机械加载通过调控骨重建和内质网应激治疗骨关节炎的机制研究

Osteoarthritis is a serious public health disease. It is important to explore novel therapy treatment and underlying mechanism. Previous work showed that pulsating joint loading effectively promoted bone formation and accelerated bone wound healing. In early osteoarthritis, mechanical loading significantly increased Wnt and SUMO-2/3 expression, and prevented cartilage degradation by reducing p38 MAPK and MMP13. However, the effect of mechanical loading on the late osteoarthritis and cartilage through the subchondral bone is still unclear. Whether mechanical loading improves abnormal bone remodeling, regulates endoplasmic reticulum stress (ER Stress; ERS) and modulates autophagy in osteoarthritis remains to be elucidated. We will use post-traumatic osteoarthritis animal models and the approaches of histology as well as cellular and molecular biology to test the hypothesis that pulsating joint loading affects abnormal bone remodeling of the subchondral bone by the SUMOylation of Wnt signaling pathway, reduces chondrocytes apoptosis by regulating ERS through phosphorylation of eIF2 alpha, and prevents cartilage degeneration by modulating autophagy of chondrocytes via p38 MAPK and NFκB. With the implementation of this project, the pathological changes of osteoarthritis and the function of subchondral bone in the development of osteoarthritis will be investigated. This study will advance our understanding of the roles of the ERS and autophagy in the development of osteoarthritis and the mechanism of the mechanical loading for osteoarthritis treatment. The project will provide a novel target for treatment of osteoarthritis.

骨关节炎严重危害人类健康，研究新的治疗方法及其机制意义重大。前期工作表明，脉冲式关节机械加载可以促进骨生长并加速骨损伤修复；在早期骨关节炎治疗中显著激活Wnt和SUMO-2/3，抑制p38 MAPK和MMP13的活性保护关节软骨。然而，机械加载对晚期骨关节炎的疗效尚不清楚，机械加载是否改善软骨下骨的异常骨重建、调控内质网应激并影响自噬的机制有待阐明。为此，我们将采用骨关节炎动物模型，利用组织学、细胞学、基因表达调节、分子生物学等手段验证假说：机械加载通过SUMO化调控Wnt信号通路影响软骨下骨的异常骨重建抑制骨关节炎病理发展，通过eIF2α磷酸化调节软骨细胞内质网应激，通过p38 MAPK、NFκB信号通路调控软骨细胞自噬实现软骨保护，治疗骨关节炎。本项目将探索骨关节炎的病理演变及机械加载治疗中软骨下骨的作用，阐明机械加载调控内质网应激和自噬治疗骨关节炎的机制，为骨关节炎开辟新的治疗途径。

骨关节炎严重危害人类健康，研究新的治疗方法及其机制意义重大。前期工作表明，脉冲式关节机械加载可以促进骨生长并加速骨损伤修复。然而，机械加载对骨关节炎治疗的机制尚不清楚，机械加载是否改善软骨下骨的异常骨重建、调控内质网应激并影响自噬的机制有待阐明。为此，我们采用了骨关节炎动物模型，利用组织学、细胞学、基因表达调节、分子生物学等手段，阐明关节机械加载通过调控SUMO化和Wnt信号通路影响软骨下骨的异常骨重建抑制骨关节炎的病理发展，通过eIF2α磷酸化调节软骨细胞内质网应激，调控p38 MAPK/NFκB信号通路及软骨细胞自噬改善软骨退化，达到治疗骨关节炎的效果。本项目通过探索关节机械加载调控软骨下骨异常骨重建、内质网应激和自噬的机制，为骨关节炎开辟了新的治疗途径。