title: TAK1 is required for dermal wound healing and homeostasis.
abstract: Dermal connective tissue is a supportive structure required for skin's barrier function; dysregulated dermal homeostasis results in chronic wounds and fibrotic diseases. The multifunctional cytokine transforming growth factor (TGF) β promotes connective tissue deposition, repair, and fibrosis. TGF-β acts through well-defined canonical pathways; however, the non-canonical pathways through which TGF-β selectively promotes connective tissue deposition are unclear. In dermal fibroblasts, we show that inhibition of the non-canonical TGF-β-activated kinase 1 (TAK1) selectively reduced the ability of TGF-β to induce expression of a cohort of wound healing genes, such as collagens, CCN2, TGF-β1, and IL-6. Fibroblast-specific TAK1-knockout mice showed impaired cutaneous tissue repair and decreased collagen deposition, α-smooth muscle actin and CCN2 expression, proliferating cell nuclear antigen staining, and c-Jun N-terminal kinase and p38, but not Smad3, phosphorylation. TAK1-deficient fibroblasts showed reduced cell proliferation, migration, cell attachment/spreading, and contraction of a floating collagen gel matrix. TAK1-deficient mice also showed progressively reduced skin thickness and collagen deposition. Thus, TAK1 is essential for connective tissue deposition in the dermis.
authors: Department of Dentistry, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
authors: Fen
authors: F
authors: Guo
authors: James
authors: J
authors: Hutchenreuther
authors: David E
authors: DE
authors: Carter
authors: Andrew
authors: A
authors: Leask
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D020405:Dermis / Q000166:cytology* / Q000502:physiology*; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D006706:Homeostasis / Q000502:physiology*; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D053773:Transforming Growth Factor beta1 / Q000378:metabolism / Q000494:pharmacology; D014945:Wound Healing / Q000502:physiology*; D015025:Zearalenone / Q000031:analogs & derivatives / Q000494:pharmacology / Q000008:administration & dosage; D000099151:MAP Kinase Kinase Kinase 7; D007783:Lactones; D012118:Resorcinols
chemical_list: D020930:MAP Kinase Kinase Kinases; D053773:Transforming Growth Factor beta1; D015025:Zearalenone; D000099151:MAP Kinase Kinase Kinase 7; C505734:7-oxozeanol; D007783:Lactones; D012118:Resorcinols