Osteoclast-secreted galectin-3 promotes articular cartilage degeneration in OVX rat 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 were 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 induce chondrocyte dysfunction.

Results: Subchondral bone loss induced osteoarthritis-like phenotypes, manifested by reduced proteoglycan content (-0.33 [95%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 (ADAMTS5: 1.32 [1.082 to 1.559], MMP3: 1.44 [1.67 to 1.71], MMP13: 1.52 [1.16 to 1.88], ACAN: -0.70 [-0.92 to 0.48], 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 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 chondrocyte. Targeting Gal-3 could be a promising therapeutic strategy for estrogen deficiency-associated OA.