Current Rheumatology Reports

, 15:304 | Cite as

Involvement of PDGF in Fibrosis and Scleroderma: Recent Insights from Animal Models and Potential Therapeutic Opportunities

  • Tomoaki Iwayama
  • Lorin E. Olson
Part of the following topical collections:
  1. Topical Collection on Scleroderma


Fibrosis is the principal characteristic of the autoimmune disease known as scleroderma or systemic sclerosis (SSc). Studies published within the last three years suggest central involvement of platelet-derived growth factors (PDGFs) in SSc-associated fibrosis. PDGFs may also be involved in SSc-associated autoimmunity and vasculopathy. The PDGF signaling pathway is well understood and PDGF receptors are expressed on collagen-secreting fibroblasts and on mesenchymal stem and/or progenitor cells that may affect SSc in profound and unexpected ways. Although much work remains before we fully understand how PDGFs are involved in SSc, there is much interest in using PDGF inhibitors as a therapeutic approach to SSc.


PDGF Scleroderma Fibrosis Mouse model Animal models Pericyte Imatinib Neutralizing antibody Therapeutic 



No potential conflicts of interest relevant to this article were reported.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Bhattacharyya S, Wei J, Varga J. Understanding fibrosis in systemic sclerosis: shifting paradigms, emerging opportunities. Nat Rev Rheumatol. 2012;8:42–54.CrossRefGoogle Scholar
  2. 2.
    Gabrielli A, Avvedimento EV, Krieg T. Scleroderma. N Engl J Med. 2009;360:1989–2003.PubMedCrossRefGoogle Scholar
  3. 3.
    Varga J, Abraham D. Systemic sclerosis: a prototypic multisystem fibrotic disorder. J Clin Invest. 2007;117:557–67.PubMedCrossRefGoogle Scholar
  4. 4.
    Mayes MD, Lacey Jr JV, Beebe-Dimmer J, et al. Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum. 2003;48:2246–55.PubMedCrossRefGoogle Scholar
  5. 5.
    Leroy EC. Connective tissue synthesis by scleroderma skin fibroblasts in cell culture. J Exp Med. 1972;135:1351–62.PubMedCrossRefGoogle Scholar
  6. 6.
    Hinz B, Phan SH, Thannickal VJ, et al. Recent developments in myofibroblast biology: paradigms for connective tissue remodeling. Am J Pathol. 2012;180:1340–55.PubMedCrossRefGoogle Scholar
  7. 7.
    Kohler N, Lipton A. Platelets as a source of fibroblast growth-promoting activity. Exp Cell Res. 1974;87:297–301.PubMedCrossRefGoogle Scholar
  8. 8.
    Ross R, Glomset J, Kariya B, Harker L. A platelet-dependent serum factor that stimulates the proliferation of arterial smooth muscle cells in vitro. Proc Natl Acad Sci USA. 1974;71:1207–10.PubMedCrossRefGoogle Scholar
  9. 9.
    Andrae J, Gallini R, Betsholtz C. Role of platelet-derived growth factors in physiology and medicine. Genes Dev. 2008;22:1276–312.PubMedCrossRefGoogle Scholar
  10. 10.
    Daoussis D, Tsamandas AC, Liossis SN, et al. B-cell depletion therapy in patients with diffuse systemic sclerosis associates with a significant decrease in PDGFR expression and activation in spindle-like cells in the skin. Arthritis Res Ther. 2012;14:R145.PubMedCrossRefGoogle Scholar
  11. 11.
    Gay S, Jones Jr RE, Huang GQ, Gay RE. Immunohistologic demonstration of platelet-derived growth factor (PDGF) and sis-oncogene expression in scleroderma. J Invest Dermatol. 1989;92:301–3.PubMedCrossRefGoogle Scholar
  12. 12.
    Klareskog L, Gustafsson R, Scheynius A, Hallgren R. Increased expression of platelet-derived growth factor type B receptors in the skin of patients with systemic sclerosis. Arthritis Rheum. 1990;33:1534–41.PubMedCrossRefGoogle Scholar
  13. 13.
    Rajkumar VS, Sundberg C, Abraham DJ, et al. Activation of microvascular pericytes in autoimmune Raynaud's phenomenon and systemic sclerosis. Arthritis Rheum. 1999;42:930–41.PubMedCrossRefGoogle Scholar
  14. 14.
    Pandolfi A, Florita M, Altomare G, et al. Increased plasma levels of platelet-derived growth factor activity in patients with progressive systemic sclerosis. Proc Soc Exp Biol Med. 1989;191:1–4.PubMedGoogle Scholar
  15. 15.
    Ludwicka A, Ohba T, Trojanowska M, et al. Elevated levels of platelet derived growth factor and transforming growth factor-beta 1 in bronchoalveolar lavage fluid from patients with scleroderma. J Rheumatol. 1995;22:1876–83.PubMedGoogle Scholar
  16. 16.
    LeRoy EC, Mercurio S, Sherer GK. Replication and phenotypic expression of control and scleroderma human fibroblasts: responses to growth factors. Proc Natl Acad Sci USA. 1982;79:1286–90.PubMedCrossRefGoogle Scholar
  17. 17.
    Olson LE, Soriano P. Increased PDGFRalpha activation disrupts connective tissue development and drives systemic fibrosis. Dev Cell. 2009;16:303–13.PubMedCrossRefGoogle Scholar
  18. 18.
    Sonnylal S, Denton CP, Zheng B, et al. Postnatal induction of transforming growth factor beta signaling in fibroblasts of mice recapitulates clinical, histologic, and biochemical features of scleroderma. Arthritis Rheum. 2007;56:334–44.PubMedCrossRefGoogle Scholar
  19. 19.
    Heldin CH, Westermark B. Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev. 1999;79:1283–316.PubMedGoogle Scholar
  20. 20.
    Bonner JC. Regulation of PDGF and its receptors in fibrotic diseases. Cytokine Growth Factor Rev. 2004;15:255–73.PubMedCrossRefGoogle Scholar
  21. 21.
    Baroni SS, Santillo M, Bevilacqua F, et al. Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis. N Engl J Med. 2006;354:2667–76.PubMedCrossRefGoogle Scholar
  22. 22.
    Classen JF, Henrohn D, Rorsman F, et al. Lack of evidence of stimulatory autoantibodies to platelet-derived growth factor receptor in patients with systemic sclerosis. Arthritis Rheum. 2009;60:1137–44.PubMedCrossRefGoogle Scholar
  23. 23.
    Loizos N, Lariccia L, Weiner J, et al. Lack of detection of agonist activity by antibodies to platelet-derived growth factor receptor alpha in a subset of normal and systemic sclerosis patient sera. Arthritis Rheum. 2009;60:1145–51.PubMedCrossRefGoogle Scholar
  24. 24.
    Hoch RV, Soriano P. Roles of PDGF in animal development. Development. 2003;130:4769–84.PubMedCrossRefGoogle Scholar
  25. 25.
    Karlsson L, Bondjers C, Betsholtz C. Roles for PDGF-A and sonic hedgehog in development of mesenchymal components of the hair follicle. Development. 1999;126:2611–21.PubMedGoogle Scholar
  26. 26.
    Ding H, Wu X, Bostrom H, et al. A specific requirement for PDGF-C in palate formation and PDGFR-alpha signaling. Nat Genet. 2004;36:1111–6.PubMedCrossRefGoogle Scholar
  27. 27.
    Soriano P. The PDGF alpha receptor is required for neural crest cell development and for normal patterning of the somites. Development. 1997;124:2691–700.PubMedGoogle Scholar
  28. 28.
    Bostrom H, Willetts K, Pekny M, et al. PDGF-A signaling is a critical event in lung alveolar myofibroblast development and alveogenesis. Cell. 1996;85:863–73.PubMedCrossRefGoogle Scholar
  29. 29.
    Karlsson L, Lindahl P, Heath JK, Betsholtz C. Abnormal gastrointestinal development in PDGF-A and PDGFR-(alpha) deficient mice implicates a novel mesenchymal structure with putative instructive properties in villus morphogenesis. Development. 2000;127:3457–66.PubMedGoogle Scholar
  30. 30.
    Lindahl P, Johansson BR, Leveen P, Betsholtz C. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science. 1997;277:242–5.PubMedCrossRefGoogle Scholar
  31. 31.
    Smith CL, Baek ST, Sung CY, Tallquist MD. Epicardial-derived cell epithelial-to-mesenchymal transition and fate specification require PDGF receptor signaling. Circ Res. 2011;108:e15–26.PubMedCrossRefGoogle Scholar
  32. 32.
    Hellstrom M, Kalen M, Lindahl P, et al. Role of PDGF-B and PDGFR-beta in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development. 1999;126:3047–55.PubMedGoogle Scholar
  33. 33.
    Lee YH, Petkova AP, Mottillo EP, Granneman JG. In vivo identification of bipotential adipocyte progenitors recruited by beta3-adrenoceptor activation and high-fat feeding. Cell Metab. 2012;15:480–91.PubMedCrossRefGoogle Scholar
  34. 34.
    Tang W, Zeve D, Suh JM, et al. White fat progenitor cells reside in the adipose vasculature. Science. 2008;322:583–6.PubMedCrossRefGoogle Scholar
  35. 35.
    Joe AW, Yi L, Natarajan A, et al. Muscle injury activates resident fibro/adipogenic progenitors that facilitate myogenesis. Nat Cell Biol. 2010;12:153–63.PubMedCrossRefGoogle Scholar
  36. 36.
    Uezumi A, Fukada S, Yamamoto N, et al. Mesenchymal progenitors distinct from satellite cells contribute to ectopic fat cell formation in skeletal muscle. Nat Cell Biol. 2010;12:143–52.PubMedCrossRefGoogle Scholar
  37. 37.
    •• Dulauroy S, Di Carlo SE, Langa F, et al. Lineage tracing and genetic ablation of ADAM12(+) perivascular cells identify a major source of profibrotic cells during acute tissue injury. Nat Med. 2012;18:1262–70. This article describes how ADAM12+ perivascular cells, which express multipotent mesenchymal stem/progenitor cell markers including PDGFRα and β, are activated after acute injury to become progenitors of collagen-overproducing cells in vivo CrossRefGoogle Scholar
  38. 38.
    Akhmetshina A, Beer J, Zwerina K, et al. Decreased lymphatic vessel counts in patients with systemic sclerosis: association with fingertip ulcers. Arthritis Rheum. 2010;62:1513–22.PubMedCrossRefGoogle Scholar
  39. 39.
    • Meinecke AK, Nagy N, Lago GD, et al. Aberrant mural cell recruitment to lymphatic vessels and impaired lymphatic drainage in a murine model of pulmonary fibrosis. Blood. 2012;119:5931–42. Unlike blood vessels, lymphatic vessels normally lack mural cells (pericytes and smooth muscle cells). By using a bleomycin-induced pulmonary fibrosis model, the authors show that PDGFRβ+ mural cells cover lymphatics in fibrotic lungs, which impairs drainage capacity. Fibrosis and lymphatic function are improved by inhibiting PDGF signaling.PubMedCrossRefGoogle Scholar
  40. 40.
    •• Krautler NJ, Kana V, Kranich J, et al. Follicular dendritic cells emerge from ubiquitous perivascular precursors. Cell. 2012;150:194–206. This article provides convincing evidence that follicular dendritic cells (FDCs) arise from ubiquitous perivascular precursors, which express PDGFRβ, as mural cells do. When the isolated PDGFRβ+ cells were transplanted into FDC-lacking mice, followed by stimulation to differentiate into FDCs, mature functional FDCs were observed de novo.PubMedCrossRefGoogle Scholar
  41. 41.
    Ponten A, Li X, Thoren P, et al. Transgenic overexpression of platelet-derived growth factor-C in the mouse heart induces cardiac fibrosis, hypertrophy, and dilated cardiomyopathy. Am J Pathol. 2003;163:673–82.PubMedCrossRefGoogle Scholar
  42. 42.
    Ponten A, Folestad EB, Pietras K, Eriksson U. Platelet-derived growth factor D induces cardiac fibrosis and proliferation of vascular smooth muscle cells in heart-specific transgenic mice. Circ Res. 2005;97:1036–45.PubMedCrossRefGoogle Scholar
  43. 43.
    Campbell JS, Hughes SD, Gilbertson DG, et al. Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma. Proc Natl Acad Sci USA. 2005;102:3389–94.PubMedCrossRefGoogle Scholar
  44. 44.
    • Olson LE, Soriano P. PDGFRbeta Signaling Regulates Mural Cell Plasticity and Inhibits Fat Development. Dev Cell. 2011;20:815–26. This article demonstrates that hyperresponsive PDGFRβ signaling induces an autoinflammatory gene signature in pericytes and other mesenchyme-derived cells. This effect is distinct from the multiorgan fibrosis observed with hyperresponsive PDGFRα signaling (see Ref. 17).PubMedCrossRefGoogle Scholar
  45. 45.
    Wang Z, Wang DZ, Hockemeyer D, et al. Myocardin and ternary complex factors compete for SRF to control smooth muscle gene expression. Nature. 2004;428:185–9.PubMedCrossRefGoogle Scholar
  46. 46.
    Antonelli A, Ferri C, Fallahi P, et al. CXCL10 (alpha) and CCL2 (beta) chemokines in systemic sclerosis–a longitudinal study. Rheumatol (Oxford). 2008;47:45–9.CrossRefGoogle Scholar
  47. 47.
    Klinghoffer RA, Hamilton TG, Hoch R, Soriano P. An allelic series at the PDGFalphaR locus indicates unequal contributions of distinct signaling pathways during development. Dev Cell. 2002;2:103–13.PubMedCrossRefGoogle Scholar
  48. 48.
    Tallquist MD, French WJ, Soriano P. Additive effects of PDGF receptor beta signaling pathways in vascular smooth muscle cell development. PLoS Biol. 2003;1:E52.PubMedCrossRefGoogle Scholar
  49. 49.
    Distler JH, Jungel A, Huber LC, et al. Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis. Arthritis Rheum. 2007;56:311–22.PubMedCrossRefGoogle Scholar
  50. 50.
    Akhmetshina A, Venalis P, Dees C, et al. Treatment with imatinib prevents fibrosis in different preclinical models of systemic sclerosis and induces regression of established fibrosis. Arthritis Rheum. 2009;60:219–24.PubMedCrossRefGoogle Scholar
  51. 51.
    Khanna D, Saggar R, Mayes MD, et al. A one-year, phase I/IIa, open-label pilot trial of imatinib mesylate in the treatment of systemic sclerosis-associated active interstitial lung disease. Arthritis Rheum. 2011;63:3540–6.PubMedCrossRefGoogle Scholar
  52. 52.
    Pope J, McBain D, Petrlich L, et al. Imatinib in active diffuse cutaneous systemic sclerosis: results of a six-month, randomized, double-blind, placebo-controlled, proof-of-concept pilot study at a single center. Arthritis Rheum. 2011;63:3547–51.PubMedCrossRefGoogle Scholar
  53. 53.
    Spiera RF, Gordon JK, Mersten JN, et al. Imatinib mesylate (Gleevec) in the treatment of diffuse cutaneous systemic sclerosis: results of a 1-year, phase IIa, single-arm, open-label clinical trial. Ann Rheum Dis. 2011;70:1003–9.PubMedCrossRefGoogle Scholar
  54. 54.
    Kavian N, Servettaz A, Marut W, et al. Sunitinib inhibits the phosphorylation of platelet-derived growth factor receptor beta in the skin of mice with scleroderma-like features and prevents the development of the disease. Arthritis Rheum. 2012;64:1990–2000.PubMedCrossRefGoogle Scholar
  55. 55.
    • Liao CH, Akazawa H, Tamagawa M, et al. Cardiac mast cells cause atrial fibrillation through PDGF-A-mediated fibrosis in pressure-overloaded mouse hearts. J Clin Invest. 2010;120:242–53. The authors use a mouse model to show that atrial fibrosis induced by pressure-overload can be attenuated by injection of a neutralizing antibody specific for PDGFRα. On the other hand, administration of PDGF-AA promotes atrial fibrosis.PubMedCrossRefGoogle Scholar
  56. 56.
    Zymek P, Nah DY, Bujak M, et al. Interleukin-10 is not a critical regulator of infarct healing and left ventricular remodeling. Cardiovasc Res. 2007;74:313–22.PubMedCrossRefGoogle Scholar
  57. 57.
    Larghero J, Farge D, Braccini A, et al. Phenotypical and functional characteristics of in vitro expanded bone marrow mesenchymal stem cells from patients with systemic sclerosis. Ann Rheum Dis. 2008;67:443–9.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Immunobiology and Cancer Research ProgramOklahoma Medical Research FoundationOklahoma CityUSA

Personalised recommendations