title: RECK-Mediated β1-Integrin Regulation by TGF-β1 Is Critical for Wound Contraction in Mice.
abstract: Fibroblasts are critical for wound contraction; a pivotal step in wound healing. They produce and modify the extracellular matrix (ECM) required for the proper tissue remodeling. Reversion-inducing cysteine-rich protein with Kazal motifs (RECK) is a key regulator of ECM homeostasis and turnover. However, its role in wound contraction is presently unknown. Here we describe that Transforming growth factor type β1 (TGF-β1), one of the main pro-fibrotic wound-healing promoting factors, decreases RECK expression in fibroblasts through the Smad and JNK dependent pathways. This TGF-β1 dependent downregulation of RECK occurs with the concomitant increase of β1-integrin, which is required for fibroblasts adhesion and wound contraction through the activation of focal adhesion kinase (FAK). Loss and gain RECK expression experiments performed in different types of fibroblasts indicate that RECK downregulation mediates TGF-β1 dependent β1-integrin expression. Also, reduced levels of RECK potentiate TGF-β1 effects over fibroblasts FAK-dependent contraction, without affecting its cognate signaling. The above results were confirmed on fibroblasts derived from the Reck+/- mice compared to wild type-derived fibroblasts. We observed that Reck+/- mice heal dermal wounds more efficiently than wild type mice. Our results reveal a critical role for RECK in skin wound contraction as a key mediator in the axis: TGF-β1-RECK-β1-integrin.
authors.affiliation: Cellular Signaling and Differentiation Laboratory (CSDL), School of Medical Technology, Health Sciences Faculty, Universidad San Sebastian, Santiago, Chile; Centro de Regeneración y Envejecimiento (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Jaime
authors.initials: J
authors.lastname: Gutiérrez
authors.affiliation: Centro de Regeneración y Envejecimiento (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile; Molecular Medicine Group, Robarts Research Institute, Western University, London, Ontario, Canada.
authors.forename: Cristian A
authors.initials: CA
authors.lastname: Droppelmann
authors.affiliation: Centro de Regeneración y Envejecimiento (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Contreras
authors.affiliation: Oncology and Molecular Biology, Cancer and Stem Cell Research Program, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Takahashi
authors.affiliation: Centro de Regeneración y Envejecimiento (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Enrique
authors.initials: E
authors.lastname: Brandan
mesh_terms: D000818:Animals; D005109:Extracellular Matrix / Q000737:chemistry / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism; D058851:GPI-Linked Proteins / Q000172:deficiency / Q000235:genetics*; D005786:Gene Expression Regulation; D057898:Hemizygote; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D061251:Primary Cell Culture; D015398:Signal Transduction; D012867:Skin / Q000293:injuries / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D014945:Wound Healing / Q000235:genetics*; D014949:Wounds, Nonpenetrating / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D058851:GPI-Linked Proteins; D019012:Integrin beta1; C492025:Reck protein, mouse; D053773:Transforming Growth Factor beta1; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse