The use of molecular cues to regenerate musculoskeletal tissues.

Introduction: Musculoskeletal tissues, including bone, tendon, cartilage, and muscle, are vital for movement and structural support, yet, their repair after injury remains a significant clinical challenge. Their regeneration relies on complex molecular signaling that regulates inflammation, repair, and remodeling. Understanding these cues, offers opportunities to design targeted therapeutic strategies. Content: This review summarizes current evidence on molecular regulators of musculoskeletal tissue regeneration with emphasis on both shared and tissue-specific mechanisms across bone, tendon, cartilage and muscle. Key molecular cues include growth factors, cytokines, extracellular matrix-derived signals, and non-coding RNAs, particularly microRNAs. Critical pathways such as TGF-β, NF-κB, FGF, and YAP/TAZ can either promote healing or drive pathological fibrosis depending on their modulation. This review discusses therapeutic strategies targeting these molecular cues, including microRNA replacement therapies, small molecules, growth factor delivery, and pathway-specific inhibitors or activators. Summary and Outlook: Understanding how these molecular cues and pathways function and interact to regulate healing and regeneration offers valuable insight into tissue-specific and cross-tissue repair strategies. These advances may support the development of targeted therapies to enhance musculoskeletal regeneration and functional recovery. Furthermore, future research should focus on integrating these molecular insights with biomaterial and mechanobiological approaches to develop next-generation regenerative interventions.