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

Nat Commun. 2024 Oct 10;15(1):8792. doi: 10.1038/s41467-024-53119-2.

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.

MeSH terms

  • Aged
  • Animals
  • Bone and Bones / metabolism
  • Bone and Bones / pathology
  • Disease Models, Animal
  • Disease Progression*
  • Feedback, Physiological
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Osteoarthritis* / genetics
  • Osteoarthritis* / metabolism
  • Osteoarthritis* / pathology
  • Osteoclasts* / metabolism
  • Osteogenesis*
  • RANK Ligand* / genetics
  • RANK Ligand* / metabolism
  • Ubiquitin Thiolesterase* / genetics
  • Ubiquitin Thiolesterase* / metabolism

Substances

  • RANK Ligand
  • Ubiquitin Thiolesterase
  • TNFSF11 protein, human
  • Tnfsf11 protein, mouse