Temporal cathepsin and matrix metalloproteinase activity in tendon extracellular matrix damage

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Parks, Akia Nichelle
Platt, Manu O.
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Tendinopathy, or tendon overuse, is one of the most common musculoskeletal disorders affecting athletes, laborers, and aging adults. If left untreated, overuse injury can progress to partial or full-thickness tears that require surgical intervention. In order to develop preventative treatment strategies, it is important to identify the factors that initiate tendon damage. The multifactorial etiology of tendon overuse includes imbalances in proteases and their endogenous inhibitors that lead to the degradation of extracellular matrix (ECM). Cysteine cathepsins and matrix metalloproteinases (MMPs) have been implicated in tendon pathogenesis. Though several studies have published the effects of a single protease on tendon degradation, this does not provide a complete picture of a very dynamic proteolytic network at play in a pathologic environment. Cells can produce and secrete many proteases and endogenous inhibitors simultaneously that can interact with each other and impact matrix degeneration. It is not well understood how cathepsins and MMPs work cooperatively within and between families to effectively degrade tendon ECM. Our lab has identified a temporal regulation of cathepsin K and cathepsin L in a rat model of rotator cuff overuse, demonstrating upregulation of cathepsins K and L early in the injury time course, while only cathepsin L continued to be upregulated during later time points. The objective of this research is to investigate the proteolytic contribution to tendon damage. It is hypothesized that cathepsins, especially cathepsin K as the most potent collagenase, act in sequence to facilitate ECM degeneration. This study uses a rat model of rotator cuff tendinopathy to determine the temporal roles of cathepsins and MMPs in supraspinatus tendon overuse injury, as well as a mouse Achilles tendon model to determine the sequential actions of multiple cathepsins on tendon matrix degradation. Together, this work determines the biochemical roles of cathepsins and MMPs on tendon damage and elucidates mechanisms of protease regulation. Understanding how the dynamic proteolytic network contributes to tendon degradation will better inform clinical treatment strategies to prevent progression to tendon failure.
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