Chenchar Anne, Mattos Pereira Vitoria, Apte Anisha, Lyttle Bailey D, Vaughn Alyssa E, Lehmann Tanner, Bardill James R, Zgheib Carlos, Liechty Kenneth W, Roballo Kelly C S, Zhang Zhaojie, Alexander Brenda M, Nair Sreejayan
School 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.
Laboratory for Fetal and Regenerative Biology, Department of Surgery, College of Medicine, University of Arizona, 1656 E Mabel Street, Tucson, Arizona 85721, United States.
ACS Pharmacol Transl Sci. 2025 Jun 20;8(7):2258-2269. doi: 10.1021/acsptsci.5c00295. eCollection 2025 Jul 11.
: 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. : 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/mm) via intradermal injection on days 0, 3, 7, and 14. For mouse studies, diabetes was induced in cathepsin K knockout ( 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. : 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. : 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.
蛋白酶活性升高会损害伤口愈合。组织蛋白酶K是一种具有强大胶原分解和弹性蛋白分解活性的半胱氨酸蛋白酶。本研究考察了组织蛋白酶K抑制剂奥丹西普对糖尿病猪模型伤口愈合的影响。此外，还评估了组织蛋白酶K基因缺失是否能改善糖尿病小鼠的伤口愈合。：将三组三个月大的雌性约克夏猪（每组八至十头猪）通过静脉注射链脲佐菌素（STZ，75mg/kg）诱导为糖尿病状态。4周后，在每只动物的背部制作10个全层（约300μm）切除性皮肤伤口，每个伤口面积为一平方英寸。在第0、3、7和14天通过皮内注射用赋形剂或奥丹西普（30或300ng/mm）处理伤口。对于小鼠研究，通过注射STZ在组织蛋白酶K基因敲除小鼠和野生型C57BL/6小鼠中诱导糖尿病，并在每只小鼠身上制作一个全层切除性伤口。在第0、7、14、21天对伤口进行拍照和评估，并每天评估直至完全愈合。通过测量伤口闭合率、CD31表达和组织学来评估伤口愈合进程。利用体外划痕试验评估奥丹西普在高糖条件下对培养的皮肤成纤维细胞和角质形成细胞迁移的影响。：奥丹西普治疗显著加速了糖尿病猪的伤口闭合，促进了上皮形成和细胞外基质稳定性。同样，与野生型对照相比，糖尿病Ctsk小鼠的愈合情况有所改善。在体外，奥丹西普在高血糖条件下增加了成纤维细胞和角质形成细胞的迁移。：本研究首次证明，通过基因或药理学方法抑制组织蛋白酶K可改善糖尿病伤口愈合。这些发现使组织蛋白酶K成为治疗慢性伤口的一个有前景的治疗靶点。
