Leucine Attenuates Osteoarthritis via mTORC1/LXRα-Mediated Macrophage Reprogramming and Rspo2/β-Catenin Axis Suppression

  • Cartilage. 2025 Nov 7:19476035251389178. doi: 10.1177/19476035251389178.
Ke Zheng  1  2 ,  Jiebin Zhang  2 ,  Wenxiang Liu  2 ,  Bin Xu  1
Affiliations
  • 1. Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
  • 2. Department of Orthopedics, Anhui No.2 Provincial People's Hospital, Hefei, China.
PMID: 41200799 DOI: 10.1177/19476035251389178
Abstract

ObjectiveThis study investigates the molecular mechanism by which leucine (Leu) ameliorates collagenase-induced osteoarthritis (CIOA) through macrophage polarization regulation.MethodsA CIOA mouse model was established and evaluated by micro-computed tomography (micro-CT) and histopathological analysis. Leu intervention was administered, and its therapeutic effects on cartilage degeneration and osteophyte formation were assessed. Integrated multi-omics analyses and mechanistic assays were performed to explore the role of the mTORC1/LXRα pathway in synovial macrophage reprogramming and its regulation of the Rspo2/β-catenin axis in chondroprogenitors. Functional validation was conducted using the LXRα inhibitor GSK2033.ResultsLeu intervention demonstrated significant therapeutic effects, reducing cartilage degeneration by 42% (Osteoarthritis Research Society International [OARSI] score) and osteophyte formation by 58% (volume reduction). Integrated multi-omics and mechanistic assays indicated that Leu activated mTORC1/LXRα to reprogram synovial macrophages toward an M2-like state, suppressed Rspo2, and attenuated β-catenin signaling in chondroprogenitors, thereby improving cartilage function. Functional validation using LXRα inhibitor GSK2033 confirmed pathway specificity, reversing Leu-mediated cartilage protection and reactivating osteogenic differentiation.ConclusionThese findings establish a novel "metabolism-immunity-cartilage" axis in which Leu coordinates mTORC1/LXRα-driven macrophage reprogramming with Rspo2/β-catenin axis suppression, offering dual-target therapeutic potential for osteoarthritis. The study redefines nutritional Amino acids as immunometabolic modulators in degenerative joint diseases, proposing Leu supplementation as a viable strategy for interrupting the inflammation-bone remodeling cycle in traumatic arthritis. No clinical trials were involved in this preclinical investigation.

Keywords
R-spondin 2; leucine; macrophage polarization; mammalian target of rapamycin complex 1/liver X receptor α signaling pathway; β-catenin signaling pathway.
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