Suppression of experimental knee osteoarthritis by combination therapy of cross-linked hyaluronate and corticosteroids via anti-senescent effects

Osteoarthritis (OA) mainly affects the knee joint. Senescence and inflammation are key factors in knee OA pathogenesis, suggesting a potential therapeutic target. This study aims to explore the therapeutic effects of the optimized cross-linked hyaluronate (cHA) combined with corticosteroids formulation in mitigating OA progression by targeting anti-senescence. Human OA chondrocytes underwent treatment with various cHA formulations along with DEX, and assessments were made by cell viability, senescence phenotypes, and gene expression, including inflammatory cytokines, and matrix metalloproteinases (MMPs). Furthermore, in a rat OA model, the therapeutic effects of the targeted cHA + DEX formulations were evaluated via dynamic weight-bearing tests, micro-CT scans, histopathological and immunohistochemical examinations, and qRT-PCR analysis. Formulations of cHA(50:50) + DEX and cHA(20:80) + DEX effectively shielded chondrocytes from DEX-induced cytotoxicity and senescence, concurrently reducing inflammatory and matrix-degrading enzyme expressions. In the rat OA model, cHA(50:50) + DEX significantly ameliorated OA features, including histological scores and dynamic weight bearing ratio (p < 0.05, both), while suppressing senescence and inflammation marker expressions. Our findings underscore the effects of cHA(50:50) + DEX combination in mitigating OA progression by addressing senescence and inflammatory responses, so called inflammaging.