Quercetin ameliorates rheumatoid arthritis-associated bone erosion via inhibiting the Wnt3a/β-catenin signaling axis.

BACKGROUND: Aberrant activation of the Wnt3A/β-catenin pathway is critically involved in the bone erosion of rheumatoid arthritis (RA). The natural flavonoid quercetin (QUE) ameliorates RA symptoms, but its mechanistic link to this pathway is poorly understood. This study investigated whether QUE attenuates bone destruction in collagen-induced arthritis (CIA) rats by inhibiting Wnt3A/β-catenin signaling. CIA rats were treated with QUE or methotrexate (MTX) for 28 days, and bone destruction, inflammatory cytokines, and the expression of Wnt3A/β-catenin were systematically assessed. RESULTS: Compared with normal rats, CIA rats exhibited significantly increased arthritis scores, hind paw volume, and pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-17 A), alongside decreased bone mass parameters (BMD, BV/TV, Tb.Th, Tb.N) and severe joint damage. Notably, Wnt3A and β-catenin were markedly upregulated in the spleen and joints. QUE intervention effectively reversed these changes: it alleviated clinical symptoms, improved bone microarchitecture, restored cytokine balance, and substantially downregulated the mRNA and protein expression of Wnt3A and β-catenin. The improvements in bone microarchitecture were comparable to those achieved with MTX. Importantly, QUE did not induce hepatorenal toxicity. CONCLUSIONS: These findings suggest that quercetin may protect against arthritic bone erosion at least in part by suppressing the Wnt3A/β-catenin pathway and coordinately regulating inflammatory-osteolytic coupling to attenuate synovitis and improve bone microarchitecture without observable toxicity. They also support its potential as a safe, disease-modifying agent for RA management, although further studies are needed to establish the direct causal relationship.