The role of the tendon ECM in mechanotransduction: disruption and repair following overuse

Purpose: Tendon overuse injuries are prevalent conditions with limited therapeutic options to halt disease progression. The specialized extracellular matrix (ECM) both enables joint function and mediates mechanical signals to tendon cells, driving biological responses to exercise or injury. With overuse, tendon ECM composition and structure changes at multiple scales, disrupting mechanotransduction and resulting in inadequate repair and disease progression. This review highlights the multiscale ECM changes that occur with tendon overuse and corresponding effects on cell-matrix interactions and cellular response to load.Results: Different functional joint requirements and tendon types experience a wide range of loading profiles, creating varied downstream mechanical stimuli. Distinct ECM structure and mechanical properties within the fascicle matrix, interfascicle matrix, and enthesis and their varied disruption with overuse are considered. The pericellular matrix (PCM) comprising the microscale tendon cell environment has a unique composition that changes with overuse injury and exercise, suggesting an important role in mechanotransduction and promoting repair. Cell-matrix interactions are mediated by structures including cilia, integrins, connexins and cytoskeleton that signal downstream homeostasis, adaptation, or repair. ECM disruption with tendon overuse may cause altered mechanical loading and cell-matrix interactions, resulting in mechanobiological understimulation, apoptosis, and ineffective repair. Current interventions to promote repair of tendon overuse injuries including exercise, targeting cell signaling, and modulating inflammation are considered.Conclusion: Future therapeutics should be assessed with regard of their effects on multiscale mechanotransduction in addition to joint function, with consideration of the central role of ECM.