Skip to main content

Advertisement

Log in

Integrin signaling in fibrosis and scleroderma

  • Published:
Current Rheumatology Reports Aims and scope Submit manuscript

Abstract

Integrins are a large family of heterodimeric transmembrane receptors for extracellular matrix proteins. As well as mediating cell attachment and the bulk of force transduction from the cytoskeleton, they convey signals from the extracellular matrix to the cell. α1β1 and α2β1 are the major collagen receptors in this family. α1β1 provides negative feedback on collagen synthesis, whereas α2β1 stimulates the synthesis of matrix metalloproteases. Each receptor modulates the signaling activity of the other to coordinate matrix synthesis and remodeling. Expression of both is reduced in scleroderma despite a paracrine environment which would be expected to upregulate them. Deficiencies in the integrins correlate with upregulated collagen synthesis and downregulated metalloprotease synthesis seen during the disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References and Recommended Reading

  1. Ruoslahti E: Integrins. J Clin Invest 1991, 87:1–5.

    PubMed  CAS  Google Scholar 

  2. Hynes RO: Integrins: versatility, modulation, and signaling in cell adhesion. Cell 1992, 69:11–25. Although now fairly mature, this review is still a very good introduction to the field of integrins as a whole, and places them in context with other cell surface adhesion receptors.

    Article  PubMed  CAS  Google Scholar 

  3. Hemler ME, Huang C, Schwarz L: The VLA protein family. Characterization of five distinct cell surface heterodimers each with a common 130,000 molecular weight β subunit. J Biol Chem 1987, 262:3300–3309.

    PubMed  CAS  Google Scholar 

  4. Pancer Z, Kruse M, Muller I, Muller WE: On the origin of Metazoan adhesion receptors: cloning of integrin a subunit from the sponge Geodia cydonium. Mol Biol Evol 1997, 14:391–398.

    PubMed  CAS  Google Scholar 

  5. Brower DL, Brower SM, Hayward DC, Ball EE: Molecular evolution of integrins: genes encoding integrin β subunits from a coral and a sponge. Proc Natl Acad Sci U S A 1997, 94:9182–9187.

    Article  PubMed  CAS  Google Scholar 

  6. Shattil SJ, Ginsberg MH: Perspectives series: cell adhesion in vascular biology. Integrin signaling in vascular biology. J Clin Invest 1997, 100:1–5.

    Article  PubMed  CAS  Google Scholar 

  7. Wary KK, Mainiero F, Isakoff SJ, et al.: The adaptor protein Shc couples a class of integrins to the control of cell cycle progression. Cell 1996, 87:733–743.

    Article  PubMed  CAS  Google Scholar 

  8. Schneller M, Vuori K, Ruoslahti E: Alphavbeta3 integrin associates with activated insulin and PDGFbeta receptors and potentiates the biological activity of PDGF. Embo J 1997, 16:5600–5607.

    Article  PubMed  CAS  Google Scholar 

  9. Ruoslahti E, Reed JC: Anchorage dependence, integrin, and apoptosis. Cell 1994, 77:477–478.

    Article  PubMed  CAS  Google Scholar 

  10. Hemler ME, Sanchez-Madrid F, Flotte TJ, et al.: Glycoproteins of 210,000 and 130,000 m.w. on activated T cells: cell distribution and antigenic relation to components on resting cells and T cell lines. J Immunol 1984, 132:3011–3018.

    PubMed  CAS  Google Scholar 

  11. Belkin VM, Belkin AM, Koteliansky VE: Human smooth muscle VLA-1 integrin: purification, substrate specificity, localization in aorta, and expression during development. J Cell Biol 1990, 111:2159–2170.

    Article  PubMed  CAS  Google Scholar 

  12. Schiro JA, Chan BM, Roswit WT, et al.: Integrin α2β1 (VLA-2) mediates reorganization and contraction of collagen matrices by human cells. Cell 1991, 67:403–410.

    Article  PubMed  CAS  Google Scholar 

  13. Camper L, Hellman U, Lundgren-Akerlund E: Isolation, cloning, and sequence analysis of the integrin subunit α10, αβ1-associated collagen binding integrin expressed on chondrocytes. J Biol Chem 1998, 273:20383–20389.

    Article  PubMed  CAS  Google Scholar 

  14. Yamamoto M, Yamato M, Aoyagi M, Yamamoto K:Identification of integrins involved in cell adhesion to native and denatured type I collagens and the phenotypic transition of rabbit arterial smooth muscle cells. Exp Cell Res 1995, 219:249–256.

    Article  PubMed  CAS  Google Scholar 

  15. Xue W, Mizukami I, Todd RF 3rd, Petty HR: Urokinase-type plasminogen activator receptors associate with β1 and β3 integrins of fibrosarcoma cells: dependence on extracellular matrix components. Cancer Res 1997, 57:1682–1689.

    PubMed  CAS  Google Scholar 

  16. Berditchevski F, Chang S, Bodorova J, Hemler ME: Generation of monoclonal antibodies to integrin-associated proteins. Evidence that α3β1 complexes with EMMPRIN/ basigin/OX47/M6. J Biol Chem 1997, 272:29174–29180.

    Article  PubMed  CAS  Google Scholar 

  17. Kreidberg JA, Donovan MJ, Goldstein SL, et al.: α3β1 integrin has a crucial role in kidney and lung organogenesis. Development 1996, 122:3537–3547.

    PubMed  CAS  Google Scholar 

  18. Langholz O, Rockel D, Mauch C, et al.: Collagen and collagenase gene expression in three-dimensional collagen lattices are differentially regulated by α1β1 and α2β1 integrins. J Cell Biol 1995, 131:1903–1915. This study used antibody induction and blockade to investigate the roles of α1 and α2 in collagen gels. This paper brought together and emphasized the roles of the two integrins relative to one another, and its central observations have been borne out by many studies since.

    Article  PubMed  CAS  Google Scholar 

  19. Gullberg D, Gehlsen KR, Turner DC, et al.: Analysis of α1β1, α2β1 and α3β1 integrins in cell—collagen interactions: identification of conformation dependent α1β1 binding sites in collagen type I. Embo J 1992, 11:3865–3873.

    PubMed  CAS  Google Scholar 

  20. Wu JE, Santoro SA: Complex patterns of expression suggest extensive roles for the α2β1 integrin in murine development. Dev Dyn 1994, 199:292–314.

    PubMed  CAS  Google Scholar 

  21. Duband JL, Belkin AM, Syfrig J, et al.: Expression of a1 integrin, a laminin-collagen receptor, during myogenesis and neurogenesis in the avian embryo. Development 1992, 116:585–600.

    PubMed  CAS  Google Scholar 

  22. Kuhn K, Eble J: The structural bases of integrin-ligand interactions. Trends Cell Biol 1994, 4:256–261. This is a very authoritative review based on the results of the paper below among others. Although it predates crystal structures of integrin I domains, it remains a very insightful analysis.

    Article  PubMed  CAS  Google Scholar 

  23. Eble JA, Golbik R, Mann K, Kuhn K: The α1β1 integrin recognition site of the basement membrane collagen molecule [α1(IV)]2α 2(IV). Embo J 1993, 12:4795–4802.

    PubMed  CAS  Google Scholar 

  24. Emsley J, King SL, Bergelson JM, Liddington RC: Crystal structure of the I domain from integrin α2β1. J Biol Chem 1997, 272:28512–28517.

    Article  PubMed  CAS  Google Scholar 

  25. Gardner H, Broberg A, Pozzi A, et al.: Absence of integrin a1b1 in the mouse causes loss of feedback regulation of collagen synthesis in normal and wounded dermis. J Cell Sci 1999, 112:263–272. Based on an analysis of the viable gene targeted a1 null animal, this paper provides the definitive evidence of the role of α1β1 as a feedback regulator of collagen synthesis in vivo.

    PubMed  CAS  Google Scholar 

  26. Riikonen T, Westermarch J, Kovisto L, et al.: Integrin α2β1 is a positive regulator of collagenase (MMP-1) and collagen α1(I) gene expression. J Biol Chem 1995, 270:13548–13552.

    Article  PubMed  CAS  Google Scholar 

  27. Ivarsson M, McWhirter A, Black CM, Rubin K: Impaired regulation of collagen pro-α1(I) mRNA and change in pattern of collagen-binding integrins on scleroderma fibroblasts. J Invest Dermatol 1993, 101:216–221. This paper makes the important observation of the relationship between scleroderma and reduced cell surface expression of integrin α1β1.

    Article  PubMed  CAS  Google Scholar 

  28. Riikonen T, Koivisto L, Vihinen P, Heino J: Transforming growth factor-β regulates collagen gel contraction by increasing α2α1 integrin expression in osteogenic cells. J Biol Chem 1995, 270:376–82.

    Article  PubMed  CAS  Google Scholar 

  29. Calderwood DA, Tuckwell DS, Eble J, et al.: The integrin α A-domain is a ligand binding site for collagens and laminin. J Biol Chem 1997, 272:12311–12317.

    Article  PubMed  CAS  Google Scholar 

  30. Lallier T, Bronner-Fraser M: Inhibition of neural crest cell attachment by integrin antisense oligonucleotides. Science 1993, 259:692–695.

    Article  PubMed  CAS  Google Scholar 

  31. Gardner H, Kreidberg J, Koteliansky V, Jaenisch R: Deletion of integrin α1 by homologous recombination permits normal murine development but gives rise to a specific deficit in cell adhesion. Dev Biol 1996, 175:301–313.

    Article  PubMed  CAS  Google Scholar 

  32. Ravanti L, Heino J, Lopez-Otin C, Kahari VM: Induction of collagenase-3 (MMP-13) expression in human skin fibroblasts by three-dimensional collagen is mediated by p38 mitogen-activated protein kinase [In Process Citation]. J Biol Chem 1999, 274:2446–2455. This is a clear dissection of the 2 mediated pathway of induction of at least one collagenase, and elegantly summarizes the work of this group over a long period.

    Article  PubMed  CAS  Google Scholar 

  33. Pozzi A, Wary KK, Giancotti FG, Gardner HA: Integrin α1β1 mediates a unique collagen-dependent proliferation pathway in vivo. J Cell Biol 1998, 142:587–594.

    Article  PubMed  CAS  Google Scholar 

  34. Slack JL, Parker MI, Bornstein P: Transcriptional repression of the α1(I) collagen gene by ras is mediated in part by an intronic AP1 site. J Cell Biochem 1995, 58:380–392.

    Article  PubMed  CAS  Google Scholar 

  35. Slack JL, Parker MI, Robinson VR, Bornstein P: Regulation of collagen I gene expression by ras. Mol Cell Biol 1992, 12:4714–4723.

    PubMed  CAS  Google Scholar 

  36. Davis BH, Chen A, Beno DW: Raf and mitogen-activated protein kinase regulate stellate cell collagen gene expression. J Biol Chem 1996, 271:11039–11042.

    Article  PubMed  CAS  Google Scholar 

  37. Broberg A, Heino J: Integrin αβ1-dependent contraction of floating collagen gels and induction of collagenase are inhibited by tyrosine kinase inhibitors. Exp Cell Res 1996, 228:29–35.

    Article  PubMed  CAS  Google Scholar 

  38. Kozlowska E, Sollberg S, Mauch C, et al.: Decreased expression of α2β1 integrin in scleroderma fibroblasts. Exp Dermatol 1996, 5:57–63.

    Article  PubMed  CAS  Google Scholar 

  39. Osada K, Seishima M, Kitajima Y, et al.: Decreased integrin α2, but normal response to TGF-β in scleroderma fibroblasts. J Dermatol Sci 1995, 9:169–175.

    Article  PubMed  CAS  Google Scholar 

  40. Vaalamo M, Mattila L, Johansson N, et al.: Distinct populations of stromal cells express collagenase-3 (MMP-13) and collagenase-1 (MMP-1) in chronic ulcers but not in normally healing wounds. J Invest Dermatol 1997, 109:96–101.

    Article  PubMed  CAS  Google Scholar 

  41. Kuroda K, Shinkai H: Gene expression of types I and III collagen, decorin, matrix metalloproteinases and tissue inhibitors of metalloproteinases in skin fibroblasts from patients with systemic sclerosis. Arch Dermatol Res 1997, 289:567–572.

    Article  PubMed  CAS  Google Scholar 

  42. Tomasek JJ, Haaksma CJ, Eddy RJ, Vaughan MB: Fibroblast contraction occurs on release of tension in attached collagen lattices: dependency on an organized actin cytoskeleton and serum. Anat Rec 1992, 232:359–368.

    Article  PubMed  CAS  Google Scholar 

  43. Heino J, Ignotz RA, Hemler ME, Crouse C, Massague J:Regulation of cell adhesion receptors by transforming growth factor-β. Concomitant regulation of integrins that share a common β1 subunit. J Biol Chem 1989, 264:380–388.

    PubMed  CAS  Google Scholar 

  44. Gailit J, Xu J, Bueller H, Clark RA: Platelet-derived growth factor and inflammatory cytokines have differential effects on the expression of integrins α1β1 and α5β1 by human dermal fibroblasts in vitro. J Cell Physiol 1996, 169:281–289.

    Article  PubMed  CAS  Google Scholar 

  45. Xu J, Clark RA: Extracellular matrix alters PDGF regulation of fibroblast integrins. J Cell Biol 1996, 132:239–249.

    Article  PubMed  CAS  Google Scholar 

  46. Xu J, Zutter MM, Santoro SA, Clark RA: PDGF induction of α2 integrin gene expression is mediated by protein kinase C-zeta. J Cell Biol 1996, 134:1301–1311.

    Article  PubMed  CAS  Google Scholar 

  47. Xu J, Clark RA: A three-dimensional collagen lattice induces protein kinase C-zeta activity: role in α2 integrin and collagenase mRNA expression. J Cell Biol 1997, 136:473–483.

    Article  PubMed  CAS  Google Scholar 

  48. Xu J, Zutter MM, Santoro SA, Clark RA: A three-dimensional collagen lattice activates NF-кB in human fibroblasts: role in integrin α2 gene expression and tissue remodeling. J Cell Biol 1998, 140:709–719. This paper and its predecessors represent a thorough and systematic dissection of the factors and processes regulating integrin 2 expression.

    Article  PubMed  CAS  Google Scholar 

  49. Santala P, Heino J: Regulation of integrin-type cell adhesion receptors by cytokines. J Biol Chem 1991, 266:23505–23509.

    PubMed  CAS  Google Scholar 

  50. Chou DH, Lee W, McCulloch CA: TNF-α inactivation of collagen receptors: implications for fibroblast function and fibrosis. J Immunol 1996, 156:4354–4362.

    PubMed  CAS  Google Scholar 

  51. Buck M, Houglum K, Chojkier M: Tumor necrosis factor-α inhibits collagen α1(I) gene expression and wound healing in a murine model of cachexia. Am J Pathol 1996, 149:195–204.

    PubMed  CAS  Google Scholar 

  52. Rapala K, Laato M, Niinikoski J, et al.: Tumor necrosis factor α inhibits wound healing in the rat. Eur Surg Res 1991, 23:261–268.

    PubMed  CAS  Google Scholar 

  53. O’Frazier K, Williams S, Kothapalli D, et al.: Stimulation of fibroblast cell growth, matrix production, and granulation tissue formation by connective tissue growth factor. J Invest Dermatol 1996, 107:404–411.

    Article  Google Scholar 

  54. Takeda K, Hatamochi A, Arakawa M, Ueki H: Effects of tumor necrosis factor-α on connective tissue metabolism in normal and scleroderma fibroblast cultures. Arch Dermatol Res 1993, 284:440–444.

    Article  PubMed  CAS  Google Scholar 

  55. Majewski S, Hunzelmann N, Schirren CG, et al.:Increased adhesion of fibroblasts from patients with scleroderma to extracellular matrix components: in vitro modulation by IFN-γ but not by TGF-β. J Invest Dermatol 1992, 98:86–91.

    Article  PubMed  CAS  Google Scholar 

  56. LeRoy EC, Trojanowska MI, Smith EA: Cytokines and human fibrosis. Eur Cytokine Netw 1990, 1:215–219.

    PubMed  CAS  Google Scholar 

  57. Eckes B, Mauch C, Huppe G, Krieg T: Differential regulation of transcription and transcript stability of pro-α1(I) collagen and fibronectin in activated fibroblasts derived from patients with systemic scleroderma. Biochem J 1996, 315:549–554.

    PubMed  CAS  Google Scholar 

  58. Westergren-Thorsson G, Coster L, Akesson A, Wollheim FA:Altered dermatan sulfate proteoglycan synthesis in fibroblast cultures established from skin of patients with systemic sclerosis. J Rheumatol 1996, 23:1398–1406.

    PubMed  CAS  Google Scholar 

  59. Izumi T, Tajima S, Nishikawa T: Stimulated expression of decorin and the decorin gene in fibroblasts cultured from patients with localized scleroderma. Arch Dermatol Res 1995, 287:417–420.

    Article  PubMed  CAS  Google Scholar 

  60. Greiling D, Clark RA: Fibronectin provides a conduit for fibroblast transmigration from collagenous stroma into fibrin clot provisional matrix. J Cell Sci 1997, 110:861–870. Description and analysis of an imaginative ex vivo system for determining the factors required for initiating fibroblast mobility into wounds, demonstrating that fibroblasts cannot migrate into fibrin without fibronectin present to supply a "bridge" from mature collagen.

    PubMed  CAS  Google Scholar 

  61. Shibata K, Kikkawa F, Nawa A, et al.: Fibronectin secretion from human peritoneal tissue induces Mr 92,000 type IV collagenase expression and invasion in ovarian cancer cell lines. Cancer Res 1997, 57:5416–5420.

    PubMed  CAS  Google Scholar 

  62. Majewski S, et al.: Expression of intercellular adhesion molecule-1 (ICAM-1) in the skin of patients with systemic scleroderma. J Invest Dermatol 1991, 97:667–671.

    Article  PubMed  CAS  Google Scholar 

  63. Gruschwitz M, von den Driesch P, Kellner I, et al.: Expression of adhesion proteins involved in cell-cell and cell-matrix interactions in the skin of patients with progressive systemic sclerosis. J Am Acad Dermatol 1992, 27:169–177.

    Article  PubMed  CAS  Google Scholar 

  64. Le Roy EC: Systemic sclerosis. A vascular perspective. Rheum Dis Clin North Am 1996, 22:675–694.

    Article  Google Scholar 

  65. Tan FK, et al.: Association of microsatellite markers near the fibrillin 1 gene on human chromosome 15q with scleroderma in a Native American population. Arthritis Rheum 1998, 41:1729–1737.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gardner, H.A. Integrin signaling in fibrosis and scleroderma. Curr Rheumatol Rep 1, 28–33 (1999). https://doi.org/10.1007/s11926-999-0021-5

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11926-999-0021-5

Keywords

Navigation