Journal of orthopaedic translationOct 31, 2026

Changing immune cells in joint and muscle diseases: from local tissue roles to treatment possibilities

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Nov 2, 2026

Abstract

Macrophages play a central role in the outcomes of degenerative musculoskeletal diseases (DMSDs) through diverse functions beyond simple polarization.

DMSDs include osteoarthritis, osteoporosis, intervertebral disc degeneration, and sarcopenia, each arising from unique tissue environments.
Macrophages contribute to various pathological tasks, such as amplifying inflammation in osteoarthritis and disrupting immune barriers in intervertebral disc degeneration.
Functional states of macrophages are influenced by factors such as gene regulation, metabolic changes, and local tissue signals.
Therapeutic approaches targeting macrophages may focus on altering stress responses, modulating inflammation, restoring cellular quality control, or improving tissue communication.
A proposed framework for macrophage-targeted therapy emphasizes the need for evidence progression, from identifying markers to achieving functional and structural improvements.

Simplified

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.

Full Text

Full text is available at the source.

View Full Text ↗

Changing immune cells in joint and muscle diseases: from local tissue roles to treatment possibilities

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

What Lands in Your Inbox Each Week:

Recent issues from the longevity & aging brief