Persistent inflammation and angiogenesis during wound healing in K14-directed Hoxb13 transgenic mice.
Chronic, nonhealing wounds and inadequate tissue repair characterized by excessive fibrosis continue to have a considerable negative effect on health and quality of life. Understanding the molecular events required for adequate healing, including the transcriptional control of wound repair, will be important for the development of future therapies. We previously showed that loss of Hoxb13 from murine skin results in enhanced cutaneous wound healing, suggesting that Hoxb13 has a negative effect on wound repair. To test this, we generated skin-specific Hoxb13 transgenic (TG) mice that overexpress Hoxb13 in the basal layer of the epidermis by the human keratin 14 promoter. Using these mice, we evaluated the effects of Hoxb13 overexpression on cutaneous wound healing. Transgenic wounds were characterized by persistence of the fibrin clot and prolonged inflammation. Notably, neutrophils, which had cleared from wild-type wounds, were still pronounced in TG wounds. Marked epidermal hyperplasia was observed at TG wound edges, and dermal vessels were grossly abnormal compared with wild-type mice. Both vascular endothelial growth factor and tumor necrosis factor-alpha were upregulated in Hoxb13 TG skin. Together, our results identify Hoxb13 as a potential important clinical target in wound healing and other pathologies characterized by abnormal or excessive inflammation, angiogenesis, or epidermal proliferation.
Mack
Judith A
JA
Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA. mackj@ccf.org
Maytin
Edward V
EV
D000818:Animals; D002478:Cells, Cultured; D002908:Chronic Disease; D003872:Dermatitis / Q000276:immunology* / Q000503:physiopathology*; D004817:Epidermis / Q000502:physiology; D015870:Gene Expression / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000166:cytology; D051379:Mice; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000502:physiology*; D010714:Phosphatidylethanolamines; D011401:Promoter Regions, Genetic / Q000502:physiology; D051381:Rats; D012867:Skin / Q000098:blood supply / Q000276:immunology / Q000293:injuries; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014945:Wound Healing / Q000502:physiology*
D018398:Homeodomain Proteins; C100943:Hoxb13 protein, mouse; D010714:Phosphatidylethanolamines; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C100004:transfectACE