Macrophage reprogramming in degenerative musculoskeletal diseases: From tissue-niche biology to therapeutic translation.

Degenerative musculoskeletal diseases (DMSDs), including osteoarthritis (OA), osteoporosis (OP), intervertebral disc degeneration (IVDD), and sarcopenia (SP), impose a major burden through pain, structural deterioration, mobility loss, fracture risk, and functional decline. Although these disorders are often grouped as age-related musculoskeletal conditions, they arise from distinct tissue niches and cannot be explained by a single pathogenic mechanism. Macrophages occupy a central position at the interface between degenerative stress and tissue outcome, but their functions extend far beyond a binary M1/M2 polarization model. This Review proposes a disease-niche-adapted framework for macrophage reprogramming in DMSDs. In this framework, macrophages are interpreted according to the pathological tasks they perform within each tissue environment: inflammatory amplification and pain-related synovial crosstalk in OA, osteoimmune remodeling in OP, immune-barrier disruption and macrophage-nucleus pulposus (NP) cell feedback in IVDD, and impaired regenerative support in aging muscle in SP. We discuss how macrophage functional states are shaped by transcriptional and epigenetic regulation, immunometabolic rewiring, inflammatory signaling, autophagy and organelle quality control, and local niche-derived cues. Therapeutic strategies are then evaluated according to whether they interrupt upstream niche stress, redirect inflammatory and metabolic decoding, restore quality-control capacity, or reshape macrophage-mediated tissue communication. Finally, we propose that macrophage-targeted therapy should be assessed through a hierarchy of evidence, progressing from marker changes to functional reprogramming, macrophage-causal validation, and disease-specific structural or functional improvement. This framework may help convert macrophage plasticity from a broad immunological concept into a more precise, testable, and disease-adapted therapeutic strategy for musculoskeletal degeneration. The translational potential of this article: This Review provides a disease-niche-adapted framework for evaluating macrophage reprogramming in degenerative musculoskeletal diseases. By linking disease-specific macrophage tasks with regulatory mechanisms, therapeutic entry points, causal validation, delivery feasibility, and tissue-relevant endpoints, this framework may help guide both the design and translational assessment of macrophage-targeted interventions for musculoskeletal degeneration.