成骨细胞Mig6-EGFR信号轴在骨关节炎起病中的作用及机制研究

骨关节炎（OA）是最常见的关节疾病，发病机制未明，暂无有效药物。调控骨重构的通路是OA药物靶点研究的重要方向。EGFR通路可调控骨发育与代谢，其在OA中的作用尚未阐明。全身高表达EGFR小鼠软骨退变加重。而我们前期发现，软骨下骨在OA中的改变可能早于软骨。软骨细胞特异性敲除EGFR上游抑制分子Mig6，上调EGFR信号，软骨退变不明显，提示软骨细胞Mig6-EGFR信号轴可能不起关键作用。我们据此假设成骨细胞Mig6-EGFR信号轴通过调控成骨及破骨细胞活性，引起骨重构，导致软骨退变。我们拟利用成骨细胞特异性敲除Mig6小鼠，研究Mig6-EGFR信号轴对成骨及破骨细胞活性和骨重构的调节作用及其与软骨退变的关系，并采用激光捕获显微切割获取软骨下骨蛋白与基因，寻找上下游靶点。最后通过细胞共培养，探索成骨细胞如何通过Mig6-EGFR信号轴调控破骨细胞形成与活性，为OA药物靶点选择提供新思路。

Osteoarthritis (OA) is the most prevalent joint disease. Its underlying mechanism remains unclear. Thus no disease-modifying drugs available. Targeting signaling pathways that modify subchondral bone remodeling is one of the most important option for OA drug development. EGFR signaling plays an important role in bone development and metabolism. However, its role in OA remain obscure. More severe OA was showed in whole body EGFR knock-in mice. Our previous studies demonstrated that pathological subchondral bone remodeling may precede and mediate cartilage damage in OA. In addition, mice with chondrocyte-specific knock-out of Mig6 (a negative regulator of EGFR signalling), which results in up-regulation of EGFR signaling, didn't show obvious OA phenotype, which indicates that chondrocytic Mig6-EGFR signaling might not be a key factor in OA pathogenesis. Here we hypothesize that cell activities and functions of osteoblasts and osteoclasts mediated by osteoblastic Mig6-EGFR signaling lead to pathological subchondral bone remodeling in early OA, followed by cartilage degeneration. We aim to investigate the regulation of metabolism and remodeling of subchondral bone by Osteoblastic Mig6-EGFR axis as well as its role in OA pathogenesis, using osteoblast specific knock-out mice of Mig6, in order to find out whether bone metabolism changes and remodeling of subchondral bone caused by osteoblastic Mig6-EGFR signaling is a key factor in OA pathogenesis. By laser-captured microdissection, subchondral bone was captured and used for RNA and protein extraction, looking for up-stream and down-steam targets of Mig6-EGFR signaling. Co-culture system is used to find out how osteoblast regulate osteoclastogenesis and osteoclast activity by Mig6-EGFR signaling. By this study, we aims to provide more evidence that targeting osteoblastic Mig6-EGFR signaling can be used in OA drug development.