Quercetin Attenuates Osteoarthritis Through SIRT1-Dependent Regulation of Synovial Macrophage Polarisation
Description
Background: Dysregulated immunoregulation of synovial macrophages, notably excessive M1 polarisation, is a critical driver of osteoarthritis (OA) progression. The role of silent information regulator 1 (SIRT1) in this process, and its potential as a therapeutic target, remain incompletely defined. This study aimed to clarify the protective effects and underlying molecular mechanisms of quercetin, a SIRT1 agonist, in regulating the polarisation of synovial macrophages in OA. Methods: SIRT1 expression and M1-associated markers were assessed in synovial tissues from patients with OA. Myeloid-specific SIRT1-deficient mice were generated, and OA was induced via destabilisation of the medial meniscus (DMM). Mice received quercetin, with or without the selective SIRT1 inhibitor EX527. Bone marrow-derived macrophages were stimulated with lipopolysaccharide (LPS) to induce M1 polarisation and subsequently exposed to quercetin. Molecular and cellular assays evaluated SIRT1/NF-κB P65 signalling and macrophage polarisation. Results: SIRT1 expression was markedly reduced in OA synovium from patients and models, inversely correlating with disease severity, while M1 polarisation increased. Myeloid-specific SIRT1 deficiency worsened synovial inflammation, cartilage degradation, and subchondral bone remodelling. Quercetin restored SIRT1 activity, suppressed M1 polarisation, and reduced pro-inflammatory cytokines and matrix metalloproteases, alleviating OA pathology. These effects were abolished by pharmacological inhibition or genetic deletion of SIRT1. Conclusion: Quercetin mitigates OA progression by modulating synovial macrophage polarisation via a SIRT1-dependent pathway that suppresses NF-κB P65 signalling. SIRT1 emerges as a key regulator of macrophage-driven inflammation, supporting quercetin as a promising therapeutic agent in OA.