Autophagy-pyroptosis crosstalk in osteoporosis: Linking mitochondrial homeostasis to inflammatory bone remodeling.
TL;DR
Experimental studies link impaired mitochondrial quality control to osteogenic dysfunction and inflammasome-associated inflammatory responses and Crosstalk between impaired autophagy, mitochondrial dysfunction, and NLRP3-associated pyroptosis may represent an important mechanism linking disrupted cellular homeostasis to inflammatory bone remodeling in osteoporosis.
Abstract
Background
Imbalanced bone formation and resorption is the central pathological feature of osteoporosis, while chronic low-grade inflammation contributes to progressive disruption of the bone marrow microenvironment. Emerging evidence suggests that NLRP3 inflammasome-mediated pyroptosis may amplify local inflammation by promoting the release of IL-1β, IL-18, and damage-associated molecular patterns. Autophagy, particularly mitophagy, may restrain this process by maintaining mitochondrial quality control and limiting oxidative stress and inflammasome activation.
Methods
Relevant clinical, animal, and cellular studies were narratively synthesized. Targeted supplementary web searches of PubMed-indexed records and publisher websites were conducted during revision on October 25, 2026, focusing on autophagy, mitophagy, mitochondrial dysfunction, inflammasome signaling, and pyroptosis in osteoporosis. Eligibility criteria were described; no formal risk-of-bias assessment was performed.
Results
Experimental studies link impaired mitochondrial quality control to osteogenic dysfunction and inflammasome-associated inflammatory responses. Evidence for pyroptotic injury involves canonical caspase-1/GSDMD-associated signaling and GSDME-associated osteoblast injury, although the supporting models and causal interventions differ. Mitophagy can preserve BMSC and osteoblast function while supporting osteoclast metabolism, and NLRP3 interventions produce divergent effects on osteoclast differentiation and resorption. Selected intercellular interactions have experimental support, but the complete multicellular feedback network and its temporal organization remain unresolved. Human findings establish disease associations more clearly than fracture prediction or therapeutic efficacy.
Conclusion
Crosstalk between impaired autophagy, mitochondrial dysfunction, and NLRP3-associated pyroptosis may represent an important mechanism linking disrupted cellular homeostasis to inflammatory bone remodeling in osteoporosis. Restoring mitochondrial quality control while limiting excessive inflammasome activation and pyroptosis may provide potential strategies for mitigating inflammatory bone loss. However, the available evidence is predominantly derived from cellular and animal models. Further studies using cell-specific genetic interventions, longitudinal models, and spatial approaches are required to clarify the cell- and disease-stage-dependent functions of this regulatory network.