Rosiglitazone induces decreases in bone mass and strength that are reminiscent of aged bone
Rosiglitazone induces decreases in bone mass and strength that are reminiscent of aged bone
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DOI：
10.1210/en.2006-1587
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发表时间：
2007-06-01
期刊：
影响因子：
4.8
通讯作者：
Lecka-Czernik, Beata
中科院分区：
文献类型：
--
作者：
Lazarenko, Oxana P.;Rzonca, Sylwia O.;Lecka-Czernik, Beata
过氧化物酶体增殖物激活受体-γ（PPAR γ）调节葡萄糖代谢和骨量。最近的证据表明，用抗糖尿病噻唑烷二酮类药物治疗性调节PPAR γ活性会对骨产生不良影响。在这项研究中，罗格列酮对生长（1个月），成年（6个月）和老年（24个月）C57 BL/6小鼠骨骼的影响进行了测定。衰老被确定为罗格列酮诱导的骨丢失的混杂因素，与骨髓间充质干细胞中PPAR γ表达增加相关。年轻生长小鼠的骨受影响最小，但骨形成率显著降低。在成年和老年动物中，罗格列酮显著降低了骨体积。在成年动物中，骨丢失与骨形成减弱相关，而在老年动物中，骨丢失与破骨细胞生成增加相关，由核因子-κ B配体（RANKL）表达的受体激活剂介导。PPAR γ激活导致骨髓结构和功能的变化，如成骨细胞数量减少，骨髓脂肪细胞增加，破骨细胞数量增加，以及骨髓间充质干细胞多能特性的丧失。总之，罗格列酮诱导骨的变化使人联想到老化骨，并似乎通过改变骨髓间充质干细胞的表型诱导骨丢失。
Peroxisome proliferator-activated receptor-gamma (PPAR gamma) regulates both glucose metabolism and bone mass. Recent evidence suggests that the therapeutic modulation of PPAR gamma activity with antidiabetic thiazolidinediones elicits unwanted effects on bone. In this study, the effects of rosiglitazone on the skeleton of growing (1 month), adult (6 month), and aged (24 month) C57BL/6 mice were determined. Aging was identified as a confounding factor for rosiglitazone-induced bone loss that correlated with the increased expression of PPAR gamma in bone marrow mesenchymal stem cells. The bone of young growing mice was least affected, although a significant decrease in bone formation rate was noted. In both adult and aged animals, bone volume was significantly decreased by rosiglitazone. In adult animals, bone loss correlated with attenuated bone formation, whereas in aged animals, bone loss was associated with increased osteoclastogenesis, mediated by increased receptor activator of nuclear factor-kappa B ligand (RANKL) expression. PPAR gamma activation led to changes in marrow structure and function such as a decrease in osteoblast number, an increase in marrow fat cells, an increase in osteoclast number, and a loss of the multipotential character of marrow mesenchymal stem cells. In conclusion, rosiglitazone induces changes in bone reminiscent of aged bone and appears to induce bone loss by altering the phenotype of marrow mesenchymal stem cells.