Targeting neuregulin-1 in cartilage homeostasis restoration: Kaempferol-3-o-rutinoside as a novel treatment for osteoarthritis.

BACKGROUND: Osteoarthritis (OA) is a progressive degenerative joint disease with no effective cure. Although Kaempferol-3-O-rutinoside (KR), a naturally occurring flavonoid glycoside, has demonstrated antioxidant and anti-inflammatory effects, however, its therapeutic potential in OA remains unexplored.

PURPOSE: This study aimed to investigate the chondroprotective and subchondral bone-preserving effects of KR in OA and to elucidate its underlying molecular mechanisms.

DESIGN: We assessed the effects of KR on chondrocyte viability, apoptosis, and the expression of inflammatory and catabolic mediators (MMP-13, ADAMTS5), as well as on anabolic markers in vitro. Chondrogenic differentiation was evaluated in adipose-derived mesenchymal stem cells (ADMSCs). We examined the in vivo efficacy of KR using a murine model of OA induced by anterior cruciate ligament transection (ACLT). Treatment outcomes were assessed based on Osteoarthritis Research Society International (OARSI) scoring and subchondral bone microstructural analysis. Finally, we performed mechanistic studies employing RNA sequencing, siRNA-mediated knockdown, and co-immunoprecipitation assays.

RESULTS: We found that KR enhanced chondrocyte viability, suppressed apoptosis, downregulated inflammatory and catabolic mediators, and upregulated anabolic marker expression in vitro. KR also promoted chondrogenesis in ADMSCs and improved cartilage integrity and subchondral bone microarchitecture in a murine model of OA. Silencing of NRG1 abolished the protective effects of KR. Mechanistically, KR disrupted the NRG1/ERBB3/GRB2 complex, thereby modulating the NRG1/AKT/mTOR signaling pathway.

CONCLUSION: KR was found to directly target the NRG1/AKT/mTOR axis, thereby conferring dual chondroprotective and bone-preserving effects in OA. These findings highlight the potential of KR as a therapeutic agent for OA.