PDF(Pubmed)
Abstract：
The peroxisome proliferator activated receptor gamma (PPARG) nuclear receptor regulates energy metabolism and insulin sensitivity. In this study, we present novel evidence for an essential role of PPARG in the regulation of osteocyte function, and support for the emerging concept of the conjunction between regulation of energy metabolism and bone mass. We report that PPARG is essential for sclerostin production, a recently approved target to treat osteoporosis. Our mouse model of osteocyte-specific PPARG deletion (Dmp1CrePparγflfl or γOTKO) is characterized with increased bone mass and reduced bone marrow adiposity, which is consistent with upregulation of WNT signaling and increased bone forming activity of endosteal osteoblasts. An analysis of osteocytes derived from γOTKO and control mice showed an excellent correlation between PPARG and SOST/sclerostin at the transcript and protein levels. The 8 kb sequence upstream of Sost gene transcription start site possesses multiple PPARG binding elements (PPREs) with at least two of them binding PPARG with dynamics reflecting its activation with full agonist rosiglitazone and correlating with increased levels of Sost transcript and sclerostin protein expression (Pearson\'s r = 0.991, p = 0.001). Older γOTKO female mice are largely protected from TZD-induced bone loss providing proof of concept that PPARG in osteocytes can be pharmacologically targeted. These findings demonstrate that transcriptional activities of PPARG are essential for sclerostin expression in osteocytes and support consideration of targeting PPARG activities with selective modulators to treat osteoporosis.
摘要：
过氧化物酶体增殖物激活受体γ(PPARG)核受体调节能量代谢和胰岛素敏感性。在这项研究中,我们提出了新的证据，证明PPARG在调节骨细胞功能中的重要作用，并支持能量代谢调节与骨量之间结合的新兴概念。我们报告说，PPARG是必不可少的硬化素生产，最近批准的治疗骨质疏松症的目标。我们的骨细胞特异性PPARG缺失小鼠模型（Dmp1CrePparγflfl或γOTKO）的特征是骨量增加和骨髓肥胖减少，这与WNT信号的上调和内骨成骨细胞的骨形成活性增加一致。对来自γOTKO和对照小鼠的骨细胞的分析显示，在转录本和蛋白质水平上，PPARG与SOST/硬化蛋白之间具有极好的相关性。Sost基因转录起始位点上游的8kb序列具有多个PPARG结合元件（PPRE），其中至少两个结合PPARG，其动力学反映出其被完全激动剂罗格列酮激活，并与Sost转录本和硬化蛋白表达水平升高相关（Pearson'sr=0.991，p=0.001）。年龄较大的γOTKO雌性小鼠在很大程度上受到TZD诱导的骨丢失的保护，这提供了可以在药理学上靶向骨细胞中的PPARG的概念证据。这些发现表明，PPARG的转录活性对于骨细胞中硬化蛋白的表达至关重要，并支持考虑用选择性调节剂靶向PPARG活性来治疗骨质疏松症。
