Subchondral Implantation of Artemisinin-Loaded Hyaluronic Acid Methacrylate Hydrogel Ameliorates Osteoarthritis

Background: Knee osteoarthritis (KOA) involves pathological subchondral bone remodeling and aberrant bone–cartilage crosstalk. This study investigated Runt-related transcription factor 2 (Runx2) upregulation in osteoarthritis (OA) osteoblasts and evaluated an artemisinin-loaded hyaluronic acid methacryloyl (HAMA-ART) hydrogel for localized modulation of the subchondral bone microenvironment. Methods: HAMA-ART was characterized for morphology, chemical composition, ART release, degradation, mechanical properties, and biocompatibility. Its effects on osteoblast–chondrocyte paracrine communication were assessed in vitro using conditioned medium-based experiments. Therapeutic efficacy was evaluated by in situ implantation into the subchondral bone of a rat OA model induced by destabilization of the medial meniscus. Results: HAMA-ART exhibited a porous network, sustained ART release, gradual degradation, and acceptable biocompatibility. It attenuated aberrant Runx2 upregulation in OA osteoblasts and reduced their pathological paracrine effects on chondrocytes, as indicated by decreased Matrix Metalloproteinase 13 (MMP13) and Type X Collagen (COLX) expression and preserved Type II Collagen Alpha 1 (COL2A1) expression. In vivo, HAMA-ART ameliorated OA-associated subchondral bone microstructural deterioration. Histological analysis showed lower Mankin scores, preserved cartilage thickness, and improved cartilage matrix homeostasis compared with untreated OA controls. Conclusions: HAMA-ART attenuated Runx2 upregulation in OA osteoblasts and alleviated subchondral bone remodeling and cartilage degeneration. Localized subchondral delivery may provide a potential strategy for OA treatment.