GelMA@APPA microspheres promote chondrocyte regeneration and alleviate osteoarthritis via Fgfr2 activation

Background: In the context of osteoarthritis (OA), a condition marked by joint degeneration, there is a notable absence of efficacious approaches to promote regenerative healing in chondrocytes. Novel therapeutic strategies like nanomicelles-hydrogel microspheres loaded with Astragalus polysaccharide (GelMA@APPA) offer promising avenues for promoting chondrocyte regeneration and mitigating OA progression.

Methods: Astragalus polysaccharide (APS) has been shown to induce chondrocyte proliferation and promote cartilage matrix secretion, demonstrating biological activity associated with chondrocyte regeneration. However, the clinical efficacy of APS remains uncertain. Therefore, this investigation validated the beneficial impact of APS on reducing knee joint damage severity induced by destabilization of the medial meniscus (DMM) in mice. The application of bioinformatics analysis and in vitro experimentation revealed that fibroblast growth factor receptor 2 (Fgfr2) in chondrocytes is a key target protein for APS in ameliorating OA-induced cartilage injury, as the deletion of chondrocyte Fgfr2 resulted in the complete loss of the therapeutic effect of APS. To enhance the efficacy of APS, we incorporated APS into nanoparticle-laden hydrogel microspheres to further bolster its potential in chondrocyte regeneration therapy. Subsequently, we developed GelMA@APPA, which exhibited no significant cytotoxic effects on normal chondrocytes in vitro and could be efficiently internalized by chondrocytes. Following subsequent in vitro and in vivo experiments, we affirmed the beneficial effects of GelMA@APPA on OA mice and cartilage cells damaged by OA, as well as its enhancement of the therapeutic effects of APS.

Results: APS significantly improved knee joint injuries in OA mice. Bioinformatics and in vitro analyses identified Fgfr2 as a critical target protein for APS's regenerative effects. Disruption of Fgfr2 negated APS's benefits. GelMA@APPA demonstrated good biocompatibility, effective internalization by chondrocytes, and enhanced the therapeutic efficacy of APS in experiments conducted both in vitro and in vivo, improving chondrocyte proliferation and reducing apoptosis.

Conclusions: This study demonstrates that GelMA@APPA microspheres effectively promote chondrocyte regeneration and OA treatment by activating Fgfr2. These findings suggest a novel therapeutic mechanism for OA and lay the groundwork for future clinical utilization of GelMA@APPA in regenerative medicine.