Osteocyte-specific gasdermin D deletion accelerates osteoarthritis via promoting subchondral inflammation and remodeling

Abstract Subchondral bone remodeling in the early stages of osteoarthritis (OA) is characterized by elevated bone turnover and is closely associated with osteocyte function within the subchondral bone. However, beyond the canonical role of gasdermin D (GSDMD) in mediating pyroptosis in immune cells, its function in osteocytes remains poorly understood. Accordingly, this study aimed to determine whether osteocyte-derived GSDMD regulates subchondral bone homeostasis or contributes to pathological remodeling during osteoarthritis progression. GSDMD expression was evident in osteocytes within the subchondral bone in both clinical and experimental models of OA, as well as in osteocytes co-cultured with stimulated chondrocytes, suggesting a potential role for osteocyte-derived GSDMD in the bone microenvironment. Remarkably, specific deletion of Gsdmd in osteocytes led to increased bone remodeling, which was accompanied by cartilage degeneration in an OA model, as well as bone loss in an osteoporosis model. Mechanistically, Gsdmd -deficient osteocytes displayed enhanced activation of CARD9/NF-κB signaling under inflammatory stimulation, leading to increased production of inflammatory mediators and osteoclastogenic factors that disrupted osteoblast-osteoclast coupling. These changes induced high-turnover subchondral bone remodeling, altered joint mechanical properties, and accelerated cartilage degeneration. Collectively, our findings identify osteocyte-derived GSDMD as an important regulator of subchondral bone remodeling and suggest that loss of this regulatory mechanism exacerbates OA progression. These results further indicate that therapeutic strategies targeting GSDMD should be approached with caution due to potential effects on bone remodeling and inflammatory signaling.