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A Protocol for Constructing a Rat Wound Model of Type 1 Diabetes
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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.

ACS Pharmacology & Translational Science
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Summary

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.

Keywords:
cathepsin Kdiabetesmouse modelodanacatibporcine modelwound healing

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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.