缺失引起移码突变,使该蛋白C末端最后18个氨基酸残基被33个新的氨基酸残基取代,且被替代的18个氨基酸残基在种属间高度保守。本课题分析了该家系ARHR患者的牙齿表型,并分析了突变蛋白的体外功能。为进一步研究该DMP1突变的分子和病理生理学机制,我们制作了含有该突变的小鼠模型并对其进行了表型分析。
第一,分析DMP1 C末端缺失患者牙齿表型发现,患者具有明显的牙齿发育异常：对该家系患者的口腔X光片分析结果发现,患者的乳牙和恒牙都表现出明显的异常,包括牙髓腔和牙根管变大,牙本质变薄,牙釉质的缺损等。
第二,体外分析提示突变蛋白保留DMP1蛋白的部分功能：对比分析由DMP1基因突变导致的ARHR患者和Dmp1基因敲除小鼠表型特点发现,两者具有一些类似表型,如低血磷症等；但也存在一些差异。这些差异可能是由于人和小鼠之间的种属特异性造成的,也可能是由于突变的DMP1蛋白仍保留有部分功能。为明确C末端缺失突变对DMP1功能的影响及其致病机制,本课题首先在体外分析了该缺失突变对DMP1蛋白水解和分泌的影响,并分析了该突变对ERK磷酸化活性的影响。结果发现DMP1蛋白的C末端突变不影响该蛋白的正常分泌和水解,C末端突变的DMP1蛋白仍保留有部分的激活ERK信号通路的功能,表明突变蛋白没有完全丧失功能。
第三,构建了具有与ARHR患者相同突变的Dmp1突变小鼠模型：为分析DMP1C末端突变的致病机制,我们首先采用转基因方法构建了一种转基因小鼠,该转基因小鼠在3.6 kb Collal启动子的启动下表达含有与ARHR患者相同突变的全长Dmp1基因。我们成功得到了11只founder小鼠,并选取了其中3个独立的品系,用RT-PCR和原位杂交的方法对其进行了表达分析,转基因在骨骼和牙齿中的表达模式与内源性的Dmp1基因基本一致,表达量高于内源性的Dmp1基因。X光片结果显示,与对照小鼠相比,表达突变型Dmp1基因的转基因小鼠没有明显的骨骼和牙齿表型。在此基础上,我们将该转基因小鼠与Dmp1基因敲除小鼠杂交,获得了仅表达外源性突变型Dmp1基因而不表达内源性野生型Dmp1基因的小鼠,即Dmp1基因突变小鼠模型。
第四,Dmp1基因突变小鼠模型从骨骼、牙齿和生化指标等多方面再现了人类突变患者的表型特征：我们利用组织学、X光片、Micro-CT、扫描电子显微镜、双荧光标记和血清生化分析等技术系统全面地分析了Dmp1基因突变小鼠的表型,并与ARHR患者的症状和Dmp1基因敲除小鼠的表型进行比较。
1)骨骼表型：小鼠全身X光片和后肢X光片显示,Dmp1基因突变小鼠表现出佝偻病表型,包括股骨和胫骨长度变短,干垢端变大、生长板变宽和骨骼形态改变。定量分析结果显示,Dmp1基因突变小鼠的胫骨长度与正常对照相比变短,但是变短程度不如Dmp1基因敲除小鼠明显。骨骼石蜡切片的Safranin-O染色也进一步验证了佝偻病特征,生长板明显变宽,其中肥大软骨细胞层的变宽程度最大,静止层和增殖层也有一定程度的变宽。Goldner染色结果显示Dmp1基因突变小鼠骨皮质中含有非常多的类骨质,表现出骨骼矿化不全和骨软化症。双荧光标记实验显示骨骼矿化速率降低、矿化过程紊乱。扫描电子显微镜结果显示Dmp1基因突变小鼠的骨细胞lacuna-canalicular系统异常,骨细胞体积变大,表面粗糙,突触变短并且变少。这些异常的骨骼表型严重程度明显低于Dmp1基因敲除小鼠,但是与ARHR患者骨骼异常一致,表明Dmp1基因突变小鼠模型较好地模拟了人类突变的骨骼方面表型。
2)牙齿表型：小鼠牙齿的X光片和Micro-CT分析结果显示,Dmp1基因突变小鼠牙本质变薄,牙髓腔和牙根管体积变大,但是表型程度比Dmp1基因敲除小鼠要轻。牙齿切片的H&E染色结果也进一步验证了X光片和Micro-CT的分析结果,Dmp1基因突变小鼠的前牙本质变宽,而牙本质变窄。双荧光标记实验显示Dmp1基因突变小鼠牙本质矿化形成的速度明显变慢、牙本质矿化过程出现异常。此外,Dmp1基因突变小鼠还表现出下颌骨节发育异常。然而以上实验结果以及反向散射扫描电子显微镜结果都没有发现Dmp1基因突变小鼠中有任何的牙釉质缺陷,这一结果与ARHR患者的牙釉质缺陷症状不同。这些结果提示Dmp1基因突变小鼠模型较好地模拟了人类突变的牙本质方面表型,而ARHR患者中发现的牙釉质缺陷可能是由于DMP1基因突变之外的其他原因导致。
3)血清生化指标分析：Dmp1基因突变小鼠血清中Fgf23分子含量升高,磷的含量降低,但是改变程度较小；血清中钙的含量没有明显变化。这一结果与ARHR患者非常一致,但改变程度比Dmp1基因敲除小鼠的改变程度小很多。
综上所述,Dmp1基因突变小鼠在以上三方面再现了人类突变表型特征,但是与Dmp1基因敲除小鼠相比,该突变所引起的表型效应较轻,也提示该突变蛋白仍保留了部分功能。
Dmp1基因突变小鼠模型的成功构建不仅为研究该突变的致病机制及寻找该疾病治疗手段奠定了基础,而且也为研究DMP1基因的其它突变提供了重要参考。
Hypophosphatemic rickets (HR) is characterized by hypomineralization of bone, rickets and osteomalacia due to abnormal Pi reabsorption in renal tubules. The clinical features of HR include hypophosphatemia, phosphaturia, rickets and osteomalacia, with an incidence of 1 in 20,000 newborns. Hypophosphatemic rickets can be inherited in autosomal dominant, autosomal recessive, or X-linked pattern. X-linked hypophosphatemic rickets (XLHR, MIM 307800) is caused by mutation in the PHEX gene (phosphate regulating endopeptidase homolog, X-linked). Autosomal dominant hypophosphatemic rickets (ADHR, MIM 193100) is caused by mutation in the FGF23 gene (Fibroblast Growth Factor 23). Autosomal recessive hypophosphatemic rickets (ARHR, MIM 241520 and 613312) is caused by mutation in the DMP1 gene (Dentin Matrix Protein 1) or in the ENPP1 gene (ectonucleotide pyrophosphatase/phosphodiesterase 1). Hereditary hypophosphatemic rickets with hypercalciuria (HHRH, MIM 241530) is caused by mutation in the SLC34A3 gene (solute carrier family 34, member 3).
DMP1 gene encodes an acidic non-collagen extracellular matrix protein, a member of the SIBLING (Small Integrin-Binding LIgand N-linked Glycoprotein) family whose members share similar features in both biological properties and genomic structure. DMP1 gene was mapped to human chromosome 4q21-22 and mouse chromosome 5q21, respectively. DMP1 is highly expressed in bone and dentin, and lower expressed in non-mineralized tissues. DMP1 is cleaved into the 37 kDa N-terminal and the 57 kDa C-terminal fragments, but it is not clear which fragment is functionally critical for bone and tooth formation both in vivo and in vitro.
Dmpl null embryos and newborns display no apparent gross abnormal phenotype, suggesting that Dmpl is not essential for early mouse skeletal or dental development. Dmpl null mice postnatally developed a profound tooth phenotype characterized by partial failure of maturation of predentin into dentin, enlarged pulp chambers and root canals, increased width of predentin zone with reduced dentin wall, and hypomineralization. Dmpl null mice also showed absence or delayed development of the third molar and periodontal breakdown, including porous alveolar and defective cementum. Dmpl null mice manifested decreased bone mineralization and osteomalacia, as well as rickets, which was characterized by shorter and wider vertebrae and long bones, delayed and malformed secondary ossification centers, irregular and highly expanded growth plate (due to increased cell proliferation in proliferating zone and reduced apoptosis in the hypertrophic zone) and increased epiphyses area (due to impaired blood vessel invasion). The rickets and osteomalacia phenotypes of Dmpl null mice were associated with isolated renal phosphate-wasting, elevated Fgf23 levels and normal calciuria.
In the patients of one of our previously reported ARHR kindreds, a homozygous deletion of nucleotides 1484-1490 in DMP1 gene was detected. The deletion of the 7 nucleotides resulted in a frameshift that replaced the conserved C-terminal 18 residues with 33 novel residues. In the present study, we characterized the tooth phenotypes of the patients, and analyzed the function of mutant protein in vitro. To further understand the molecular and pathophysiologic mechanism of this DMP1 mutation, we generated and characterized a mouse model with this specific mutation.
Firstly, we examined the tooth phenotype of the patients with DMP1 C-terminal mutation, and found that the patients displayed obvious abnormalities during tooth development:the radiographs from the patient teeth (both primary and permanent teeth) showed significantly enlarged pulps and root canals with extremely thin dentin and loss of enamel.
Secondly, in vitro function assays suggested that the mutant protein maintained partial function of DMP1:ARHR patients with DMP1 mutation and Dmpl null mice share some common features, such as hypophosphatemia. However, minor differences exist between the mouse model and the human ARHR patients. These differences could be due to species-specificity of human versus mouse, or that the mutant DMP1 in human may maintain partial function of DMP1. To determine the function of the C-terminal mutant DMP1 and the mechanism in which it causes ARHR, we examined the cleavage and secretion of the C-terminal mutant DMP1, and its function on ERK phosphorylation. The C-terminal mutant DMP1 can be secreted and cleaved normally and maintained partial function on ERK phosphorylation. These data suggested that the mutant protein did not completely lose its function.
Thirdly, we genetated a mouse model harboring the human DMP1 1481-1490 deletion mutation. To study the mechanism in which DMP1 C-terminal mutation cause ARHR, we generated transgenic mice harboring the full-length Dmpl cDNA with the same deletion mutation as observed in ARHR patients under control of the 3.6 kb Collal promoter. Eleven founder mice were got and 3 independent lines were used for expression analyses by RT-PCR and in situ hybridization. The expression pattern of the transgene in bone and teeth is the same as endogenous Dmpl gene, and the expression level is higher than endogenous Dmpl gene. Radiographs showed that the transgenic mice expressing the mutant Dmpl gene did not show an apparent bone and teeth phenotype compared to the WT control mice. Then, these transgenic lines were crossed to Dmpl null mice, and the homozygous mice with Dmpl mutation but without endogenous Dmpl gene were obtained.
Fourthly, the Dmpl mutant mice recaptured the human ARHR patients' phenotypes, including bone, tooth and serum markers:The phenotypes of Dmpl mutant mice were characterized and compared with those of ARHR patients and Dmpl null mice using several assays including histology, radiography, Micro-CT, SEM, calcein/alizarin red double labeling, and serum biochemistry.
1) Bone phenotype:As showed in radiographs of the whole bodies and hind limbs, Dmpl mutant mice displayed rickets phenotype, including shorter femur and tibia, expanded metaphyses, enlarged growth plates and malformed bone shape. Quantitative analyses of tibia length confirmed that the long bones in Dmpl mutant mice are shorter compared to the control mice, but are not as severe as Dmpl null mice. Histological data of Safranin-O staining further confirmed the rickets phenotype such as striking expansion of the growth plate, including resting zone, proliferation zone and hypertrophic zone with the last one expanded most. Goldner assay showed abundant osteoid in the mineral of cortical bone in Dmpl mutant mice, a significant sign of hypo-mineralization and osteomalacia phenotype. Double fluorochrome labeling assay showed slow rate and disruption of bone mineralization in Dmpl mutant mice. Dmpl mutant mice also showed abnormalities in the osteocyte lacuna-canalicular system by SEM, such as enlarged size and buckled surface of the osteocytes, and fewer and shorter synapses. These phenotypes of Dmpl mutant mice were consistent with observations in samples from ARHR patients, but milder than those in Dmpl null mice, suggesting that the Dmpl mutant mice can recapture the human ARHR bone phenotype.
2) Tooth phenotype:Dmpl mutant mice showed thin dentin and enlarged pulp cavities and root canals with radiograph and Micro-CT analyses, but the phenotype is milder than that in Dmpl null mice. Histological data of H&E staining further confirmed the dentin phenotype in Dmpl mutant mice:the expanded predentin and the thin dentin. The double labeling assay also showed reduction of the dentin formation rate and diffused labeling lines in Dmpl mutant mice. Dmpl mutant mice also showed defects in condyle formation. However, all these analyses as well as backscattered SEM results did not show any enamel defects in Dmpl mutant mice, which is different from the enamel defects in ARHR patients. These data suggested that the Dmpl mutant mice can recapture the human ARHR tooth phenotype, and the enamel defects in ARHR patients may be due to reasons other than DMP1 mutation.
3) Serum biochemistry:we also showed a mild increase of serum Fgf23 in the Dmpl mutant mice compared to the control. Similarly, the decrease in serum Pi level was also mild in all three age groups tested. The serum calcium level is largely unchanged in the Dmpl mutant mice. These data of Dmpl mutant mice were consistent with those in ARHR patients, but milder than those of Dmpl null mice.
In summary, Dmpl mutant mice recaptured the phenotype of the human ARHR patients in all 3 aspects mentioned above. However, the phenotype of Dmpl mutant mice is milder that that of Dmpl null mice, suggesting that the mutant DMP1 molecule maintained a partial function of this protein.
Successful generation and characterization of the DMP1 C-terminal mutant mice model will provide a foundation for studies on the mechanism in which DMP1 mutation causes ARHR, a powerful tool for studies of clinical therapy of this disease, and an important clue for the studies on other mutations of DMP1 gene.
引文
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