Inhibiting the cytosolic function of CXXC5 accelerates diabetic wound healing by enhancing angiogenesis and skin repair

Abstract

Diabetic wound healing, including diabetic foot ulcer (DFU), is a serious complication of diabetes. Considering the complexity of DFU development, the identification of a factor that mediates multiple pathogeneses is important for treatment. In this study, we found that CXXC-type zinc finger protein 5 (CXXC5), a negative regulator of the Wnt/β-catenin pathway, was overexpressed with suppression of the Wnt/β-catenin pathway and its target genes involved in wound healing and angiogenesis in the wound tissues of DFU patients and diabetes-induced model mice. KY19334, a small molecule that activates the Wnt/β-catenin pathway by inhibiting the CXXC5-Dvl interaction, accelerated wound healing in diabetic mice. The enhancement of diabetic wound healing could be achieved by restoring the suppressed Wnt/β-catenin signaling and subsequently inducing its target genes. Moreover, KY19334 induced angiogenesis in hindlimb ischemia model mice. Overall, these findings revealed that restorative activation of Wnt/β-catenin signaling by inhibiting the function of cytosolic CXXC5 could be a therapeutic approach for treating DFUs.

Diabetes: A road to recovery of long-lasting foot ulcers

Drugs that alleviate a molecular blockade against wound healing and vessel growth could offer effective therapies for diabetic foot ulcers (DFU). Such chronic wounds are a serious consequence of type 2 diabetes, and current therapies only manage the symptoms without providing recovery. Researchers led by Kang-Yell Choi of Yonsei University, Seoul, South Korea, have determined that DFU from human patients and animal models exhibit elevated levels of CXXC5, a protein that inhibits genes associated with healing and angiogenesis. Treatment with an agent that selectively blocks CXXC5 function reversed this inhibition in two different mouse models, accelerating both wound repair and the formation of new blood vessels. The latter is thought to be an especially important aspect of DFU recovery, suggesting that this treatment approach could give long-lasting relief to patients.