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Updated: Sep 11, 2025
A Protocol for Constructing a Rat Wound Model of Type 1 Diabetes
Published on: February 17, 2023
Targeting Cathepsin K to Accelerate Diabetic Wound Healing
Anne Chenchar1,2,3,4, Vitoria Mattos Pereira1,2,3,4, Anisha Apte2
1School of Pharmacy, Biomedical Sciences Graduate Program, Department of Zoology and Physiology, Department of Animal Sciences, University of Wyoming, 1000 E. University Avenue, Laramie, Wyoming 82071, United States.
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.
Insights
Inhibiting cathepsin K, a protease that impairs healing, significantly improved wound closure in diabetic pigs and mice. This suggests targeting cathepsin K could be a novel therapeutic strategy for chronic wounds.
Area of Science:
- Biochemistry
- Dermatology
- Pharmacology
Background:
- Elevated protease activity, particularly cathepsin K, is linked to impaired wound healing.
- Cathepsin K possesses collagenolytic and elastolytic properties that can degrade extracellular matrix components essential for repair.
- Diabetic individuals often experience delayed wound healing due to various factors, including altered protease activity.
Purpose of the Study:
- To investigate the therapeutic potential of inhibiting cathepsin K in diabetic wound healing.
- To evaluate the efficacy of odanacatib, a cathepsin K inhibitor, in a diabetic porcine wound model.
- To assess the impact of genetic cathepsin K deletion on wound healing in diabetic mice.
Main Methods:
- Diabetic porcine and mouse models were established using streptozotocin (STZ).
- Excisional skin wounds were created and treated with odanacatib or vehicle in pigs, and compared in cathepsin K knockout and wild-type mice.
- Wound closure, epithelialization, CD31 expression, histology, and in vitro fibroblast/keratinocyte migration were assessed.
Main Results:
- Odanacatib treatment significantly accelerated wound closure and improved epithelialization and ECM stability in diabetic pigs.
- Diabetic mice lacking cathepsin K (Ctsk-/-) demonstrated enhanced wound healing compared to wild-type controls.
- In vitro studies showed odanacatib promoted fibroblast and keratinocyte migration under high-glucose conditions.
Conclusions:
- This study provides the first evidence that inhibiting cathepsin K, pharmacologically or genetically, enhances diabetic wound healing.
- Cathepsin K represents a promising therapeutic target for managing chronic wounds, particularly in diabetic patients.
