Accelerated re-epithelialization in beta3-integrin-deficient- mice is associated with enhanced TGF-beta1 signaling.
The upregulation of TGF-beta1 and integrin expression during wound healing has implicated these molecules in this process, but their precise regulation and roles remain unclear. Here we report that, notably, mice lacking beta(3)-integrins show enhanced wound healing with re-epithelialization complete several days earlier than in wild-type mice. We show that this effect is the result of an increase in TGF-beta1 and enhanced dermal fibroblast infiltration into wounds of beta(3)-null mice. Specifically, beta(3)-integrin deficiency is associated with elevated TGF-beta receptor I and receptor II expression, reduced Smad3 levels, sustained Smad2 and Smad4 nuclear localization and enhanced TGF-beta1-mediated dermal fibroblast migration. These data indicate that alpha(v)beta(3)-integrin can suppress TGF-beta1-mediated signaling, thereby controlling the rate of wound healing, and highlight a new mechanism for TGF-beta1 regulation by beta(3)-integrins.
Reynolds
L E
LE
Cell Adhesion and Disease Laboratory, Department of Tumour Biology, Cancer Research UK, Bart's & The London, Queen Mary's School of Medicine & Dentistry, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK.
Conti
F J
FJ
Lucas
M
M
Grose
R
R
Robinson
S
S
Stone
M
M
Saunders
G
G
Dickson
C
C
Hynes
R O
RO
Lacy-Hulbert
A
A
Hodivala-Dilke
K
K
D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004848:Epithelium / Q000033:anatomy & histology / Q000473:pathology / Q000502:physiology*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D050883:HSC70 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D017403:In Situ Hybridization; D039661:Integrin beta3 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051785:Smad Proteins; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D014945:Wound Healing / Q000502:physiology*
D004268:DNA-Binding Proteins; D050883:HSC70 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; C494372:Hspa8 protein, mouse; D039661:Integrin beta3; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; C508961:Tgfb1 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1