Quercetin attenuates osteoarthritis through SIRT1-dependent regulation of synovial macrophage polarisation.

Excessive M1 polarisation of synovial macrophages contributes substantially to the dysregulated immune environment that drives osteoarthritis (OA) progression, although the role of silent information regulator 1 (SIRT1) and its therapeutic relevance remain uncertain. We investigated whether quercetin protects against OA by modulating synovial macrophage polarisation and SIRT1-related signalling. SIRT1 expression and M1-associated markers were examined in synovial tissues from patients with OA. Myeloid-specific SIRT1-deficient mice were generated, and OA was induced by destabilisation of the medial meniscus (DMM). The animals received quercetin, either alone or together with the selective SIRT1 inhibitor EX527. In parallel, bone marrow-derived macrophages (BMDMs) were stimulated with lipopolysaccharide (LPS) to induce M1 polarisation before quercetin treatment. Molecular and cellular assays were used to evaluate macrophage polarisation and NF-κB p65 signalling. SIRT1 expression was markedly reduced in OA synovium and was lower in severe OA than in moderate OA, whereas M1 polarisation was enhanced. Myeloid-specific SIRT1 deficiency aggravated synovial inflammation, cartilage degradation, and subchondral bone remodelling. Quercetin increased SIRT1 activity, suppressed M1 polarisation, lowered pro-inflammatory cytokine and matrix metalloproteinase expression, and alleviated OA pathology. These protective effects were weakened by either pharmacological inhibition or genetic deletion of SIRT1. Collectively, the findings suggest that quercetin attenuates OA progression by regulating synovial macrophage polarisation through a mechanism that is at least partly dependent on SIRT1 and associated with modulation of NF-κB p65 signalling.