NLRP3 Inflammasome‐Mediated Pyroptosis in Osteoporosis: Osteoimmune Mechanisms and Therapeutic Targeting

Osteoporosis (OP) is a chronic, age-related skeletal disorder characterised by progressive bone loss and microstructural deterioration, which increases bone fragility and fracture risk. The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, a multi-subunit protein complex involved in bone homeostasis, mediates inflammatory cascades in response to external stimuli and pathological conditions. This process triggers pyroptosis in various bone-related cells, disrupting bone repair and remodelling. Oestrogen deficiency and aging lead to the overactivation of the NLRP3 inflammasome, stimulate bone immunity, metabolism and other abnormalities and disrupt angiogenesis-osteogenesis coupling. These factors contribute significantly to the pathological progression of OP. However, the precise mechanisms remain poorly understood and are lacking clinical validation. Therefore, this review summarises the mechanisms of NLRP3 inflammasome in response to bone immune signals, external stress and intercellular communication, as well as its role in metabolic regulation, including reprogramming and post-translational modification, thereby influencing pyroptosis in macrophages, endothelial cells, mesenchymal stem cells and osteoblasts. It explores potential therapeutic strategies that target NLRP3 activation, including exosome (Exos)-based interventions and traditional Chinese medicine components, which may modulate its differential expression and affect angiogenesis-osteogenesis differentiation. These approaches offer promising avenues for the prevention and treatment of OP.