Osteoclast-secreted galectin-3 promotes articular cartilage degeneration in OVX rats via LRP1/beta-catenin axis.

Abstract

OBJECTIVE: Postmenopausal women exhibit a higher incidence of osteoarthritis (OA) than age-matched men. This study aimed to investigate the effects of osteoclasts under estrogen deficiency on chondrocytes and to elucidate the associated molecular mechanisms. DESIGN: Rat ovariectomy-induced OA (OVX-OA) model was employed to induce bone loss and cartilage degeneration. Chondrocytes were co-cultured with osteoclasts derived from OVX or sham-operated rats. Proteomics was employed to screen proteins mediating the osteoclast-chondrocyte interaction. Co-immunoprecipitation combined with proteomics was employed to investigate the molecular mechanisms through which the screened protein induces chondrocyte dysfunction. RESULTS: Subchondral bone loss induced OA-like phenotypes, manifested by reduced proteoglycan content (-0.33 [95% confidence interval (CI): -0.47 to -0.19]) and disrupted metabolism in chondrocyte. When co-cultured with osteoclasts derived from OVX rats, chondrocytes exhibited enhanced catabolism and suppressed anabolism (matrix metalloproteinases (MMP) 13: 1.52 [1.16 to 1.88], COL2A1: -0.60 [-0.78 to -0.42]). These effects were reversible when osteoclasts were pretreated with the osteoclast inhibitor alendronate. We identified galectin-3 (Gal-3) as the key mediator of osteoclast-induced chondrocyte dysfunction. Gal-3 knockdown in osteoclasts reversed the detrimental effects of osteoclasts on chondrocytes. Gal-3 was found to interact with LRP1, activating the β-catenin pathway and promoting OA development. CONCLUSIONS: Osteoclast-secreted Gal-3 promotes articular cartilage degeneration in OVX rats by combining with LRP1 and activating β-catenin pathway in chondrocytes. Targeting Gal-3 could be a promising therapeutic strategy for estrogen deficiency-associated OA.