MAGI1 attenuates osteoarthritis by regulating osteoclast fusion in subchondral bone through the RhoA-ROCK1 signaling pathway

作者：Jing Zhang, Wenhui Hu, Yuheng Li, Fei Kang, Xuan Yao, Jian‐Mei Li, Shiwu Dong · 发表于：Journal of Orthopaedic Translation · 年份：2025 · DOI：10.1016/j.jot.2025.04.007 · 被引用次数：9 · 研究领域：Osteoarthritis Treatment and Mechanisms、Bone Metabolism and Diseases、TGF-β signaling in diseases

Background Osteoarthritis (OA) is a chronic joint disorder that predominantly affects middle-aged or elderly individuals. Subchondral bone remodeling due to osteoclast hyperactivation is regarded as a major feature of early OA. During osteoclast fusion and multinucleation, the cytoskeleton reorganization leads to the formation of actin belts and ultimately bone resorption . Membrane-associated guanylate kinase with an inverted repeat member 1 (MAGI1) is a scaffolding protein that is crucial for linking the extracellular environment to intracellular signaling pathways and cytoskeleton . However, the role of MAGI1 in subchondral bone osteoclast fusion remains unclear. Methods In this study, we collected knee joint samples from OA patients and established the OA mouse model to examine the expression of MAGI1. Furthermore, we established the OA rat model and locally injected rAAV9-mediated shMagi1 into the subchondral bone to knock down MAGI1 expression. Micro-CT, histological staining, and immunofluorescence were employed to assess the effects of MAGI1 knockdown on subchondral bone homeostasis and OA process. We isolated and cultured osteoclasts from femoral and tibial bone marrow. Receptor activator of nuclear factor-κB ligand (RANKL)-stimulated osteoclasts served as an in vitro model for OA and underwent RNA sequencing . We employed gain- and loss-of-function experiments using MAGI1-overexpression plasmids and small interfering RNA to explore the role of MAGI1 in osteoclast di...