Targeting Cathepsin K to Accelerate Diabetic Wound Healing

Abstract

Objective: Elevated protease activity impairs wound healing. Cathepsin K is a cysteine protease with potent collagenolytic and elastolytic activity. This study examined the effects of odanacatib, a cathepsin K inhibitor, on wound healing in a diabetic porcine model. Additionally, it assessed whether the genetic deletion of cathepsin K improves wound healing in diabetic mice. Approach: Three cohorts of three-month-old female Yorkshire pigs (eight to ten pigs per cohort) were rendered diabetic via intravenous injections of streptozotocin (STZ, 75 mg/kg). After 4 weeks, ten full-thickness (∼300 μm) excisional skin wounds, each measuring one square inch, were created on the dorsal surface of each animal. The wounds were treated with either vehicle or odanacatib (30 or 300 ng/mm²) via intradermal injection on days 0, 3, 7, and 14. For mouse studies, diabetes was induced in cathepsin K knockout (Ctsk ^-/- ) and wild-type C57BL/6 mice via STZ injections, and a single full-thickness excisional wound was created on each mouse. The wounds were photographed and assessed on days 0, 7, 14, 21, and daily until complete closure. Wound healing progression was evaluated by measuring wound closure rates, CD31 expression, and histology. An in vitro scratch assay was utilized to assess the effect of odanacatib on the migration of cultured skin fibroblasts and keratinocytes under high-glucose conditions. Results: Odanacatib treatment significantly accelerated wound closure in diabetic pigs, promoting epithelialization and ECM stability. Similarly, diabetic Ctsk^-/- mice exhibited improved healing compared to wild-type controls. In vitro, odanacatib increased the migration of fibroblasts and keratinocytes under hyperglycemic conditions. Innovation and Conclusion: This study is the first to demonstrate that inhibiting cathepsin K, either genetically or pharmacologically, improves diabetic wound healing. These findings position cathepsin K as a promising therapeutic target for the treatment of chronic wounds.