Cao Jay, Ou Guomin, Yang Nianlan, Ding Kehong, Kream Barbara E, Hamrick Mark W, Isales Carlos M, Shi Xing-Ming
USDA ARS Grand Forks Human Nutrition Research Center, Grand Forks, ND, United States.
Department of Neuroscience & Regenerative Medicine, Georgia Regents University, Augusta, GA, United States.
Mol Cell Endocrinol. 2015 Jul 15;410:27-34. doi: 10.1016/j.mce.2015.01.045. Epub 2015 Feb 7.
Peroxisome proliferator-activated receptor gamma (PPARγ), known as the master regulator of adipogenesis, has been regarded as a promising target for new anti-osteoporosis therapy due to its role in regulating bone marrow mesenchymal stem/progenitor cell (BMSC) lineage commitment. However, the precise mechanism underlying PPARγ regulation of bone is not clear as a bone-specific PPARγ conditional knockout (cKO) study has not been conducted and evidence showed that deletion of PPARγ in other tissues also have profound effect on bone. In this study, we show that mice deficiency of PPARγ in cells expressing a 3.6 kb type I collagen promoter fragment (PPAR(fl/fl):Col3.6-Cre) exhibits a moderate, site-dependent bone mass phenotype. In vitro studies showed that adipogenesis is abolished completely and osteoblastogenesis increased significantly in both primary bone marrow culture and the BMSCs isolated from PPARγ cKO mice. Histology and histomorphometry studies revealed significant increases in the numbers of osteoblasts and surface in the PPARγ cKO mice. Finally, we found that neither the differentiation nor the function of osteoclasts was affected in the PPARγ cKO mice. Together, our studies indicate that PPARγ plays an important role in bone remodeling by increasing the abundance of osteoblasts for repair, but not during skeletal development.
过氧化物酶体增殖物激活受体γ（PPARγ），被称为脂肪生成的主要调节因子，由于其在调节骨髓间充质干/祖细胞（BMSC）谱系定向中的作用，已被视为新型抗骨质疏松治疗的一个有前景的靶点。然而，由于尚未进行骨特异性PPARγ条件性敲除（cKO）研究，且有证据表明在其他组织中敲除PPARγ也会对骨骼产生深远影响，因此PPARγ调节骨骼的确切机制尚不清楚。在本研究中，我们发现，在表达3.6 kb I型胶原启动子片段的细胞中缺乏PPARγ的小鼠（PPAR(fl/fl):Col3.6-Cre）表现出中度的、位点依赖性的骨量表型。体外研究表明，在原代骨髓培养以及从PPARγ cKO小鼠分离的BMSC中，脂肪生成被完全消除，而成骨细胞生成显著增加。组织学和组织形态计量学研究显示，PPARγ cKO小鼠的成骨细胞数量和表面显著增加。最后，我们发现PPARγ cKO小鼠中破骨细胞的分化和功能均未受到影响。总之，我们的研究表明，PPARγ通过增加用于修复的成骨细胞数量在骨重塑中发挥重要作用，但在骨骼发育过程中并非如此。
