Myostatin调控骨代谢的作用机制研究

Myostatin is a key factor linking muscle and bone mass. Our studies showed that myostatin had no direct effect on murine osteoclast differentiation, and its receptor could be detected in bone marrow-derived mesenchymal stem cells (BMSCs). During osteogenic differentiation of BMSCs, myostatin inhibited the increase of Smad3 phosphorylation and β-catenin expression,and also the mineralized nodule formation of osteoblasts. These findings indicated that myostatin might regulate bone metablism mediated through both Smad3 and Wnt/β-catenin signals pathway. In the present study, the effect of myostatin on Smad3 and Wnt/β-catenin will be evaluated in vitro in both osteogenic culture and three-dimensional co-culture of osteoblast-progenitor with osteoclast-progenitor. Furthermore,the effects of myostatin neutralizing antibody (Mstn-mAb) and a soluble myostatin decoy receptor (ActRIIB-Fc) on either aged C57BL/6 mice or a rat model of localized muscle paralysis will be intensively evaluated. Finally, the reletionship of serum myostatin with skelatal muslce and bone metabolism will be also investigated.Deeply exploring the mechanism of myostatin on bone metabolism is warranted to help us to find a new way to prevent osteoporosis.

Myostatin是调控肌肉与骨量的重要纽带。我们研究发现Myostatin对小鼠破骨细胞的分化无影响，其受体主要在骨髓间充质干细胞表达。在成骨诱导过程中，Myostatin抑制Smad3磷酸化和β-catenin的表达，以及矿化结节形成，提示Myostatin可能通过上述通路调节骨代谢。本课题拟首先明确Myostatin经Smad3和β-catenin信号通路对小鼠BMSCs向成骨细胞增殖、分化的影响；进而采用成/破骨前体细胞三维培养的方式，观察Myostatin间接调控破骨细胞的作用。同时应用抑制剂Mstn-mAb和诱饵受体ActRIIB-Fc分别干预老龄C57BL6小鼠和肉毒素局部肌肉麻痹大鼠进行体内验证。最后，系统评价循环Myostatin水平与老龄人群和脊髓损伤患者的肌肉与骨骼代谢的关系。为阐明其调控骨代谢的作用机制，探索骨质疏松防治新途径打下基础。

我们前期的研究发现Myostatin 对小鼠破骨细胞的分化无影响，其受体主要在骨髓间充质干细胞表达。在本课题资助下，我们从细胞分子、动物以及人体水平，较为系统地研究了Myostatin对骨代谢的影响。我们发现，Myostatin可促进小鼠骨髓间充质干细胞向成骨细胞分化，并上调β-catenin的水平，该效应可被β-catenin siRNA转染所抑制，Myostatin调控骨代谢的作用主要通过调控β-catenin下游信号通路的表达而实现。我们还发现肌肉组织中Myostatin等肌源性因子表达的变化，与废用性骨质疏松症的发生、发展密切相关。并可能通过影响OPG/RANKL通路调控骨代谢。此外，我们的研究还阐明了循环中Myostatin水平与绝经后骨质疏松的关系。探讨了绝经后女性血脂代谢与骨代谢的关系，系统评价和筛选了绝经后女性骨质疏松和骨折的风险因素，探讨了骨折风险预测软件（FRAX模型）在中国人群的应用价值。最后，我们首次构建成功了成骨细胞特异性Hsd11b1基因敲除小鼠模型。并获得了国家自然科学基金等多项基金的连续资助。本研究系列结果在J Clin Endocrinol Metab、Am J Clin Nutr、Osteoporos Int、Bone、Clin Endocrinol (Oxf)、Ann Nutr Metab和中华骨质疏松和骨矿盐疾病杂志等各类杂志发表论文17篇，参加国际、国内会议交流论文7人次以上，获得各级优秀会议论文3篇。培养已毕业硕士研究生4名。