title: Role of connective tissue growth factor and its interaction with basic fibroblast growth factor and macrophage chemoattractant protein-1 in skin fibrosis.
abstract: Activation of the immune system and abnormal growth of skin fibroblasts cause systemic sclerosis. Growth factors have various biological activities, including mediation of immune reactions. The growth factor family includes basic fibroblast growth factor (bFGF), transforming growth factor-beta (TGF-beta), and connective tissue growth factor (CTGF). CTGF, an important downstream mediator of TGF-beta in fibrosis, has been suggested to play a specific role in fibrotic disorders. We have directed our attention to the role of CTGF in sustaining skin fibrosis. To better understand its effects in vivo, we established an animal model of skin fibrosis induced by exogenous application of growth factors. In this model, bFGF transiently induced subcutaneous fibrosis. Simultaneous injection of bFGF and CTGF increased skin fibrosis compared with a single injection of bFGF. Serial injections of bFGF for 3 days followed by CTGF for 4 days, or of CTGF followed by bFGF, did not cause skin fibrosis but simultaneous injections increased macrophage chemoattractant protein-1 (MCP-1) mRNA expression levels. To further define the mechanisms of skin fibrosis in vivo, bFGF and CTGF were injected simultaneously into MCP-1 knockout mice, resulting in decreased collagen levels in granulation tissues on day 8. The number of inflammatory cells, such as mast cells, macrophages and lymphocytes, was significantly decreased in MCP-1 knockout mice compared with wild-type mice. These results suggest that bFGF induces collagen production by stimulating skin fibroblasts and CTGF cooperates with bFGF. Our results indicate that the induction of MCP-1 is necessary for infiltration of inflammatory cells.
authors.affiliation: Department of Dermatology, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan.
authors.forename: Sonoko
authors.initials: S
authors.lastname: Chujo
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Shirasaki
authors.forename: Miki
authors.initials: M
authors.lastname: Kondo-Miyazaki
authors.forename: Yuka
authors.initials: Y
authors.lastname: Ikawa
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Takehara
mesh_terms: D000818:Animals; D002465:Cell Movement; D018932:Chemokine CCL2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D003094:Collagen / Q000378:metabolism; D024042:Collagen Type I; D055513:Connective Tissue Growth Factor / Q000008:administration & dosage; D004195:Disease Models, Animal; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis; D006097:Granulation Tissue / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007279:Injections, Subcutaneous; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D012867:Skin / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D012871:Skin Diseases / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors
chemical_list: C526317:CCN2 protein, human; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D024042:Collagen Type I; D012333:RNA, Messenger; D016222:Fibroblast Growth Factor 2; D055513:Connective Tissue Growth Factor; D003094:Collagen