Decoding melatonin's role in musculoskeletal health: mechanistic foundations and clinical applications

Melatonin (N‑acetyl‑5‑methoxytryptamine), traditionally viewed as a pineal neurohormone regulating circadian rhythms, is now recognized as a pleiotropic molecule with significant implications for musculoskeletal (MSK) health. Its receptor‑dependent and receptor‑independent actions influence bone, cartilage, muscle, tendon, ligament, and spine biology, positioning melatonin as a potential therapeutic agent across diverse MSK pathologies.

Experimental, translational, and clinical studies were surveyed to evaluate melatonin's role in MSK medicine. The literature was analyzed for insights into molecular mechanisms, therapeutic targets, and clinical applications, with particular emphasis on receptor signaling pathways, antioxidant and mitochondrial effects, and epigenetic regulation. Evidence spanning bone, cartilage, muscle, tendon, ligament, spine, and autoimmune MSK conditions was incorporated to provide a comprehensive synthesis.

Melatonin exerts its effects through MT1/MT2 receptor signaling, stabilization of Wnt/β‑catenin pathways, modulation of circadian clock genes, andreceptor‑independent mechanisms such as antioxidant activity, mitochondrial protection, and regulation via non‑coding RNAs. In bone biology, it enhances osteoblastogenesis, suppresses osteoclastogenesis, and modulates RANKL/OPG and NLRP3 inflammasome pathways, thereby mitigating osteoporosis and accelerating fracture healing through angiogenesis and callus formation, although dosing requires careful optimization to balance remodeling. In cartilage, melatonin resynchronizes disrupted circadian clocks, inhibits NF‑κB‑mediated inflammation, and preserves extracellular matrix integrity, with novel delivery systems currently under investigation. Skeletal muscle studies highlight its role in Pax7 regulation and Wnt signaling, contributing to the prevention of sarcopenia and cachexia. Evidence also supports its benefits in tendon and ligament repair, while in spinal pathologies melatonin demonstrates protective effects against intervertebral disc degeneration, spinal cord injury, and chronic back pain. Beyond structural tissues, melatonin exhibits cytoprotective roles in musculoskeletal oncology and shows therapeutic promise in systemic autoimmune conditions such as rheumatoid arthritis, lupus, gout, and fibromyalgia. Clinical trials further reveal analgesic, sedative, and sleep‑modulating effects, though translation gaps remain regarding optimal dosing strategies and bioavailability.

Melatonin is a multifaceted agent bridging molecular cytoprotection with translational musculoskeletal medicine. Its diverse actions across bone, cartilage, muscle, tendon, ligament, and spine highlight therapeutic promise. However, clinical translation requires precision‑based dosing strategies, improved bioavailability, and rigorous validation in large‑scale trials to fully establish its role in MSK health.