PPAR-γ regulates osteoclastogenesis in mice
PPAR-γ regulates osteoclastogenesis in mice
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DOI：
10.1038/nm1672
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发表时间：
2007-12-01
期刊：
影响因子：
82.9
通讯作者：
Evans, Ronald M.
中科院分区：
文献类型：
--
作者：
Wan, Yihong;Chong, Ling-Wa;Evans, Ronald M.
破骨细胞是来源于单核细胞-巨噬细胞谱系的造血前体的骨吸收细胞。破骨细胞功能的调节是理解骨质疏松症、类风湿性关节炎和骨硬化症等骨疾病的核心（1）。尽管过氧化物酶体增殖物激活受体-γ（PPAR-gamma）已被证明可抑制成骨细胞分化（2，3），但其在破骨细胞中的作用（如果有的话）尚不清楚。这是一个临床上至关重要的问题，因为据报道，PPAR-gamma激动剂，如噻唑烷二酮类，一类胰岛素增敏药物，会导致人类患者骨折的发生率更高（4，5）。在这里，我们已经发现了一个前破骨细胞的PPAR-gamma的作用，通过使用Tie 2Cre/flox小鼠模型，其中PPAR-gamma是删除破骨细胞，但不是在成骨细胞。这些小鼠发生以骨量增加、髓腔空间减少和脾脏髓外造血为特征的骨硬化症。这些缺陷是破骨细胞分化受损和核因子-κ B配体信号传导的受体激活剂受损的结果，并且可以通过骨髓移植来挽救。此外，罗格列酮对PPAR-gamma的配体激活以受体依赖性方式加剧破骨细胞分化。我们对潜在机制的研究表明，PPAR-gamma是c-fos表达的直接调节剂，是破骨细胞生成的重要介质（6）。因此，PPAR-gamma及其配体在促进破骨细胞分化和骨吸收中具有以前未认识到的作用。
Osteoclasts are bone-resorbing cells derived from hematopoietic precursors of the monocyte-macrophage lineage. Regulation of osteoclast function is central to the understanding of bone diseases such as osteoporosis, rheumatoid arthritis and osteopetrosis(1). Although peroxisome proliferator-activated receptor-gamma (PPAR-gamma) has been shown to inhibit osteoblast differentiation(2,3), its role, if any, in osteoclasts is unknown. This is a clinically crucial question because PPAR-gamma agonists, ''such as thiazolidinediones-'' a class of insulin-sensitizing drugs, have been reported to cause a higher rate of fractures in human patients(4,5). Here we have uncovered a pro-osteoclastogenic effect of PPAR-gamma by using a Tie2Cre/flox mouse model in which PPAR-gamma is deleted in osteoclasts but not in osteoblasts. These mice develop osteopetrosis characterized by increased bone mass, reduced medullary cavity space and extramedullary hematopoiesis in the spleen. These defects are the result of impaired osteoclast differentiation and compromised receptor activator of nuclear factor-kappa B ligand signaling and can be rescued by bone marrow transplantation. Moreover, ligand activation of PPAR-gamma by rosiglitazone exacerbates osteoclast differentiation in a receptor-dependent manner. Our examination of the underlying mechanisms suggested that PPAR-gamma functions as a direct regulator of c-fos expression, an essential mediator of osteoclastogenesis(6). Therefore, PPAR-gamma and its ligands have a previously unrecognized role in promoting osteoclast differentiation and bone resorption.