以NF-κB非经典信号通路为靶标治疗骨质疏松症的基础研究

Developing new drug with anti-resorptive or anabolic effect, particularly, with dual anti-resorptive and anabolic effect simultaneously, offer a great promise for the prevention and treatment of osteoporosis. We found that TNF receptor associated factor 3 (TRAF3) plays important dual role to inhibit osteoclast and also stimulate osteoblast differentiation by negatively regulating NF-kB inducing kinase (NIK) that controls the activation of non-canonical NF-kB signaling pathway. We also found that protein level of RANKL and TGFβ1 are significantly increased in the bone of aged mice and they degrade TRAF3 in the precursors of osteoclasts and osteoblasts respectively to promote bone resorption and inhibit formation. In addition, we have identified a small molecular compound that is able to inhibit osteoclast differentiation by blocking NIK activity. In this proposal, we will investigate 1) if TGFβ1 promote TRAF3 ubiquintin degradation by inducing the expression of inhibitor of apoptosis proteins; 2) if NIK inhibitor inhibit osteoclast and also promote osteoblast differentiation by blocking the activation of non-canonical NF-kB signaling pathway; and 3) if NIK inhibitor can prevent ovariectomy-induced osteoporosis in mice by inhibiting bone resorption and also stimulating bone formation. Completion of the proposed research not only determine the novel molecular mechanism whereby TRAF3 is degraded to result in bone loss in age-related osteoporosis but also provide a lead compound that inhibits bone resorption and also possible stimulate bone formation simultaneously for the therapy of osteoporosis.

开发新的抗骨吸收或者促骨合成药物，尤其是具有抗吸收和促合成双重作用的药物，对骨质疏松症（OPO）的防治具有远大前景。我们发现，1）TNF受体相关因子3（TRAF3）通过负性调节NFkB诱导激酶（NIK）所控制的非经典NFkB通路而抑制骨吸收、又维持骨合成；2）老年骨骼RANKL和TGFβ1含量显著上升，分别降解破骨细胞（OC）和成骨细胞（OB）前体细胞的TRAF3而促进骨吸收、抑制骨形成；3）一种化合物通过抑制NIK活性而抑制OC形成。本项目将探讨，1）TGFβ1是否因刺激凋亡蛋白抑制因子的表达而促进TRAF3的泛素化降解；2）NIK抑制剂是否可以阻断非经典NFkB 通路而抑制OC、促进OB分化；3）NIK抑制剂是否可以抑制骨吸收、并促进骨形成而预防卵巢切除所致的骨质疏松。本项目的完成不仅可以揭示老年性OPO全新的分子机制，也可获得具有抑制骨吸收、促进骨形成双重作用的先导化合物。