Restoring cartilage-subchondral bone metabolism with biphasic magnesium microspheres ameliorate early osteoarthritis

The spatiotemporal histopathological features of articular cartilage in osteoarthritis (OA) remain inadequately characterized, which impedes the advancement of strategies to halt irreversible joint deterioration. Herein a murine OA model, the initial phase (<10 days post-surgery) is characterized by pronounced mitochondrial dysfunction in chondrocytes and concurrent activation of subchondral osteoclasts. Beyond this period, irreversible cartilage degeneration ensues, marked by chondrocyte apoptosis and subchondral bone sclerosis. We further identified magnesium (Mg) as a key regulator of cellular metabolic balance, capable of reinstating homeostasis in inflamed chondrocytes while modulating osteoclast overactivity. Based on this, we developed dual-concentration Mg-releasing biphasic microspheres that effectively halted early OA progression in vivo. In contrast, delayed administration conferred benefits predominantly limited to the subchondral bone, without achieving cartilage preservation. These results underscore the existence of a critical therapeutic window for metabolic intervention in OA, wherein Mg-based biomaterials exert protective effects exclusively during the early disease stage. Thus, this study offers a new strategic perspective for the clinical management of OA.