Programmed cell death in degenerative skeletal diseases: molecular crosstalk and combinatorial therapeutic strategies.

Degenerative skeletal diseases, including osteoarthritis (OA), intervertebral disc degeneration (IVDD) and osteoporosis (OP), are major causes of chronic pain, disability and loss of skeletal function, yet effective disease-modifying therapies remain limited. Although these disorders affect distinct tissues and cell populations, they share persistent inflammation, oxidative stress, mitochondrial dysfunction, metabolic imbalance and defective tissue remodelling. Programmed cell death (PCD) is a critical link between these disturbances and progressive structural failure. Apoptosis, pyroptosis, necroptosis, ferroptosis and autophagy-associated cell-fate regulation rarely operate independently. Their activation and biological consequences are determined by cell type, anatomical niche, disease stage and stress intensity. However, the concurrent detection of multiple death-associated markers is often misinterpreted as mechanistic crosstalk, hindering accurate identification of causal pathways and therapeutic targets. This Review proposes an evidence-graded, disease-stage-, cell-type- and microenvironment-dependent framework for interpreting PCD interactions in OA, IVDD and OP. It distinguishes shared upstream triggers, convergent regulatory nodes, sequential transitions, direct molecular conversion and functional coexistence according to their evidential strength. We further evaluate therapeutic strategies targeting the cell death-inflammation-metabolism axis, including multi-target agents, nanomaterials, extracellular vesicles, biomaterials and tissue engineering. Most evidence remains preclinical, underscoring the urgent need for human validation, causal target confirmation and rigorous assessment of delivery, durability, safety and manufacturability. This framework may improve mechanistic precision and accelerate the development of context-specific therapies for degenerative skeletal diseases.