A RANKL-UCHL1-sCD13 negative feedback loop limits osteoclastogenesis in subchondral bone to prevent osteoarthritis progression

作者：Wenquan Liang, Ru Feng, Xiaojia Li, Xingwei Duan, Shourui Feng, Jun Chen, Yicheng Li, Junqi Chen, Zezheng Liu, Xiaogang Wang, Guangfeng Ruan, Su’an Tang, Changhai Ding, Bin Huang, Zhipeng Zou, Tianyu Chen · 发表于：Nature Communications · 年份：2024 · DOI：10.1038/s41467-024-53119-2 · 被引用次数：38 · 研究领域：Bone Metabolism and Diseases、Bone health and treatments、Osteoarthritis Treatment and Mechanisms

Abnormal subchondral bone remodeling plays a pivotal role in the progression of osteoarthritis (OA). Here, we analyzed subchondral bone samples from OA patients and observed a significant upregulation of ubiquitin carboxy-terminal hydrolase L1 (UCHL1) specifically in subchondral bone osteoclasts. Notably, we found a strong correlation between UCHL1 expression and osteoclast activity in the subchondral bone during OA progression in both human and murine models. Conditional UCHL1 deletion in osteoclast precursors exacerbated OA progression, while its overexpression, mediated by adeno-associated virus 9, alleviated this process in male mice. Mechanistically, RANKL stimulates UCHL1 expression in osteoclast precursors, subsequently stabilizing CD13, augmenting soluble CD13 (sCD13) release, and triggering an autocrine inhibitory effect on the MAPK pathway, thereby suppressing osteoclast formation. These findings unveil a previously unidentified negative feedback loop, RANKL-UCHL1-sCD13, that modulates osteoclast formation and presents a potential therapeutic target for OA. Abnormal subchondral bone remodeling plays a pivotal role in the progression of osteoarthritis. Here, the authors reveal a negative feedback loop, RANKL-UCHL1-sCD13, which limits osteoclastogenesis in the subchondral bone to prevent osteoarthritis progression.