Stechschulte L A, Czernik P J, Rotter Z C, Tausif F N, Corzo C A, Marciano D P, Asteian A, Zheng J, Bruning J B, Kamenecka T M, Rosen C J, Griffin P R, Lecka-Czernik B
Dept. Orthopaedic Surgery, University of Toledo Health Science Campus, Toledo, OH 43614, United States; Center for Diabetes and Endocrine Research, University of Toledo Health Science Campus, Toledo, OH 43614, United States.
Dept. Orthopaedic Surgery, University of Toledo Health Science Campus, Toledo, OH 43614, United States.
EBioMedicine. 2016 Aug;10:174-84. doi: 10.1016/j.ebiom.2016.06.040. Epub 2016 Jun 29.
The peroxisome proliferator-activated receptor gamma (PPARγ) regulates osteoblast and osteoclast differentiation, and is the molecular target of thiazolidinediones (TZDs), insulin sensitizers that enhance glucose utilization and adipocyte differentiation. However, clinical use of TZDs has been limited by side effects including a higher risk of fractures and bone loss. Here we demonstrate that the same post-translational modifications at S112 and S273, which influence PPARγ pro-adipocytic and insulin sensitizing activities, also determine PPARγ osteoblastic (pS112) and osteoclastic (pS273) activities. Treatment of either hyperglycemic or normoglycemic animals with SR10171, an inverse agonist that blocks pS273 but not pS112, increased trabecular and cortical bone while normalizing metabolic parameters. Additionally, SR10171 treatment modulated osteocyte, osteoblast, and osteoclast activities, and decreased marrow adiposity. These data demonstrate that regulation of bone mass and energy metabolism shares similar mechanisms suggesting that one pharmacologic agent could be developed to treat both diabetes and metabolic bone disease.
过氧化物酶体增殖物激活受体γ（PPARγ）调节成骨细胞和破骨细胞的分化，是噻唑烷二酮类药物（TZDs）的分子靶点，这类胰岛素增敏剂可增强葡萄糖利用和脂肪细胞分化。然而，TZDs的临床应用受到包括骨折和骨质流失风险较高在内的副作用限制。在此，我们证明在S112和S273处相同的翻译后修饰，既影响PPARγ的促脂肪生成和胰岛素增敏活性，也决定PPARγ的成骨（pS112）和破骨（pS273）活性。用SR10171（一种阻断pS273但不阻断pS112的反向激动剂）治疗高血糖或正常血糖动物，可增加小梁骨和皮质骨，同时使代谢参数正常化。此外，SR10171治疗可调节骨细胞、成骨细胞和破骨细胞的活性，并减少骨髓脂肪。这些数据表明，骨量和能量代谢的调节具有相似机制，提示可开发一种药物来治疗糖尿病和代谢性骨病。
