Gao Bo, Huang Qiang, Jie Qiang, Wang Long, Zhang Hong-Yang, Liu Jian, Yang Liu, Luo Zhuo-Jing
Department of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, People's Republic of China.
Department of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, People's Republic of China.
Biochimie. 2015 Mar;110:36-44. doi: 10.1016/j.biochi.2015.01.001. Epub 2015 Jan 7.
Estrogen plays an essential role in bone formation, and estrogen modulation dysfunction is tightly associated with postmenopausal osteoporosis (PMOP). The underlying mechanisms of estrogen-mediated osteogenic differentiation have not been well defined. In this study, murine bone marrow mesenchymal stem cells were induced to undergo osteogenic differentiation, and gene expression analysis or GPR40 expression manipulation was performed. Bilateral ovariectomized or sham-operated C57BL/6 mice were administered GPR40 agonist (GW9508) for bone mineral density analysis. We identified GPR40, a long chain unsaturated fatty acid receptor, to be regulated by estrogen and involved in osteogenic differentiation both in vivo and in vitro. Mechanistically, the Wnt/β-catenin signaling pathway is essential for GPR40 to promote osteogenic differentiation. Furthermore, in vivo GW9508 administration rescued estrogen-deficient bone loss, indicating the essential role of the GPR40 receptor. To our knowledge, this is the first study that provides evidence for GPR40 as a positive regulator of osteogenesis and Wnt/β-catenin signaling. These results indicate that GPR40 may function as an endogenous promoter of estrogen-induced osteogenic differentiation through Wnt/β-catenin signaling activation. Therefore, as the global population of ages and the prevalence of metabolic-related disorders, especially PMOP, increases, our findings suggest that GPR40 is a key in understanding the link between bone and fat. It may also be a useful target for the treatment of bone complications in the future.
雌激素在骨形成中起重要作用，雌激素调节功能障碍与绝经后骨质疏松症（PMOP）密切相关。雌激素介导的成骨分化的潜在机制尚未完全明确。在本研究中，诱导小鼠骨髓间充质干细胞进行成骨分化，并进行基因表达分析或GPR40表达操作。对双侧卵巢切除或假手术的C57BL/6小鼠给予GPR40激动剂（GW9508）进行骨密度分析。我们发现GPR40，一种长链不饱和脂肪酸受体，受雌激素调节，并在体内和体外参与成骨分化。机制上，Wnt/β-连环蛋白信号通路对于GPR40促进成骨分化至关重要。此外，体内给予GW9508可挽救雌激素缺乏导致的骨质流失，表明GPR40受体的重要作用。据我们所知，这是第一项为GPR40作为成骨和Wnt/β-连环蛋白信号的正向调节因子提供证据的研究。这些结果表明，GPR40可能通过激活Wnt/β-连环蛋白信号作为雌激素诱导成骨分化的内源性促进因子。因此，随着全球人口老龄化以及代谢相关疾病，尤其是PMOP的患病率增加，我们的研究结果表明GPR40是理解骨骼与脂肪之间联系的关键。它未来也可能是治疗骨并发症的有用靶点。
