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Targeting Cathepsin K To Promote Diabetic Wound Healing
Non-healing wound affects ~25% of people with diabetes and represents a primary cause of ~85% of amputation of lower limbs, which is an enormous clinical problem and a substantial economic burden. There is a paucity of clinically approved agents that aid in the healing of diabetic wounds, warranting discovery and characterization of novel pharmacological targets for treating diabetic wounds. The development of chronic diabetic wounds is characterized by a highly proteolytic microenvironment or ‘catabolic state’. The elevated proteolytic activity leads to a continuous breakdown of the extracellular matrix proteins, sustaining a prolonged destructive state that delays wound healing. Collagen is the major extracellular matrix protein which plays a critical role in wound healing and is a major target for proteolysis. Wound dressings that modulate endogenous proteases by providing exogenous collagen as ‘suicide substrates’ have been developed as options to facilitate diabetic wounds. However, a more direct approach would be to inhibit the activity of the endogenous collagenase in the wound. Therefore, this project aims to evaluate the role of cathepsin K – the most potent mammalian collagenolytic and elastolytic enzyme known in diabetic wound healing. Preliminary studies presented here show that skin tissue from diabetic human subjects had lower levels of collagen and elevated levels of the cathepsin K compared to skin from nondiabetic humans. Furthermore, preliminary data demonstrate that cathepsin K is upregulated in diabetic wounds and that whole-body knockout of cathepsin K facilitates wound healing in a diabetic mouse model, which provide a strong rationale for this proposal. The objective of this application is to characterize the role of cathepsin K in diabetic wound healing and to determine the efficacy of targeting cathepsin K in facilitating healing. The overall hypothesis is that cathepsin K is detrimental to wound healing and inhibition of cathepsin K promotes wound healing. The following are the specific aims i) Determine the role of cathepsin K in diabetic wound healing in a clinically-relevant porcine model. ii) Validate the role of dysregulated cathepsin K in diabetic wound healing using recombinant cathepsin K and cathepsin K siRNA. The outcome of the proposed study will help identify and characterize cathepsin K as a potentially novel pharmacological target to promote healing of diabetic wounds, which remains a major unmet need.

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