Myostatin调控破骨细胞分化在绝经后骨质疏松症中的作用及机制研究

Postmenopausal osteoporosis is the most common type of primary osteoporosis, with the incidence increases year by year, which poses a serious threat to the physical and mental health of older women.The excessive activation of osteoclasts is one of the key factors for the development of postmenopausal osteoporosis. Therefore, regulating osteoclast differentiation through cytokines is an important way to prevent postmenopausal osteoporosis. Myostatin is an important factor in the process of muscle growth, but there is still no report of its role in postmenopausal osteoporosis. According to the present studies, in addition to the significant increase in muscle content in Myostatin deficient mice, bone mineral density also significantly increased. We found that Myostatin levels in patients with postmenopausal osteoporotic fracture in the serum was significantly higher than that of premenopausal patients.According to our further in vitro research, primary mouse mononuclear cells highly expressed the Myostatin receptor; Addition of Myostatin during osteoclastogenesis in vitro could significantly promote the formation of osteoclasts. Therefore, this study intends to elucidate the role of myostatin in the regulation of osteoclast differentiation in vivo and in vitro experiments, and explore the potential clinical values of serum Myostatin as a diagnostic marker and therapeutic intervention target,which will provide a new idea for the prevention and treatment of osteoporosis .

绝经后骨质疏松症发病率逐年增高，严重威胁着老年女性的身心健康。破骨细胞过度激活是绝经后骨质疏松症发生发展的关键因素。因此，通过调节各种细胞因子进而调控破骨细胞分化是防治绝经后骨质疏松症的重要思路。Myostatin是在肌肉生长过程中发挥重要调节作用的因子，但是，其在绝经后骨质疏松症的作用尚未有研究报道。现有研究表明，Myostatin基因缺失的小鼠除肌肉含量较野生小鼠显著增加外，骨密度也显著增加；同时，课题组研究发现绝经后骨质疏松性骨折患者血清中Myostatin表达显著高于绝经前患者；通过体外实验进一步发现小鼠单核细胞高表达Myostatin受体；诱导破骨细胞分化时加入Myostatin能够显著促进破骨细胞分化。因此，本研究拟通过体内外实验阐明Myostatin调控破骨细胞分化在绝经后骨质疏松中的作用及分子机制，探索其作为干预靶点及诊断标准的可行性，为绝经后骨质疏松症防治提供新思路。

肌生长抑制素（Myostatin）是一种机体必需的细胞因子，广泛存在于骨骼肌中，并负向调节肌细胞的生长和发育。最近的研究表明，肌生长抑制素可能在骨骼代谢中起重要作用。故本研究针对破骨细胞分化领域，深入探讨Myostatin在调节骨代谢相关作用和具体机制。我们的研究主要报道了在破骨细胞分化过程中，Myostatin能够激活Ⅱ型受体ActRⅡB的表达。Myostatin的表达能够促进破骨细胞分化、功能和破骨细胞相关标志物表达，包括c-Src，MMP9，CTR，CK和NFATc1。从机制上来看，Myostatin通过增强Smad2的磷酸化，激活下游NF-κB和MAPKs信号通路来促进破骨细胞分化。通过基因分析发现Ccdc50是在Myostatin干预下的破骨细胞生成中表达高度降低的基因之一。Ccdc50可以通过阻断NF-κB和MAPKs途径来抑制Myostatin在促进破骨细胞分化和功能上的作用。总之，我们发现Myostatin通过激活Smad2并进一步激活NF-κB和MAPKs途径来促进RANKL诱导的破骨细胞分化。此外，Ccdc50抑制了Myostatin在诱导破骨细胞分化上的作用。上述研究表明Myostatin可以作为过度活化导致骨质疏松相关病理过程的潜在靶标，并为未来的研究中理解骨骼重塑的机制提供基础。