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

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 () and Tianyu Chen ()
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Wenquan Liang: Southern Medical University
Ru Feng: The Third Affiliated Hospital of Southern Medical University
Xiaojia Li: The Third Affiliated Hospital of Southern Medical University
Xingwei Duan: Southern Medical University
Shourui Feng: Sun Yat-sen University
Jun Chen: Nanfang Hospital of Southern Medical University
Yicheng Li: The Third Affiliated Hospital of Southern Medical University
Junqi Chen: The Third Affiliated Hospital of Southern Medical University
Zezheng Liu: The Third Affiliated Hospital of Southern Medical University
Xiaogang Wang: The Third Affiliated Hospital of Southern Medical University
Guangfeng Ruan: Guangzhou First People’s Hospital
Su’an Tang: Southern Medical University
Changhai Ding: Southern Medical University
Bin Huang: The Third Affiliated Hospital of Southern Medical University
Zhipeng Zou: Southern Medical University
Tianyu Chen: The Third Affiliated Hospital of Southern Medical University

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-53119-2

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