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

Author

Listed:
  • Wenquan Liang

    (Southern Medical University
    Southern Medical University)

  • Ru Feng

    (The Third Affiliated Hospital of Southern Medical University
    Capital Medical University
    China Rehabilitation Research Center)

  • 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
    Third Hospital of Hebei Medical University)

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.

Suggested Citation

  • 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 & Zhipen, 2024. "A RANKL-UCHL1-sCD13 negative feedback loop limits osteoclastogenesis in subchondral bone to prevent osteoarthritis progression," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53119-2
    DOI: 10.1038/s41467-024-53119-2
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    References listed on IDEAS

    as
    1. William J. Boyle & W. Scott Simonet & David L. Lacey, 2003. "Osteoclast differentiation and activation," Nature, Nature, vol. 423(6937), pages 337-342, May.
    2. Julia Reichelt & Wiebke Sachs & Sarah Frömbling & Julia Fehlert & Maja Studencka-Turski & Anna Betz & Desiree Loreth & Lukas Blume & Susanne Witt & Sandra Pohl & Johannes Brand & Maire Czesla & Jan Kn, 2023. "Non-functional ubiquitin C-terminal hydrolase L1 drives podocyte injury through impairing proteasomes in autoimmune glomerulonephritis," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
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