Resveratrol and Curcumin Attenuate <i>Ex Vivo</i> Sugar-Induced Cartilage Glycation, Stiffening, Senescence, and Degeneration
Shikhar Mehta, Cameron C. Young, Matthew R. Warren, Sumayyah Akhtar, Sandra J. Shefelbine, Justin D. Crane, Ambika G. Bajpayee
Abstract
OBJECTIVE: Advanced glycation end-product (AGE) accumulation is implicated in osteoarthritis (OA) pathogenesis in aging and diabetic populations. Here, we develop a representative nonenzymatic glycation-induced OA cartilage explant culture model and investigate the effectiveness of resveratrol, curcumin, and eugenol in inhibiting AGEs and the structural and biological hallmarks of cartilage degeneration. DESIGN: Bovine cartilage explants were treated with AGE-bovine serum albumin, threose, and ribose to determine the optimal conditions that induce physiological levels of AGEs while maintaining chondrocyte viability. AGE crosslinks, tissue stiffness, cell viability, metabolism and senescence, nitrite release and loss of glycosaminoglycans were assessed. Explants were cotreated with resveratrol, curcumin, or eugenol to evaluate their anti-AGE properties. Blind docking analysis was conducted to estimate binding energies of drugs with collagen II. RESULTS: Treatment with 100 mM ribose significantly increased AGE crosslink formation and tissue stiffness, resulting in reduced chondrocyte metabolism and enhanced senescence. Blind docking analysis revealed stronger binding energies of both resveratrol and curcumin than ribose, with glycation sites along a human collagen II fragment, indicating their increased likelihood of competitively inhibiting ribose activity. Resveratrol and curcumin, but not eugenol, successfully inhibited AGE crosslink formation and its associated downstream biological response. CONCLUSIONS: nonenzymatic glycation-induced model provides a tool for screening OA drugs, to simultaneously evaluate AGE-induced biological and mechanical changes.