Wnt5a/Ror2信号通路介导的软骨-软骨下骨间信息交流在OA中的作用及机制

Osteoarthritis (OA) is one of the leading causes of disability in the elderly, abnormal subchondral bone remodeling greatly contributes to the development of OA, the crosstalk and critical interlinked signaling pathways between cartilage and subchondral bone are becoming the key target for developing effective strategies of OA prevention and treatment. Previous studies from our group and others have shown that the Wnt5a/Ror2 signaling pathway is one such pathway overexpressed in OA tissues and capable of regulating the activity of chondrocytes, osteoblasts and osteoclasts. We hypothesize the Wnt5a/Ror2 signaling pathway mediates a pathologic interaction between the above mentioned cells following trauma to the joint triggering both the pathologic subchondral bone remodeling and cartilage catabolic metabolism. This project aims to investigate the role and mechanism of Wnt5a/Ror2 signaling pathway mediated crosstalk between bone and cartilage in OA development, by establishing ACLT (Anterior cruciate ligament transection, ACLT) or combined OVX (Ovariectomy, OVX) model in transgenic mice with osteoblast- or chondrocyte-specific knockout of Wnt5a, or pre-osteoclast-specific knockout of Ror2 by Cre-loxp methodology. These models will test our hypothesis, providing support for developing Wnt5a/Ror2 signaling inhibition as new approach for the prevention and/or treatment of OA, and providing an example for other studies aiming to develop new small molecule or gene modifying strategies for OA treatment through the targeted-regulation of both cartilage and subchondral bone signaling mechanisms.

骨关节炎（Osteoarthritis,OA）是中老年人群主要致残原因之一，软骨下骨骨重建异常是OA的重要病理环节，骨-软骨间信息交流及相关信号通路已成为OA防治研究的关键靶点。课题组及其他学者前期研究证实Wnt5a/Ror2信号通路在OA病损组织高表达，同时具有调控软骨细胞、成骨细胞与破骨细胞功能活性的作用。我们推测该通路介导的上述细胞之间的相互作用很可能同时启动了软骨下骨骨重建和软骨基质分解代谢。本研究拟通过建立关节不稳或合并高骨转换OA小鼠模型，结合Cre-loxp细胞特异性基因敲除技术，分别以软骨细胞/成骨细胞为靶向敲除Wnt5a或前破骨细胞靶向敲除Ror2，探索Wnt5a/Ror2信号通路介导的骨-软骨间的信息交流在OA发生发展中的作用，明确细胞特异性干预该通路对OA的干预效果及分子机制，为以Wnt5a/Ror2或其他双靶向信号通路为靶点开发小分子或基因治疗OA提供依据和参考。

骨关节炎（Osteoarthritis, OA）是最常见的骨关节疾病之一，软骨下骨骨重建异常是OA的重要病理环节，骨-软骨间信息交流在OA发生发展中的作用已成为本领域的热点之一。本研究通过前交叉韧带切断术（ACLT)）建立关节不稳OA小鼠模型，应用Cre-loxp细胞特异性基因敲除技术，分别以软骨细胞/成骨细胞为靶向敲除Wnt5a，探索Wnt5a信号通路介导的骨-软骨间的信息交流在OA发生发展中的作用。主要研究结果如下：1.在成骨细胞靶向敲除Wnt5a小鼠经ACLT建立OA模型中，初步发现该敲除方案可以部分阻止ACLT诱发的软骨二型胶原丢失，但是对骨关节炎的整体表型无显著影响。2.在胶原酶诱导的OA模型中，初步发现特异性靶向成骨细胞敲除Wnt5a的小鼠中骨量显著增加。3.在正常生理下，成骨细胞条件性敲除 Wnt5a 的小鼠相较于未敲除小鼠骨量显著下降、骨微结构异常改变，骨强度下降；在尾悬吊诱导的骨丢失状态下，成骨细胞条件性敲除 Wnt5a 的小鼠相较于未敲除小鼠骨量与骨微结构无显著变化。4.在未行卵巢切除术(Ovariectomy,OVX)的小鼠中，成骨细胞条件性敲除Wnt5a可以促进骨折愈合进程，OVX组中敲除Wnt5a对骨折愈合没有显著影响。.上述研究结果初步明确细胞特异性敲除Wnt5a对OA的干预效果及分子机制，并通过拓展研究探索了在骨质疏松和骨折等不同条件下细胞特异性敲除Wnt5a对成骨/破骨功能活性的影响及机制，为以Wnt5a或其他双靶向信号通路为靶点开发小分子或基因治疗OA和骨代谢相关疾病提供了依据和参考。