Tendinopathies are common musculoskeletal injuries that lead to tendon rupture and disuse. Degenerative changes in ruptured tendons suggest that subrupture fatigue damage accumulation from wear and tear is an integral component in the pathogenesis of tendinopathy. Consequently, we have previously developed an in vivo model of sub-rupture fatigue damage accumulation using the rat patellar tendon to investigate the onset and pathogenesis of tendinopathy. We have shown that even just one bout of fatigue loading leads to development of collagen damage kinks and a 20% decrease in stiffness of the tendon that is not recovered out to at least 8- weeks. A major hurdle to progress in management of developing chronic tendinopathies is that the mechanism of tendon repair is unknown, largely because it does not naturally occur. Our previous work investigating the utility of exercise as a therapeutic showed that exercise leads to repair when initiated 2-weeks after onset of sub- rupture fatigue injury but promotes further degeneration when initiated 1-day after sub-rupture fatigue injury. Generation of these two contrasting models (effective therapeutic exercise and detrimental therapeutic exercise of fatigue damaged tendons) will be invaluable to unraveling the mechanisms that drive the response of fatigue damaged tendons to conservative treatment. Interestingly, the main difference in the degenerative versus reparative outcome from therapeutic exercise is the time of initiation even though the fatigue damaged tendons at both timepoints exhibit similar macroscopic mechanical properties. It is therefore critical to determine the biomechanical conditions wherein conservative treatment, such as exercise, will promote repair and not further degeneration. In addition, an increase in population of myofibroblasts and integrin ?5 was uniquely associated with repair of fatigue damaged tendons from effective therapeutic exercise leading to generation of a novel mechanistic hypothesis for repair of sub-rupture fatigue damaged tendons. We hypothesize that repair of fatigue damage follows 3-phases. In phase 1, regions of matrix damage are repopulated with tenocytes that have re- established cell-ECM interactions. In phase 2, myofibroblasts are activated in regions of matrix damage, likely driven by integrin ?5 and the fibronectin splice variant, FN-EDA. In phase 3, myofibroblasts tension the damage kinks and increase cross-linking. The proposed studies will interrogate our mechanistic hypothesis by evaluating the cell-ECM interactions that evolve over the 2-weeks after onset of injury (Aim 1) and interrogating the role of myofibroblasts in repair of fatigue damage injury (Aim 2). Lastly, the role of integrin ?5 (dependent or independent of myofibroblasts) in repair of sub-rupture fatigue injuries will be interrogated (Aim 3). The proposed studies will (A) identify biological and mechanical factors that should be considered prior to initiation of conservative treatment such as exercise, (B) determine the therapeutic potential of myofibroblasts, and (C) identify alternative therapeutic approaches by identifying mechanisms that could be interrogated to drive remodeling and myofibroblast activation.
Tendinopathies are common musculoskeletal injuries that lead to tendon rupture and disuse. A major hurdle to progress in management of developing chronic tendinopathies is that the mechanism of tendon repair is unknown, largely because it does not naturally occur. The proposed studies will (A) identify biological and mechanical factors that should be considered prior to initiation of conservative treatment such as exercise, (B) determine the therapeutic potential of myofibroblasts, and (C) identify alternative biological targets that could be interrogated to drive repair and myofibroblast activation.
