FBXO6对骨质疏松症的保护作用及其机制研究

The incidence rates of osteoporosis and osteoporotic fracture are growing as aging of the society. However, the mechanism of osteoporosis is still not utterly uncovered. Osteoblast and its related cytokines，such as BMP, TGF-β and FGF etc. play an important role during the development of osteoporosis as reported. We found the expression of FBXO6 is significantly reduced in bone tissue of patients of osteoporotic fracture. The tibiae of fbxo6-/- transgenic mice also present severe osteoporosis. FBXO6 were also significantly up-regulated in different stages of osteoblast differentiation. Further LC-MS study exhibited that FBXO6 could combine with TGF-β1. Our in vitro experiments elucidated FBXO6 could up-regulated the levels of TGF-β1 both in supernatant and whole cell lysate. Results of co-IP confirmed that the combination of FBXO6 and TGF-β1 is controlled by the FBA domain of FBXO6.Analysis of the promotor of FBXO6 suggests that TGF-β/SMAD2/3/4 may up-regulate FBXO6 and this is confirmed by in vitro experiment. Thus, we plan to investigate the effect of FBXO6 knockout on metabolism of bone and differentiation, proliferation and function of osteoblast by histological, morphological, cell biological and molecular biological methods. We also plan to identify the molecular mechanism of FBXO6-TGF-β1 interaction. These studies will lead to discovery of new targets for exploring mechanism and treatment of osteoporosis.

随着人口老龄化，骨质疏松症和骨质疏松性骨折的发病率逐年上升，而其发病机制尚未完全阐明。研究报道成骨细胞及其相关细胞因子(BMP、TGF-β和FGF等)的功能改变在骨质疏松发生中有重要作用。我们前期研究发现FBXO6基因敲除小鼠表现出严重的骨质疏松，且在成骨分化时FBXO6表达也可显著上调。我们在质谱筛选实验中发现FBXO6可与TGF-β1相互作用，体外实验证实FBXO6可以提高TGF-β1水平，且FBXO6的FBA结构域突变后这一作用消失。此外，FBXO6启动子分析提示TGF-β/SMAD2/3/4信号通路可能调节FBXO6表达，体外实验也证明了这一点。因此，本课题拟进一步通过形态学、细胞学和分子生物学等手段研究FBXO6基因敲除对骨代谢和成骨功能的影响，进一步明确FBXO6作用于TGF-β1，以及TGF-β1促进FBXO6表达的分子机制，以期为骨质疏松症的分子机制研究提供新的思路。

随着人口老龄化，骨质疏松症和骨质疏松性骨折的发病率逐年上升，而其发病机制尚未完全阐明。研究报道成骨和破骨失衡在骨质疏松发生中有重要作用。我们研究发现FBXO6基因敲除小鼠表现出严重的骨质疏松，且在骨质疏松和OVX小鼠中FBXO6表达也可显著下调。成骨和破骨分化过程中FBXO6表达可显著上升。我们之前在质谱筛选实验中发现FBXO6可与TGF-β1和AC45相互作用，FBXO6沉默和过表达实验证实FBXO6和TGF-β1水平相关， coIP实验证明FBXO6可以与TGF-β1和AC45蛋白-蛋白相互作用。此外，FBXO6启动子分析提示TGF-β/SMAD2/3/4信号通路可能调节FBXO6表达。根据研究结果，我们认为FBXO6可能通过促进成骨抑制破骨来保护骨质疏松的进展，该研究为骨质疏松症的分子机制研究提供了新的思路。