Background and Hypothesis: Impaired wound healing is a serious complication of diabetes and accounts for over 70,000 amputations annually in the United States. Accumulating evidence suggests that wounds with poor healing process display persistently elevated protease activity. Here we tested the hypothesis that genetic knockout or pharmacological inhibition of cathepsin K, a cysteine protease with potent collagenolytic and elastolytic activity, accelerates wound closure in diabetic mice.
Methods: Diabetes was induced in cathepsin K knockout (Ctsk-/-) and wild type litter-mates by intraperitoneal injection of streptozotocin (STZ, 120 mg/Kg). Two weeks following STZ injection, a full thickness 8-mm excisional wound was created on the dorsum of the mice. In a separate set of experiments, excisional skin wounds were created in genetically diabetic (db+/db+) and their normoglycemic litter-mates. The wounds were treated with cathepsin K inhibitor II (0.35μg/d on days 0, 3, and 5), or vehicle, given as intradermal injections along the circumference of the wound. Wound healing was evaluated by measuring the wound closure rate, CD31 expression, and histological analysis.
Results: In the STZ-induced diabetic model, wounds in the cathepsin K-knockout mice closed significantly earlier than the vehicle-treated wounds. Similarly, pharmacological inhibition of cathepsin K in db/db mice resulted in near complete resolution of the wound in 22 days compared to about 29 days in vehicle-treated mice. Histological evaluations demonstrated that topical delivery of cathepsin K inhibition resulted in higher levels of collagen deposition and increased angiogenesis. In an in vitro scratch-assay using cultured human fibroblasts, cell migration, which was significantly impaired by high-glucose concentrations, was restored by cathepsin K inhibitor-II.
Conclusion: Cathepsin K may represent a potential treatment-target to facilitate diabetic wound healing.
R. Guo: None. L. Zhang: None. A. Thakar: None. T.E. Brown: None. J. Ren: None. C. Zgheib: None. J. Xu: None. K.W. Liechty: Consultant; Spouse/Partner; Cell research. S. Nair: None.
National Institute of General Medical Sciences (2P20GM1034320); University of Wyoming