吡格列酮对去卵巢大鼠IL-1β、IL-6、TNF-a的影响及与骨代谢关系的实验研究
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摘要
随着社会老龄化，骨质疏松症（Osteoporosis,OP）发病率呈上升趋势，当前我国50岁以上人口中有6940万人罹患骨质疏松症，而绝经后妇女骨质疏松症（postmenopausal osteoporosis，PMOP）占1/3以上，严重OP引起的骨痛、骨折造成患者生活质量的下降，给社会和家庭带来沉重的的负担。因此，深入研究PMOP的发生机制，为其预防及治疗提供新的思路及方法已成为迫切需要。
骨在整个生命过程都在不断的重建中,骨重建的过程就是破骨细胞吸收旧骨和成骨细胞形成新骨的过程,两者紧密偶联,在正常情况下保持动态平衡。当骨重建不平衡时,可导致许多代谢性骨病，如骨质疏松症（Osteoporosis,OP）、骨质硬化症、软骨病等的发生。OP在骨重建过程中骨量过多流失、骨组织微结构破坏，按转换率的不同可分为高转换型和低转换型。既往研究表明PMOP属于高转换型。
过氧化物酶体增殖物激活受体（Peroxisome proliferators activatedreceptor,PPARγ）是一组配体活化的转录因子,属于核受体超家族,广泛存在于人体内。近年来相关研究不断深入，发现PPARγ2在骨髓干细胞分化及骨代谢的过程中可能也起着关键的作用。研究表明PPARγ2的人工合成配体噻唑烷二酮类（TZDs）药物如罗格列酮、吡格列酮在降低胰岛素抵抗治疗糖尿病的同时能够增加PMOP的发生率。目前PPARγ2影响PMOP骨代谢及骨转换影响还不明确，国内外研究尚少。
绝经后女性由于体脂增加导致脂肪细胞分泌IL-1β、IL-6、TNF-a增加，同时雌激素下降导致骨髓单核细胞分泌IL-1β、TNF-a和间质细胞分泌IL-6增多，可能为引发糖脂代谢紊乱及胰岛素抵抗的机制之一；而IL-1β、IL-6、TNF-a作为破骨细胞最强的刺激因子，在绝经后可明显加速骨吸收，成为PMOP发生的原因之一。吡格列酮激活PPARγ2可能通过抑制IL-1β、IL-6、TNF-a途径降低胰岛素抵抗，从而也可间接抑制破骨细胞活性起到骨保护作用。本实验拟观察不同浓度吡格列酮激活PPARγ2对去卵巢大鼠骨形成指标及细胞因子水平的影响，为进一步探讨PMOP的发生机制提供新思路。
目的：通过观察不同浓度的吡格列酮对假手术组及去卵巢组大鼠体脂、骨密度、骨形态计量参数及成骨细胞标志基因骨碱性磷酸酶（BALP）、骨钙素（OCN）、破骨细胞刺激因子IL-1β、IL-6、TNF-a表达水平的影响，探讨TZDs应用在绝经后个体引起骨量改变的可能机制。
方法：选取144只3月龄雌性Wistar大鼠，随机分为去卵巢（OXV）组和假手术(sham)组，每组分别予生理盐水、低剂量吡格列酮组（4mg/kg.d）、高剂量吡格列酮组（20mg/kg.d）灌胃给药，于0周、吡格列酮干预4周、8周及12周时处死留取标本，采用葡萄糖氧化酶法测定全血空腹血糖（FPG），血生化分析仪测定血清血脂、Ca、P、ALP，放射酶联免疫法测定血清胰岛素(FNS)、E2及睾酮、骨髓上清液OCN，ELISA法检测骨髓上清液细胞因子IL-1β、IL-6、TNF-a、BALP，RT-PCR法检测骨髓细胞PPARγ2mRNA表达，DPX双能X线骨密度扫描仪判定股骨干骺端骨量变化，脱钙腰椎骨病理切片染色观察骨形态学变化。
结果：
1.去卵巢组大鼠与假手术组比较，体重、TG、CHO、LDLC、血ALP、FNS、HOMA-IR、OCN、BALP、PPARγ2、IL-1β、IL-6、TNF-α均升高，E2、HDLC、BMD下降，差异有统计学意义（P＜0.01）。
2.不同浓度吡格列酮不同时间干预后去卵巢组PPARγ2、OCN、IL-1β、IL-6、TNF-α比较差异有统计学意义（P＜0.01），呈时间剂量依赖性上升；不同时间吡格列酮干预后BALP比较差异有统计学意义（P＜0.01），呈时间依赖性下降。
3.吡格列酮20mg/kg·d干预后骨密度明显下降（P＜0.01），且呈时间依赖
4.去卵巢组松质骨骨小梁变细、断裂、数量减少，假手术组骨小梁规则无明显变化，随吡格列酮干预后两组骨小梁不同程度破坏但去卵巢组更为严重。
结论：
1.去卵巢大鼠体重、血脂明显增高，胰岛素水平及胰岛素抵抗指数升高；细胞因子IL-1β、IL-6、TNF-a分泌增多促进破骨细胞分化、增殖，加速骨吸收。
2.吡格列酮激活PPARγ2转录活性上调PPARγ2表达，降低成骨细胞标志基因OCN、BALP抑制成骨过程；同时抑制破骨细胞刺激因子IL-1β、IL-6、TNF-a表达，降低PMOP高转换率，但总体上加重PMOP发生风险。
The incidence of Osteoporosis (OP) has increased obviously with the aging ofsociety ,69400000 people over the age of 50 suffering from OP in our country,andOP in postmenopausal women (postmenopausal osteoporosis ,PMOP) account for1/3,which will bring bone pain and fracture for patients and heavy burden for socialand family.Therefore,it has become an urgent need to study the mechanism ofPMOP .
The bone is continuously being remodeled following two opposite andcoordinated processes.Under normal conditions, specialized cells called osteoclaststransiently break down old bone (resorption process) at multiple sites as other cellsknown as osteoblasts are replacing it with new tissue (bone formation);otherwise,when the bone remodeling is imbalanced,it can lead to many metabolicbone diseases,such as OP,bone sclerosis,rickets.OP results in bone excessive loss andbone tissue microstructure damage.It is known OP could be divided into high andlow conversion type according to the conversion rate,and previous study showed thatPMOP belong to high conversion type.
Peroxisome proliferators-activated receptor (PPARγ) is a group of ligandactivated transcription factor,widely exist in the human body,belonging to the nuclearreceptor superfamily. The view that the effect of PPARγ2 on the differentiation ofbone marrow stem cells and bone metabolism is reported differently by theresearch .Research shows that thiazolidine two ketone (TZDs)–as the synthetic ligandof PPARγ2,such as rosiglitazone,pioglitazone,can reduce insulin resistance in diabetestreatment,also increase the incidence rate of PMOP. Howerer, there is little researchabout the effect of PPARγon bone metabolism and bone turnover of PMOP at homeand abroad.
For postmenopausal women with body fat increased ,fat cells and bonemarrow mononuclear cells secrete more Interleukin 1 beta (IL-1β), Interleukin 6(IL-6),tumor necrosis factor alpha (TNF-α), which may be a reason for triggering aglycolipid metabolism disorder and insulin resistance.As OC strongest factor , IL-1β、IL-6、TNF-a, can accelerate bone resorption,become a resson forPMOP.Pioglitazone–activated PPARγ2 can reduce insulin resistance through inhibition of IL-1β、IL-6、TNF-a,which may also indirectly inhibit OC activity .Thepurpose of our study is to observe the effect of pioglitazone on bone formationmarkers and cytokine levels of ovariectomized rats,to provide new ideas for exploringthe mechamism of PMOP.
Objective:To observe the effect of pioglitazone on fat ,bone density andhistomorphomertry,expression of bone formation marker bone alkaline phosphatase(BALP),osteocalcin (OCN) and OC stimulating factor IL-1β、IL-6、TNF-a andmRNA expression of PPARγ2 of ovariectomized and sham operation rats,andinvestigate the possible mechanism of postmenopausal bone mass changes caused byTZDs.
Methods:The PMOP rat models were established by removal of ovaries,the ratswere randomly assigned to ovariectomized group, ovariectomized added low dose ofpioglitazone (4mg/kg﹒d) and high dose of pioglitazone (20mg/kg﹒d) group,shamoperation group, sham operation added low dose of pioglitazone (4mg/kg﹒d) andhigh dose of pioglitazone (20mg/kg﹒d) group.Then all rats were killed bybloodletting of abdominal artery at different time,to examine the contence of serumlipids,Ca,P,Insulin,E2and the activites of bone formation makers BALP,OCN, IL-1β、IL-6、TNF-a and mRNA expression of PPARγ2 of bone marrow supernatant,and bonedensity and histomorphometry.
Results:
1 Compared with the sham operation group,body weight,TG,CHO,LDL-C,ALP,FNS,HOMA-IR,OCN,BALP, PPARγ2,IL-1β,IL-6、TNF-a were increased,butHDL-C, E2were decreased for ovariectomized rats.Statistical significance was foundin interclass comparison (P＜0.01).
2 The result showed that pioglitazone up-regulated the mRNA expression ofPPARγ2,and increased the level of OCN, IL-1β、IL-6、TNF-a for ovariectomized ratsin a time and dose–dependent manner, Statistical significance was found in interclasscomparison (P＜0.01);while it increased the level of BALP for ovariectmized rats in atime–dependent manner,statistical significance was found in interclass comparison (P＜0.01).
3 The high dose of pioglitazone decreased bone mineral density significantly ina time-dependent manner. statistical significance was found in interclass comparison(P＜0.01).
4 The result also showed that bone trabeculars had been thinning,fracture and the number of them had reduced for ovariectmized rats,but for sham operation ratsthere were no changes.With the intervention of pioglitazone, bone trabeculars weredamaged from all the groups,but they were more serious from ovariectomized groups.
Conclusions:
1 Body weight,blood lipid,insulin and insulin resistance index wereincreased;IL-1β、IL-6、TNF-a secretion promoted OC differentiation,proliferationand accelerated bone resorption.
2 Pioglitazone activated the transcription activity and promoted the expressionof PPARγ2, reduced the level of BALP and OCN and suppressed bone formation;while inhibited IL-1β、IL-6、TNF-a expression,decreased high conversion rate ofPMOP.Howere,it may increase the risk of PMOP.
骨在整个生命过程都在不断的重建中,骨重建的过程就是破骨细胞吸收旧骨和成骨细胞形成新骨的过程,两者紧密偶联,在正常情况下保持动态平衡。当骨重建不平衡时,可导致许多代谢性骨病，如骨质疏松症（Osteoporosis,OP）、骨质硬化症、软骨病等的发生。OP在骨重建过程中骨量过多流失、骨组织微结构破坏，按转换率的不同可分为高转换型和低转换型。既往研究表明PMOP属于高转换型。
过氧化物酶体增殖物激活受体（Peroxisome proliferators activatedreceptor,PPARγ）是一组配体活化的转录因子,属于核受体超家族,广泛存在于人体内。近年来相关研究不断深入，发现PPARγ2在骨髓干细胞分化及骨代谢的过程中可能也起着关键的作用。研究表明PPARγ2的人工合成配体噻唑烷二酮类（TZDs）药物如罗格列酮、吡格列酮在降低胰岛素抵抗治疗糖尿病的同时能够增加PMOP的发生率。目前PPARγ2影响PMOP骨代谢及骨转换影响还不明确，国内外研究尚少。
绝经后女性由于体脂增加导致脂肪细胞分泌IL-1β、IL-6、TNF-a增加，同时雌激素下降导致骨髓单核细胞分泌IL-1β、TNF-a和间质细胞分泌IL-6增多，可能为引发糖脂代谢紊乱及胰岛素抵抗的机制之一；而IL-1β、IL-6、TNF-a作为破骨细胞最强的刺激因子，在绝经后可明显加速骨吸收，成为PMOP发生的原因之一。吡格列酮激活PPARγ2可能通过抑制IL-1β、IL-6、TNF-a途径降低胰岛素抵抗，从而也可间接抑制破骨细胞活性起到骨保护作用。本实验拟观察不同浓度吡格列酮激活PPARγ2对去卵巢大鼠骨形成指标及细胞因子水平的影响，为进一步探讨PMOP的发生机制提供新思路。
目的：通过观察不同浓度的吡格列酮对假手术组及去卵巢组大鼠体脂、骨密度、骨形态计量参数及成骨细胞标志基因骨碱性磷酸酶（BALP）、骨钙素（OCN）、破骨细胞刺激因子IL-1β、IL-6、TNF-a表达水平的影响，探讨TZDs应用在绝经后个体引起骨量改变的可能机制。
方法：选取144只3月龄雌性Wistar大鼠，随机分为去卵巢（OXV）组和假手术(sham)组，每组分别予生理盐水、低剂量吡格列酮组（4mg/kg.d）、高剂量吡格列酮组（20mg/kg.d）灌胃给药，于0周、吡格列酮干预4周、8周及12周时处死留取标本，采用葡萄糖氧化酶法测定全血空腹血糖（FPG），血生化分析仪测定血清血脂、Ca、P、ALP，放射酶联免疫法测定血清胰岛素(FNS)、E2及睾酮、骨髓上清液OCN，ELISA法检测骨髓上清液细胞因子IL-1β、IL-6、TNF-a、BALP，RT-PCR法检测骨髓细胞PPARγ2mRNA表达，DPX双能X线骨密度扫描仪判定股骨干骺端骨量变化，脱钙腰椎骨病理切片染色观察骨形态学变化。
结果：
1.去卵巢组大鼠与假手术组比较，体重、TG、CHO、LDLC、血ALP、FNS、HOMA-IR、OCN、BALP、PPARγ2、IL-1β、IL-6、TNF-α均升高，E2、HDLC、BMD下降，差异有统计学意义（P＜0.01）。
2.不同浓度吡格列酮不同时间干预后去卵巢组PPARγ2、OCN、IL-1β、IL-6、TNF-α比较差异有统计学意义（P＜0.01），呈时间剂量依赖性上升；不同时间吡格列酮干预后BALP比较差异有统计学意义（P＜0.01），呈时间依赖性下降。
3.吡格列酮20mg/kg·d干预后骨密度明显下降（P＜0.01），且呈时间依赖
4.去卵巢组松质骨骨小梁变细、断裂、数量减少，假手术组骨小梁规则无明显变化，随吡格列酮干预后两组骨小梁不同程度破坏但去卵巢组更为严重。
结论：
1.去卵巢大鼠体重、血脂明显增高，胰岛素水平及胰岛素抵抗指数升高；细胞因子IL-1β、IL-6、TNF-a分泌增多促进破骨细胞分化、增殖，加速骨吸收。
2.吡格列酮激活PPARγ2转录活性上调PPARγ2表达，降低成骨细胞标志基因OCN、BALP抑制成骨过程；同时抑制破骨细胞刺激因子IL-1β、IL-6、TNF-a表达，降低PMOP高转换率，但总体上加重PMOP发生风险。
The incidence of Osteoporosis (OP) has increased obviously with the aging ofsociety ,69400000 people over the age of 50 suffering from OP in our country,andOP in postmenopausal women (postmenopausal osteoporosis ,PMOP) account for1/3,which will bring bone pain and fracture for patients and heavy burden for socialand family.Therefore,it has become an urgent need to study the mechanism ofPMOP .
The bone is continuously being remodeled following two opposite andcoordinated processes.Under normal conditions, specialized cells called osteoclaststransiently break down old bone (resorption process) at multiple sites as other cellsknown as osteoblasts are replacing it with new tissue (bone formation);otherwise,when the bone remodeling is imbalanced,it can lead to many metabolicbone diseases,such as OP,bone sclerosis,rickets.OP results in bone excessive loss andbone tissue microstructure damage.It is known OP could be divided into high andlow conversion type according to the conversion rate,and previous study showed thatPMOP belong to high conversion type.
Peroxisome proliferators-activated receptor (PPARγ) is a group of ligandactivated transcription factor,widely exist in the human body,belonging to the nuclearreceptor superfamily. The view that the effect of PPARγ2 on the differentiation ofbone marrow stem cells and bone metabolism is reported differently by theresearch .Research shows that thiazolidine two ketone (TZDs)–as the synthetic ligandof PPARγ2,such as rosiglitazone,pioglitazone,can reduce insulin resistance in diabetestreatment,also increase the incidence rate of PMOP. Howerer, there is little researchabout the effect of PPARγon bone metabolism and bone turnover of PMOP at homeand abroad.
For postmenopausal women with body fat increased ,fat cells and bonemarrow mononuclear cells secrete more Interleukin 1 beta (IL-1β), Interleukin 6(IL-6),tumor necrosis factor alpha (TNF-α), which may be a reason for triggering aglycolipid metabolism disorder and insulin resistance.As OC strongest factor , IL-1β、IL-6、TNF-a, can accelerate bone resorption,become a resson forPMOP.Pioglitazone–activated PPARγ2 can reduce insulin resistance through inhibition of IL-1β、IL-6、TNF-a,which may also indirectly inhibit OC activity .Thepurpose of our study is to observe the effect of pioglitazone on bone formationmarkers and cytokine levels of ovariectomized rats,to provide new ideas for exploringthe mechamism of PMOP.
Objective:To observe the effect of pioglitazone on fat ,bone density andhistomorphomertry,expression of bone formation marker bone alkaline phosphatase(BALP),osteocalcin (OCN) and OC stimulating factor IL-1β、IL-6、TNF-a andmRNA expression of PPARγ2 of ovariectomized and sham operation rats,andinvestigate the possible mechanism of postmenopausal bone mass changes caused byTZDs.
Methods:The PMOP rat models were established by removal of ovaries,the ratswere randomly assigned to ovariectomized group, ovariectomized added low dose ofpioglitazone (4mg/kg﹒d) and high dose of pioglitazone (20mg/kg﹒d) group,shamoperation group, sham operation added low dose of pioglitazone (4mg/kg﹒d) andhigh dose of pioglitazone (20mg/kg﹒d) group.Then all rats were killed bybloodletting of abdominal artery at different time,to examine the contence of serumlipids,Ca,P,Insulin,E2and the activites of bone formation makers BALP,OCN, IL-1β、IL-6、TNF-a and mRNA expression of PPARγ2 of bone marrow supernatant,and bonedensity and histomorphometry.
Results:
1 Compared with the sham operation group,body weight,TG,CHO,LDL-C,ALP,FNS,HOMA-IR,OCN,BALP, PPARγ2,IL-1β,IL-6、TNF-a were increased,butHDL-C, E2were decreased for ovariectomized rats.Statistical significance was foundin interclass comparison (P＜0.01).
2 The result showed that pioglitazone up-regulated the mRNA expression ofPPARγ2,and increased the level of OCN, IL-1β、IL-6、TNF-a for ovariectomized ratsin a time and dose–dependent manner, Statistical significance was found in interclasscomparison (P＜0.01);while it increased the level of BALP for ovariectmized rats in atime–dependent manner,statistical significance was found in interclass comparison (P＜0.01).
3 The high dose of pioglitazone decreased bone mineral density significantly ina time-dependent manner. statistical significance was found in interclass comparison(P＜0.01).
4 The result also showed that bone trabeculars had been thinning,fracture and the number of them had reduced for ovariectmized rats,but for sham operation ratsthere were no changes.With the intervention of pioglitazone, bone trabeculars weredamaged from all the groups,but they were more serious from ovariectomized groups.
Conclusions:
1 Body weight,blood lipid,insulin and insulin resistance index wereincreased;IL-1β、IL-6、TNF-a secretion promoted OC differentiation,proliferationand accelerated bone resorption.
2 Pioglitazone activated the transcription activity and promoted the expressionof PPARγ2, reduced the level of BALP and OCN and suppressed bone formation;while inhibited IL-1β、IL-6、TNF-a expression,decreased high conversion rate ofPMOP.Howere,it may increase the risk of PMOP.
引文
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[18] Peng S, Zhang G, He Y，et al. Epimedium-derived flavonoids promoteosteoblastogenesis and suppress adipogenesis in bone marrow stromal cellswhile exerting an anabolic effect on osteoporotic bone. Bone.2009,45(3):534-544.
[19] Chen Y, Wang S, Bu S, Wang Y, et al. Treadmill training prevents bone loss byinhibition of PPARγexpression but not promoting of Runx2 expression inovariectomized rats. Eur J Appl Physiol. 2011 ,111(8):1759-1767.
[20] Lubahn DB,Moyer JS,Golding TS,et al.Alteration of reproductive function butnot prenatal sexual development afer insertion disruption of the mouse estrogenreceptor gene.Proc.Natl.Acad.Sci.USA 1993,90,11162-11166.
[21]何兢，雷涛.肥胖对骨质疏松影响的研究进展.同济大学学报.2010,31（6）：116-118.
[22] Llaneza P,Ifiarrea J,Gonzalez C,et al.Differences in health related quality of lifein a sample of Spanish menopausal women with and withoutobesity.Maturitas.2007,58(4):387-394
[23] Zhao LJ，Jiang H，Papsian CJ，et al.Correlation of obesity and osteoporosis:Effect of fat mass on the determination of osteoPorosis.J bone and minerres.2008，23:17-29.
[24] Zhao LJ，Liu YJ，Liu PY，et al.RelationshiP of obesity with osteoporosis. J ClinEndoerinol Metab.2007，92:1640-1646.
[25] Tremollieres FA，Pouilles JM，Ribot C.Vertebral postmenopausal bone loss isredueed in overweight women:a longitudinal study in 155 earlypostmenopausal women.[J}.Clin Endocrinol Metab.1993,77(3):683-686.
[26] Homtamisligigl GS, Amer P, Caro JF, et al. Increasedadipose tissue expressionof tumor necrosis factor in human obesity andinsulinresistance.ClinInvest.1995;95:2409.
[27] Fernandez-Real JM,Ricart W.Insulin resisitance and chronic cardiovascularinflammatory syndrome.Endocr Rev.2003,24(3):278-301.
[28] Fain JN,Madam AK,Hiler ML,et al.Comparison of the release of adipokine byadipose tissue,adipose tissue matrix,and adipocytes from visceral andsubcutaneous abdominal adipose tissues of obesehumans.Endocrinology.2004,145(5):2273-2282.
[29] Burgess A, Li M, Vanella L,et al. Adipocyte heme oxygenase-1 inductionattenuates metabolic syndrome in both male and female obese mice.Hypertension. 2010,56(6):1124-1130.
[30] Halade GV, Jamali A, Williams PJ,et al. Obesity-mediated inflammatorymicroenvironment stimulates osteoclastogenesis and bone loss in mice.Gerontol. 2011,46(1):43-52.
[31] Turner RT,Backup P,Sherman PJ,et al.Machism of action of estrogen onintramembranous bone formation:Regulation of osteoblast differentiation andactivity.Endocrinology.1992,131:883-889.
[32] Westerlind KC,Wakley GK,Evans GL,et al.Estrogen does not increase bonefoemation in growing rats.Endocrinology.1993,133:2924-2934.
[33] Kwantat S,Padrines M,Thedeyre S,et al. IL-6,RANKL,TNF-α/IL-1β:interrelations in bone resorption pathophysiology [J].Cytokine GrowthFactor.2004,15(1):49-53.
[34] Scheidt-Nave C, Bismar H, Leidig-Bruckner G, et al. Serum interleukin 6 is amajor predictor of bone loss in women specific to the first decade pastmenopause[J]. JClin Endocrinol Metab. 2001, 86(5):2032-2042.
[35] Ralston SH .Analysis of gene expression in human bone biopsies bypolymerasechain reaction: evidence for enhanced cytokine expression inpostmenopausal osteoporosis[J]. J Bone Miner Res.1994, 9(6):883–890.
[36] Feng D, Ishibashi H, Yamamoto S, et al.Association between bone loss andpromoter polymorphism in the IL-6 gene in elderly Japanese women with hipfracture[J]. J Bone Miner Metab. 2003, 21(4):225-228.
[37] Nakamura M, Udagawa N, Matsuura S, et a1. Osteoprotogerin regulates boneformation through a coupling mechanism with bone resorqtion[J].Endocrinology.2003; 144(12):5441-5449.
[38] D’Amelio P, Grimaldi A, Di Bella S, et al. Estrogen deficiency increasesosteolcastogenesis up-regulating T cells activity: a key mechanism inosteoporosis.Bone.2008; 43:92–100.
[39] Girasole G, Jilka RL,Passeri G ,et al. 17 beta-estradiol inhibits interleukin-6production by bone marrow -derived stromal cells and osteoblasts in vitro ; apotential mechanism for the antiosteoporotic effect of estrogens[J]. J ClinInvest.1992, 89(3): 883-891.
[40] Waki Y,Nomua M,Kasugis S,et al. Walker 256/scarcinosarcoma causesosteoporosis-like changes through ectopical secreation of luteinizinghormone-releasing hormone[J]. Cancer Res.1999, 59(6): 1219-1224.
[41] Pivirotto LA, Cissel DS, Keeting PE. Sex hormones mediated interleukin-1beta production by human osteoblastic HOBIT cells [J]. Mol CellEndocrinol.1995,111(1): 67-74.
[42] Kobayashi K, Takahashi N, Jimi E,etal. Tumor necrosis factor alpha stimulatesosteoblast differentiation by a mechanism independent of theODF/RANKL-RANK interaction[J]. J Exp Med. 2000, 191(2): 275-86.
[43] Hofbauer LC, Lacey DL, Dunstan CR, et al. Interleukin-1βand tumor necrosisfactor-α, but not IL-6 stimulate osteoprotegerin ligand gene expressiom inhuman osteoblastic cells[J]. Bone.1999;25(3) : 255-259.
[44] Ammann P,Rizzoli R,Bonjor J,et al . Transgenic mice expressing soluble tumornecrosis factor-receptor are protected against bone less caused by estrogendeficiency[J]. J Clin Invest. 1997, 99(7):1699-1703.
[45] Kimble RB, Bain S, Pacifici R. The functional block of TNF but not of IL-6prevents bone loss in ovariectomized mice [J]. J Bone Miner Res.1997,12(6):935-41.
[46] Hube F, Hauner H. Therole of TNF-alpha in human adipose tissue: preventionof weight gainat theexpenseof insulin resistance?HormMetab Res. 1999, 31:626-631.
[47] lefsky JM. Treatment of insulin resistance with peroxisomeproliferator-activated receptor gamma agonists. J Clin Invest.000, 106:467-472.
[48] Burant CF,Sreenan S, Hirano K,et al. Troglitazoneaction isindependent ofadipose tissue.J Clin Invest.1997, 100: 2900-2906.
[49] Ogawa S，Urano T，Hosoi T，et al.Association of bone mineral density with apolymorphism of the peroxisome proliferator -activated receptor gamma gene：PPARgamma expression in osteoblasts.Biochem Biophys Res Commun.1999，260：122-126.
[50] Rhee EJ，Oh KW，Lee WY，et al.The effects of C161→T polymorphisms inexon 6 of peroxisome proliferator-activated receptor-gamma gene on bonemineral metabolism and serum osteoprotegerin levels in healthy middle-agedwomen.Am J Obstet Gynecol.2005，192：1087-1093.
[51] Strotmeyer ES,Cauley B. Diabetes mellitus bonemineral density and fracturerisk. Curr Opin Endocrinol DiabetesObes.2007,14(6):429–435.
[52]杨金奎.ADOPT研究的最新结果[ J].国际内分泌代谢杂志.2007, 27(1): 1-3.
[53] Soroceanu MA, Miao D, Bai XY, et al. Rosiglitazone impacts negatively onbone by promoting osteoblast/osteocyte apoptosis. Endocrinology.2004, 183(1):203-216.
[54] Akune T,Ohba S,Kamekura S,et al. PPAR gamma insufficiency enhanceosteogensis through osteoblast formation from bone marrow progenitors.ClinInvest.2004,113(6):846-855.
[55] Kelly K ,Tanaka S,Baron R,et al.Murine bone marrow stromally derived BMS2adipocytes support differentiation and function of osteoclast-like cells invitro.Endocrinology.1998,139（4）:2092-2101.
[56] Wan Y,Ohizumi H,Fujitani Y,et al. PPAR gamma regulates osteoclastogenesisin mice.Nat Med.2007,13(12):1496-1503.
[1] IOF.Epidemiology,cost and burden of osteoporsis in Asia 2009.
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[8] Rosen ED,Sarraf P,Troy AE, et al. PPAR gamma is required for thedifferentiation of adipose tissue in vivo and in vitro. Mol Cell,1999,4(4):611–617.
[9] Akune, T. et al. (2004) PPARgamma insufficiency enhances osteogenesisthrough osteoblast formation from bone marrow progenitors. J. Clin. Invest.113, 846–855.
[10] Barak Y,Nelson MC,Ong ES, et al. PPAR gamma is required for placental,cardiac, and adipose tissue development. Mol. Cell,1999, 4(4):585–595.
[11] Li X, Cui Q, Kao C, et al. Lovastatin inhibits adipogenic and stimulatesosteogenic differentiation by suppressing PPARγ2 and increasing Cbfa1/Runx 2expression in bone marrowmesenchymel cell cultures.Bone,2003,33:652-659.
[12] Akune T,Ohba S,Kamekura S,et al. PPAR gamma insufficiency enhanceosteogensis through osteoblast formation from bone marrow progenitors.J ClinInvest.2004,113(6):846-855.
[13] Kelly K ,Tanaka S,Baron R,et al.Murine bone marrow stromally derived BMS2adipocytes support differentiation and function of osteoclast-like cells invitro.Endocrinology,1998,139（4）:2092-2101.
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[4] Sun YR,Yang Z. Advances of nuclear translation factor:peroxisomeproliferator-actived receptor-γ2. Hereditas.2003, 25(6): 713-717.
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[6] Rosen ED,Sarraf P,Troy AE, et al. PPAR gamma is required for thedifferentiation of adipose tissue in vivo and in vitro. Mol Cell.1999,4(4):611–617.
[7] Li X, Cui Q, Kao C, et al. Lovastatin inhibits adipogenic and stimulatesosteogenic differentiation by suppressing PPARγ2 and increasing Cbfa1/Runx2 expression in bone marrowmesenchymel cellcultures.Bone.2003,33:652-659.
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[13] Rhee EJ,Oh KW,Lee WY,et al.The effects of C161→T polymorphisms inexon6 of Peroxisome proliferator-activated receptor-gamma gene on bonemineral metabolism and serum osteoprotegerin levels in healthy middle-agedwomen.Am J Obstet Gynecol.2005,192:1087-1093.
[14]朱亦堃，李丽婷，郗光霞等PPARγ2内源性配体对成骨细胞骨代谢相关基因表达的影响.中华内内米代谢杂志.2012，28（3）：53-57.
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[17] Martin RB．Fatigue microdamage as an essential element of bone mechanicsand biology．CalcifTissue Int.2003，73:101-107．
[18] Peng S, Zhang G, He Y，et al. Epimedium-derived flavonoids promoteosteoblastogenesis and suppress adipogenesis in bone marrow stromal cellswhile exerting an anabolic effect on osteoporotic bone. Bone.2009,45(3):534-544.
[19] Chen Y, Wang S, Bu S, Wang Y, et al. Treadmill training prevents bone loss byinhibition of PPARγexpression but not promoting of Runx2 expression inovariectomized rats. Eur J Appl Physiol. 2011 ,111(8):1759-1767.
[20] Lubahn DB,Moyer JS,Golding TS,et al.Alteration of reproductive function butnot prenatal sexual development afer insertion disruption of the mouse estrogenreceptor gene.Proc.Natl.Acad.Sci.USA 1993,90,11162-11166.
[21]何兢，雷涛.肥胖对骨质疏松影响的研究进展.同济大学学报.2010,31（6）：116-118.
[22] Llaneza P,Ifiarrea J,Gonzalez C,et al.Differences in health related quality of lifein a sample of Spanish menopausal women with and withoutobesity.Maturitas.2007,58(4):387-394
[23] Zhao LJ，Jiang H，Papsian CJ，et al.Correlation of obesity and osteoporosis:Effect of fat mass on the determination of osteoPorosis.J bone and minerres.2008，23:17-29.
[24] Zhao LJ，Liu YJ，Liu PY，et al.RelationshiP of obesity with osteoporosis. J ClinEndoerinol Metab.2007，92:1640-1646.
[25] Tremollieres FA，Pouilles JM，Ribot C.Vertebral postmenopausal bone loss isredueed in overweight women:a longitudinal study in 155 earlypostmenopausal women.[J}.Clin Endocrinol Metab.1993,77(3):683-686.
[26] Homtamisligigl GS, Amer P, Caro JF, et al. Increasedadipose tissue expressionof tumor necrosis factor in human obesity andinsulinresistance.ClinInvest.1995;95:2409.
[27] Fernandez-Real JM,Ricart W.Insulin resisitance and chronic cardiovascularinflammatory syndrome.Endocr Rev.2003,24(3):278-301.
[28] Fain JN,Madam AK,Hiler ML,et al.Comparison of the release of adipokine byadipose tissue,adipose tissue matrix,and adipocytes from visceral andsubcutaneous abdominal adipose tissues of obesehumans.Endocrinology.2004,145(5):2273-2282.
[29] Burgess A, Li M, Vanella L,et al. Adipocyte heme oxygenase-1 inductionattenuates metabolic syndrome in both male and female obese mice.Hypertension. 2010,56(6):1124-1130.
[30] Halade GV, Jamali A, Williams PJ,et al. Obesity-mediated inflammatorymicroenvironment stimulates osteoclastogenesis and bone loss in mice.Gerontol. 2011,46(1):43-52.
[31] Turner RT,Backup P,Sherman PJ,et al.Machism of action of estrogen onintramembranous bone formation:Regulation of osteoblast differentiation andactivity.Endocrinology.1992,131:883-889.
[32] Westerlind KC,Wakley GK,Evans GL,et al.Estrogen does not increase bonefoemation in growing rats.Endocrinology.1993,133:2924-2934.
[33] Kwantat S,Padrines M,Thedeyre S,et al. IL-6,RANKL,TNF-α/IL-1β:interrelations in bone resorption pathophysiology [J].Cytokine GrowthFactor.2004,15(1):49-53.
[34] Scheidt-Nave C, Bismar H, Leidig-Bruckner G, et al. Serum interleukin 6 is amajor predictor of bone loss in women specific to the first decade pastmenopause[J]. JClin Endocrinol Metab. 2001, 86(5):2032-2042.
[35] Ralston SH .Analysis of gene expression in human bone biopsies bypolymerasechain reaction: evidence for enhanced cytokine expression inpostmenopausal osteoporosis[J]. J Bone Miner Res.1994, 9(6):883–890.
[36] Feng D, Ishibashi H, Yamamoto S, et al.Association between bone loss andpromoter polymorphism in the IL-6 gene in elderly Japanese women with hipfracture[J]. J Bone Miner Metab. 2003, 21(4):225-228.
[37] Nakamura M, Udagawa N, Matsuura S, et a1. Osteoprotogerin regulates boneformation through a coupling mechanism with bone resorqtion[J].Endocrinology.2003; 144(12):5441-5449.
[38] D’Amelio P, Grimaldi A, Di Bella S, et al. Estrogen deficiency increasesosteolcastogenesis up-regulating T cells activity: a key mechanism inosteoporosis.Bone.2008; 43:92–100.
[39] Girasole G, Jilka RL,Passeri G ,et al. 17 beta-estradiol inhibits interleukin-6production by bone marrow -derived stromal cells and osteoblasts in vitro ; apotential mechanism for the antiosteoporotic effect of estrogens[J]. J ClinInvest.1992, 89(3): 883-891.
[40] Waki Y,Nomua M,Kasugis S,et al. Walker 256/scarcinosarcoma causesosteoporosis-like changes through ectopical secreation of luteinizinghormone-releasing hormone[J]. Cancer Res.1999, 59(6): 1219-1224.
[41] Pivirotto LA, Cissel DS, Keeting PE. Sex hormones mediated interleukin-1beta production by human osteoblastic HOBIT cells [J]. Mol CellEndocrinol.1995,111(1): 67-74.
[42] Kobayashi K, Takahashi N, Jimi E,etal. Tumor necrosis factor alpha stimulatesosteoblast differentiation by a mechanism independent of theODF/RANKL-RANK interaction[J]. J Exp Med. 2000, 191(2): 275-86.
[43] Hofbauer LC, Lacey DL, Dunstan CR, et al. Interleukin-1βand tumor necrosisfactor-α, but not IL-6 stimulate osteoprotegerin ligand gene expressiom inhuman osteoblastic cells[J]. Bone.1999;25(3) : 255-259.
[44] Ammann P,Rizzoli R,Bonjor J,et al . Transgenic mice expressing soluble tumornecrosis factor-receptor are protected against bone less caused by estrogendeficiency[J]. J Clin Invest. 1997, 99(7):1699-1703.
[45] Kimble RB, Bain S, Pacifici R. The functional block of TNF but not of IL-6prevents bone loss in ovariectomized mice [J]. J Bone Miner Res.1997,12(6):935-41.
[46] Hube F, Hauner H. Therole of TNF-alpha in human adipose tissue: preventionof weight gainat theexpenseof insulin resistance?HormMetab Res. 1999, 31:626-631.
[47] lefsky JM. Treatment of insulin resistance with peroxisomeproliferator-activated receptor gamma agonists. J Clin Invest.000, 106:467-472.
[48] Burant CF,Sreenan S, Hirano K,et al. Troglitazoneaction isindependent ofadipose tissue.J Clin Invest.1997, 100: 2900-2906.
[49] Ogawa S，Urano T，Hosoi T，et al.Association of bone mineral density with apolymorphism of the peroxisome proliferator -activated receptor gamma gene：PPARgamma expression in osteoblasts.Biochem Biophys Res Commun.1999，260：122-126.
[50] Rhee EJ，Oh KW，Lee WY，et al.The effects of C161→T polymorphisms inexon 6 of peroxisome proliferator-activated receptor-gamma gene on bonemineral metabolism and serum osteoprotegerin levels in healthy middle-agedwomen.Am J Obstet Gynecol.2005，192：1087-1093.
[51] Strotmeyer ES,Cauley B. Diabetes mellitus bonemineral density and fracturerisk. Curr Opin Endocrinol DiabetesObes.2007,14(6):429–435.
[52]杨金奎.ADOPT研究的最新结果[ J].国际内分泌代谢杂志.2007, 27(1): 1-3.
[53] Soroceanu MA, Miao D, Bai XY, et al. Rosiglitazone impacts negatively onbone by promoting osteoblast/osteocyte apoptosis. Endocrinology.2004, 183(1):203-216.
[54] Akune T,Ohba S,Kamekura S,et al. PPAR gamma insufficiency enhanceosteogensis through osteoblast formation from bone marrow progenitors.ClinInvest.2004,113(6):846-855.
[55] Kelly K ,Tanaka S,Baron R,et al.Murine bone marrow stromally derived BMS2adipocytes support differentiation and function of osteoclast-like cells invitro.Endocrinology.1998,139（4）:2092-2101.
[56] Wan Y,Ohizumi H,Fujitani Y,et al. PPAR gamma regulates osteoclastogenesisin mice.Nat Med.2007,13(12):1496-1503.
[1] IOF.Epidemiology,cost and burden of osteoporsis in Asia 2009.
[2] Beresford JN,Benlled JH,Devlin C, et al. Ecidence for inverse relationshipbetween the differentiation of adipocy and osteogenic cells in rat marrowstromal cell cultures. Cell Sci,1992,102:341-345.
[3] Ackert-Bicknell C,Rosen C.The Genetics of PPARG and the Skeleton[J]. PPARRes, 2006: 932-958.
[4] Sun YR,Yang Z. Advances of nuclear translation factor:peroxisomeproliferator-actived receptor-γ2. Hereditas, 2003, 25(6): 713-717.
[5] Wu, X, Shi W, Cao X. Multiplicity of BMP signaling in skeletal development.Ann N Y Acad Sci, 2007,1116:29–49.
[6] Cock TA, Back J,Elefteriou F, et al. Enhanced bone formation in lipodystrophicPPARgamma(hyp/hyp) mice relocates haematopoiesis to the spleen. EMBORep, 2004,5(10):1007–1012.
[7] Kubota N, Terauchi Y, Miki H, et al. PPAR gamma mediates high-fatdiet-induced adipocyte hypertrophy and insulin resistance. Mol Cell,1999,4(4):597–609.
[8] Rosen ED,Sarraf P,Troy AE, et al. PPAR gamma is required for thedifferentiation of adipose tissue in vivo and in vitro. Mol Cell,1999,4(4):611–617.
[9] Akune, T. et al. (2004) PPARgamma insufficiency enhances osteogenesisthrough osteoblast formation from bone marrow progenitors. J. Clin. Invest.113, 846–855.
[10] Barak Y,Nelson MC,Ong ES, et al. PPAR gamma is required for placental,cardiac, and adipose tissue development. Mol. Cell,1999, 4(4):585–595.
[11] Li X, Cui Q, Kao C, et al. Lovastatin inhibits adipogenic and stimulatesosteogenic differentiation by suppressing PPARγ2 and increasing Cbfa1/Runx 2expression in bone marrowmesenchymel cell cultures.Bone,2003,33:652-659.
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