A RANKL-UCHL1-sCD13 negative feedback loop limits osteoclastogenesis in subchondral bone to prevent osteoarthritis progression
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.
Authors
- Tianyu Chen (ORCID: https://orcid.org/0000-0001-7056-2947)
- Wenquan Liang (ORCID: https://orcid.org/0000-0003-0881-6808)
- Guangfeng Ruan (ORCID: https://orcid.org/0000-0002-1471-7358)
- Changhai Ding (ORCID: https://orcid.org/0000-0002-9479-730X)
- Xiaojia Li
- Zhipeng Zou (ORCID: https://orcid.org/0000-0003-0421-4738)
- Su’an Tang (ORCID: https://orcid.org/0000-0002-1391-5838)
- Bin Huang (ORCID: https://orcid.org/0000-0001-6295-6647)
- Xiaogang Wang (ORCID: https://orcid.org/0000-0001-9798-834X)
- Jun Chen (ORCID: https://orcid.org/0000-0001-9896-6898)
- Junqi Chen
- Yicheng Li (ORCID: https://orcid.org/0000-0003-4431-0003)
- Xingwei Duan
- Zezheng Liu (ORCID: https://orcid.org/0009-0000-2285-593X)
- Shourui Feng
- Ru Feng (ORCID: https://orcid.org/0000-0001-5758-1609)
Institutions
- Hebei Medical University (CN)
- Sun Yat-sen University (CN)
- Capital Medical University (CN)
- China Rehabilitation Research Center (CN)
- Third Hospital of Hebei Medical University (CN)
- Third Affiliated Hospital of Southern Medical University (CN)
- Nanfang Hospital (CN)
- Guangzhou First People's Hospital (CN)
- Zhujiang Hospital (CN)
- Southern Medical University (CN)
- Guangzhou Medical University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-10-10
- DOI
- https://doi.org/10.1038/s41467-024-53119-2
- Citations
- 30
- Primary Topic
- Bone Metabolism and Diseases
- Type
- article
- Field-Weighted Citation Impact
- 7.01
Funders
- National Natural Science Foundation of China
- Natural Science Foundation of Guangdong Province
- Natural Science Foundation of Hebei Province
- Hebei Medical University
- Basic and Applied Basic Research Foundation of Guangdong Province