PPARG in osteocytes controls sclerostin expression, bone mass, marrow adiposity and mediates TZD-induced bone loss.
PPARG in osteocytes controls sclerostin expression, bone mass, marrow adiposity and mediates TZD-induced bone loss.
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骨细胞中的PPARG控制硬化蛋白表达、骨量、骨髓肥胖并介导tzd诱导的骨质流失。
DOI：
10.1016/j.bone.2021.115913
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发表时间：
2021-06
期刊：
影响因子：
4.1
通讯作者：
Lecka-Czernik B
中科院分区：
文献类型：
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作者：
Baroi S;Czernik PJ;Chougule A;Griffin PR;Lecka-Czernik B
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PPARG在调节骨细胞功能的重要作用，并支持新兴的概念之间的连接调节能量代谢和骨量。我们报告说，PPARG是必不可少的硬化素生产，最近批准的目标，以治疗骨质疏松症。我们的骨细胞特异性PPARG缺失小鼠模型（Dmp 1CrePpar γflfl或γOTKO）的特征是骨量增加和骨髓肥胖减少，这与WNT信号转导上调和骨内膜成骨细胞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PPARG和SOST/sclerostin在转录物和蛋白质水平上具有极好的相关性。Sost基因转录起始位点上游的8 kb序列具有多个PPARG结合元件（PPRE），其中至少两个结合PPARG，其动力学反映了完全激动剂罗格列酮对其的激活，并与Sost转录物和sclerostin蛋白表达水平的增加相关（Pearson's r=0.9910，p=0.001）。年龄较大的γOTKO雌性小鼠在很大程度上免受TZD诱导的骨丢失，这提供了骨细胞中的PPARG可以被靶向的概念证据。这些发现表明，PPARG的转录活性对于骨细胞中的硬化蛋白表达是必不可少的，并支持考虑用选择性调节剂靶向PPARG活性以治疗骨质疏松症。
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=0.9910, 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.
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影响因子：
6.2
作者：
Jastrzebski, Sandra;Kalinowski, Judith;Stolina, Marina;Mirza, Faryal;Torreggiani, Elena;Kalajzic, Ivo;Won, Hee Yeon;Lee, Sun-Kyeong;Lorenzo, Joseph
通讯作者：
Lorenzo, Joseph
使用四氧化锇和微型计算机断层扫描 (micro-CT) 对小鼠进行冠状动脉壁成像。
影响因子：
2.4
作者：
Pai VM;Kozlowski M;Donahue D;Miller E;Xiao X;Chen MY;Yu ZX;Connelly P;Jeffries K;Wen H
通讯作者：
Wen H
影响因子：
2.3
作者：
Brandenburg VM;Kramann R;Koos R;Krüger T;Schurgers L;Mühlenbruch G;Hübner S;Gladziwa U;Drechsler C;Ketteler M
通讯作者：
Ketteler M
影响因子：
4.1
作者：
Cawthorn WP;Bree AJ;Yao Y;Du B;Hemati N;Martinez-Santibañez G;MacDougald OA
通讯作者：
MacDougald OA
影响因子：
82.9
作者：
通讯作者：
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