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PMID: 18246199 Published · ppublish English Journal Article

alpha3beta1 integrin-controlled Smad7 regulates reepithelialization during wound healing in mice.

The Journal of clinical investigation ·Vol. 118 ·No. 3 ·2008-03-00 ·Pages 965-74

Reynolds LE, Conti FJ, Silva R, Robinson SD, Iyer V, Rudling R, Cross B, Nye E, Hart IR, Dipersio CM, Hodivala-Dilke KM

Abstract

Effective reepithelialization after injury is essential for correct wound healing. The upregulation of keratinocyte alpha3beta1 integrin during reepithelialization suggests that this adhesion molecule is involved in wound healing; however, its precise role in this process is unknown. We have shown here that retarded reepithelialization in Itga3(-/-) mouse skin wounds is due predominantly to repressed TGF-beta1-mediated responses. Specifically, expression of the inhibitor of TGF-beta1-signaling Smad7 was elevated in Itga3(-/-) keratinocytes. Indeed, in vivo blockade of Smad7 increased the rate of reepithelialization in Itga3(-/-) and WT wounds to similar levels. Our data therefore indicate that the function of alpha3beta1 integrin as a mediator of keratinocyte migration is not essential for reepithelialization but suggest instead that alpha3beta1 integrin has a major new in vivo role as an inhibitor of Smad7 during wound healing. Moreover, our study may identify a previously undocumented function for Smad7 as a regulator of reepithelialization in vivo and implicates Smad7 as a potential novel target for the treatment of cutaneous wounds.

MeSH Terms
Animals Epithelium/physiology Integrin alpha3beta1/physiology Integrin alpha5beta1/physiology Mice Signal Transduction Smad7 Protein/physiology Transforming Growth Factor beta1/physiology Wound Healing
Chemicals
Integrin alpha3beta1 Integrin alpha5beta1 Smad7 Protein Smad7 protein, mouse Transforming Growth Factor beta1
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Reynolds Louise E
Centre for Tumour Biology, Institute of Cancer Research and Cancer Research UK Clinical Centre, Barts and The London, Queen Mary's School of Medicine and Dentistry, John Vane Science Centre, London, United Kingdom.
Conti Francesco J
Silva Rita
Robinson Stephen D
Iyer Vandana
Rudling Rob
Cross Barbara
Nye Emma
Hart Ian R
Dipersio C Michael
Hodivala-Dilke Kairbaan M
References (45)
45 references, click to expand
  1. The MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling.
    Cell. 1997 Jun 27;89(7):1165-73 PMID: 9215638
  2. Keratinocyte motility induced by TGF-beta1 is accompanied by dramatic changes in cellular interactions with laminin 5.
    Cell Motil Cytoskeleton. 2003 Jan;54(1):64-80 PMID: 12451596
  3. The alpha3 laminin subunit, alpha6beta4 and alpha3beta1 integrin coordinately regulate wound healing in cultured epithelial cells and in the skin.
    J Cell Sci. 1999 Aug;112 ( Pt 16):2615-29 PMID: 10413670
  4. Suprabasal alpha6beta4 integrin expression in epidermis results in enhanced tumourigenesis and disruption of TGFbeta signalling.
    J Cell Sci. 2003 Sep 15;116(Pt 18):3783-91 PMID: 12902406
  5. Alpha 3 beta 1 integrin has a crucial role in kidney and lung organogenesis.
    Development. 1996 Nov;122(11):3537-47 PMID: 8951069
  6. Essential role of Smad3 in the inhibition of inflammation-induced PPARbeta/delta expression.
    EMBO J. 2004 Oct 27;23(21):4211-21 PMID: 15470497
  7. Laminin 5 deposition regulates keratinocyte polarization and persistent migration.
    J Cell Sci. 2004 Mar 15;117(Pt 8):1351-63 PMID: 14996912
  8. Wound repair, keratinocyte activation and integrin modulation.
    J Cell Sci. 1992 Jan;101 ( Pt 1):1-5 PMID: 1569118
  9. Smad regulation in TGF-beta signal transduction.
    J Cell Sci. 2001 Dec;114(Pt 24):4359-69 PMID: 11792802
  10. Integrin receptors and RGD sequences in human keratinocyte migration: unique anti-migratory function of alpha 3 beta 1 epiligrin receptor.
    J Invest Dermatol. 1992 May;98(5):764-70 PMID: 1569325
  11. Aberrant integrin expression during epidermal wound healing and in psoriatic epidermis.
    J Clin Invest. 1992 Jun;89(6):1892-901 PMID: 1601996
  12. Accelerated re-epithelialization in beta3-integrin-deficient- mice is associated with enhanced TGF-beta1 signaling.
    Nat Med. 2005 Feb;11(2):167-74 PMID: 15654327
  13. Rapid up-regulation of alpha4 integrin-mediated leukocyte adhesion by transforming growth factor-beta1.
    Mol Biol Cell. 2003 Jan;14(1):54-66 PMID: 12529426
  14. Novel roles for alpha3beta1 integrin as a regulator of cytoskeletal assembly and as a trans-dominant inhibitor of integrin receptor function in mouse keratinocytes.
    J Cell Biol. 1998 Sep 7;142(5):1357-69 PMID: 9732295
  15. How cells read TGF-beta signals.
    Nat Rev Mol Cell Biol. 2000 Dec;1(3):169-78 PMID: 11252892
  16. Overexpression of Smad7 results in severe pathological alterations in multiple epithelial tissues.
    EMBO J. 2002 Jun 3;21(11):2580-90 PMID: 12032071
  17. Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling.
    Nature. 1997 Oct 9;389(6651):631-5 PMID: 9335507
  18. Estrogen accelerates cutaneous wound healing associated with an increase in TGF-beta1 levels.
    Nat Med. 1997 Nov;3(11):1209-15 PMID: 9359694
  19. Smad3 deficiency alters key structural elements of the extracellular matrix and mechanotransduction of wound closure.
    Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9250-5 PMID: 16754864
  20. Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response.
    Nat Cell Biol. 1999 Sep;1(5):260-6 PMID: 10559937
  21. Regulation of cell adhesion receptors by transforming growth factor-beta. Concomitant regulation of integrins that share a common beta 1 subunit.
    J Biol Chem. 1989 Jan 5;264(1):380-8 PMID: 2491849
  22. Cutaneous wound healing.
    N Engl J Med. 1999 Sep 2;341(10):738-46 PMID: 10471461
  23. Distinctive integrin expression in the newly forming epidermis during wound healing in humans.
    J Invest Dermatol. 1993 Oct;101(4):600-4 PMID: 8409530
  24. Distinct functions for integrins alpha 3 beta 1 in focal adhesions and alpha 6 beta 4/bullous pemphigoid antigen in a new stable anchoring contact (SAC) of keratinocytes: relation to hemidesmosomes.
    J Cell Biol. 1990 Dec;111(6 Pt 2):3141-54 PMID: 2269668
  25. alpha3beta1-integrin regulates hair follicle but not interfollicular morphogenesis in adult epidermis.
    J Cell Sci. 2003 Jul 1;116(Pt 13):2737-47 PMID: 12759370
  26. Direct binding of Smad3 and Smad4 to critical TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene.
    EMBO J. 1998 Jun 1;17(11):3091-100 PMID: 9606191
  27. Role of elevated plasma transforming growth factor-beta1 levels in wound healing.
    Am J Pathol. 1999 Apr;154(4):1115-24 PMID: 10233850
  28. Laminin 5 deposition promotes keratinocyte motility.
    Exp Cell Res. 1996 Sep 15;227(2):309-22 PMID: 8831569
  29. TGF-beta 1 stimulates expression of keratinocyte integrins during re-epithelialization of cutaneous wounds.
    J Invest Dermatol. 1994 Aug;103(2):221-7 PMID: 8040614
  30. Roles for alpha 1 connexin in morphogenesis of chick embryos revealed using a novel antisense approach.
    Dev Genet. 1999;24(1-2):33-42 PMID: 10079509
  31. alpha3beta1 Integrin is required for normal development of the epidermal basement membrane.
    J Cell Biol. 1997 May 5;137(3):729-42 PMID: 9151677
  32. Mapping of the functional determinants of the integrin beta 1 cytoplasmic domain by site-directed mutagenesis.
    Cell Regul. 1990 Jul;1(8):597-604 PMID: 2078570
  33. The phagokinetic tracks of 3T3 cells.
    Cell. 1977 Jun;11(2):395-404 PMID: 329998
  34. Keratinocyte migration requires alpha2beta1 integrin-mediated interaction with the laminin 5 gamma2 chain.
    J Cell Sci. 2001 Feb;114(Pt 4):811-23 PMID: 11171386
  35. Mouse keratinocytes immortalized with large T antigen acquire alpha3beta1 integrin-dependent secretion of MMP-9/gelatinase B.
    J Cell Sci. 2000 Aug;113 ( Pt 16):2909-21 PMID: 10910775
  36. Transforming growth factor-beta 1 modulates beta 1 and beta 5 integrin receptors and induces the de novo expression of the alpha v beta 6 heterodimer in normal human keratinocytes: implications for wound healing.
    J Cell Biol. 1995 May;129(3):853-65 PMID: 7537276
  37. Effect of TGF-beta 1 on re-epithelialization of human keratinocytes in vitro: an organotypic model.
    J Invest Dermatol. 1994 Oct;103(4):554-9 PMID: 7930681
  38. Integrin and growth factor receptor crosstalk.
    Circ Res. 2001 Dec 7;89(12):1104-10 PMID: 11739274
  39. Normal development, wound healing, and adenovirus susceptibility in beta5-deficient mice.
    Mol Cell Biol. 2000 Feb;20(3):755-9 PMID: 10629031
  40. Transforming growth factor beta enhances integrin expression and type IV collagenase secretion in human monocytes.
    Proc Natl Acad Sci U S A. 1993 May 15;90(10):4577-81 PMID: 8506302
  41. Integrins regulate GTP-Rac localized effector interactions through dissociation of Rho-GDI.
    Nat Cell Biol. 2002 Mar;4(3):232-9 PMID: 11862216
  42. Blocking Smad7 restores TGF-beta1 signaling in chronic inflammatory bowel disease.
    J Clin Invest. 2001 Aug;108(4):601-9 PMID: 11518734
  43. Deposition of laminin 5 by keratinocytes regulates integrin adhesion and signaling.
    J Biol Chem. 2000 Oct 13;275(41):31896-907 PMID: 10926936
  44. A crucial role of beta 1 integrins for keratinocyte migration in vitro and during cutaneous wound repair.
    Development. 2002 May;129(9):2303-15 PMID: 11959837
  45. Increased expression of beta6-integrin in skin leads to spontaneous development of chronic wounds.
    Am J Pathol. 2004 Jan;164(1):229-42 PMID: 14695336
Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI33538
Published
2008-03-00
Pages
965-74
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC2215730
Subset
IM
External Links
PubMed source DOI: 10.1172/JCI33538 PMC Full Text View journal details
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