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

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.

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