MICRORNAS AS MECHANOBIOLOGICAL REGULATORS AND BIOMARKERS FOR TENDON REGENERATION

The remodeling of tendon tissue in response to physical activity is regulated by a complex interplay of anabolic and catabolic signals. Mechanical forces generated during exercise or daily activities influence cellular behaviors, including proliferation, differentiation, and matrix production, which are critical for tendon homeostasis and regeneration. For decades, it has been recognized that physical therapy and exercise are essential for successful rehabilitation after tendon injuries or surgical repairs. However, the underlying mechanisms of tendon healing in the context of mechanobiology remain incompletely understood. Investigating the molecular regulators of these mechanobiological pathways is therefore crucial for advancing our understanding of tendon adaptation to exercise and healing. MicroRNAs (miRNAs), a family of small non-coding RNAs, have emerged as promising candidates for tissue-specific biomarkers of injury, disease, and remodeling processes. These molecules regulate gene expression and protein production across diverse biological pathways. Circulating and exosomal miRNAs have been extensively studied in cancer, cardiovascular diseases, and musculoskeletal adaptation to exercise, particularly in muscle and bone remodeling. However, the role of miRNAs in tendon mechanobiology remains poorly understood, largely due to the low vascularization and metabolic activity of tendons compared to muscles and bones. This limits the pace of tendon adaptation to exercise and complicates the identification of molecular markers for tendon injury or remodeling. However, recent evidence highlights the potential of miRNAs as markers of tendon remodeling and degeneration severity. The downregulation of specific miRNAs, such as miR-29a, miR-29c, miR-210-3p, and miR-140-3p, has been reported in chronic tendinopathy and degenerative tendon conditions, suggesting their implication in such processes. Additionally, we have reported the upregulation of antifibrotic miRNAs, including miR-16-5p and miR-133a-3p, during the early stages of tendon-to-bone enthesis healing, which highlights these miRNAs as potential therapeutic candidates for tendon-to-bone enthesis repair. However, a correlation between tendon-specific miRNA expression and mechanical loading or exercise intensity has yet to be established. Exploring the dynamic interactions between miRNAs and mechanical forces in tendon tissue could provide valuable insights into tendon adaptation, injury and recovery, which could inspire novel therapeutic strategies. This knowledge has the potential to transform tendon rehabilitation and sports medicine, offering new diagnostic and regenerative solutions to improve patient outcomes.