一种新的小分子化合物激活Wnt信号传导通路促进骨质疏松性骨折愈合与成骨及其机制研究

The incident of osteoporosis fracture increases every year. The rate of delayed union and nonunion is very high. The major reason is osteoporosis and less ability of fracture healing. But no available drug can help fracture healing and improve bone density at the same time. Recent studies show that canonical Wnt signaling can promote bone formation and repress bone resorpotion. Meanwhile, the pathway can accelerate fracture healing. Wnt signaling can improve bone marrow derived mesenchymal stem cells (BMSC) proliferation and osteoblast differentiation. .Our group identified a new small molecular, BR-536 , which can activate canonical Wnt signaling and promote expression of downstream target genes. BR-536 promoted bone marrow derived mesenchymal stem cells differentiate to osteoblasts. This proposal will identify the molecular mechanism of BR-536 in activating canonical Wnt signaling. The bone formation and fracture healing will be investigated in vivo. We will check the character of bone marrow derived mesenchymal stem cells differentiation and bone formation mechanism. The PCR array will be used to identify the Wnt genes which change in the two group. In that way, the mechanism could be identified for BR-536 roles in Wnt signaling. This proposal will provide evidence and theoretical basis for osteoporosis fracture treatment.

老年骨质疏松性骨折发生率逐年上升，其延迟愈合和不愈合率较高，主要原因是骨质疏松和成骨能力较差，一线抗骨松药物有可能影响骨折愈合，限制其临床使用，目前更没有同时提高骨密度和的促骨折愈合药物。近来研究表明经典Wnt通路可以促骨形成和抑制骨吸收，可以同时促骨折愈合和提高骨量，Wnt通路还可促进干细胞增殖和定向成骨分化。本课题组前期通过化学遗传方法筛选发现一种新的小分子化合物BR-536可以激活Wnt信号通路和促进其下游目的基因的表达，并可促进骨髓间充质干细胞向成骨细胞分化。本研究拟进一步研究BR-536在体外调控Wnt通路的分子机制和其在体内对骨形成和骨折愈合的影响。研究其对骨髓基质干细胞成骨分化的特征、功能表型变化和诱导骨生成的发生机制，使用PCR芯片找出被此小分子影响的Wnt通路基因，进一步阐述其激活Wnt通路的机制。本研究的实施将为骨质疏松骨折治疗提供理论依据和思路，并有可能进行药物研发。

老年骨质疏松性骨折发生率逐年增高，其延迟愈合和不愈合率较高，主要原因是骨质疏松和成骨能力较差，一线抗骨松药物有可能影响骨折愈合，限制其临床使用，目前更没有同时提高骨密度和的促骨折愈合药物。近来研究表明经典Wnt通路可以促骨形成和抑制骨吸收，可以同时促骨折愈合和提高骨量。本研究发现Wnt通路可促进干细胞增殖和定向成骨分化。本课题组发型小分子TGIF可以激活Wnt信号通路和促进其下游目的基因的表达，并可促进骨髓间充质干细胞向成骨细胞分化。其在体外调控Wnt通路的分子机制和其在体内对骨形成和骨折愈合。发型其通过激活Wnt通路促进骨髓基质干细胞成骨分化，进一步发现其激活Wnt通路的分子机制，相关结果发表在JIMM和Cancer Cell杂志上，在美国骨矿研究学会和欧洲骨盐学会年会上进行大会发言并获奖。本研究的实施将为骨质疏松骨折治疗提供理论依据和思路，并有可能进行药物研发。