title: Neutralizing monoclonal antibody to human connective tissue growth factor ameliorates transforming growth factor-beta-induced mouse fibrosis.
abstract: Skin fibrotic disorders such as systemic sclerosis (SSc) are characterized by an excessive accumulation of extracellular matrix (ECM) and are understood to develop under the influence of fibrogenic growth factors. To better understand the detailed mechanisms of persistent fibrosis in SSc, we have previously established an animal model of skin fibrosis induced by exogenous application of growth factors. In this model, transforming growth factor-beta (TGF-beta) transiently induced subcutaneous fibrosis and serial injections of connective tissue growth factor (CTGF) after TGF-beta caused persistent fibrosis. These results suggest that CTGF plays an important role in the development of persistent skin fibrosis and that CTGF may be a potential and specific therapeutic target in skin fibrosis. Therefore, the aim of the current study is to develop a neutralizing monoclonal antibody against human CTGF. We also investigated the neutralizing effect of the antibodies in our animal model. Firstly, by using the DNA immunization method, we developed a panel of anti-CTGF antibodies recognizing the native conformation of human CTGF. Next, to examine the anti-fibrosing effects of these antibodies, newborn B6 mice received subcutaneous injections of TGF-beta for 3 days with either anti-CTGF neutralizing antibodies or control purified immunoglobulin. Anti-CTGF antibodies significantly reduced skin fibrosis and collagen contents compared with the control group. These results suggest that our anti-CTGF antibodies are capable of blocking the development of skin fibrosis at least partially and these anti-CTGF neutralizing antibodies may be useful as the feasible strategy to treat skin fibrotic diseases as SSc.
authors.affiliation: Department of Dermatology, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Ikawa
authors.forename: Poh-Sing
authors.initials: PS
authors.lastname: Ng
authors.forename: Koki
authors.initials: K
authors.lastname: Endo
authors.forename: Miki
authors.initials: M
authors.lastname: Kondo
authors.forename: Sonoko
authors.initials: S
authors.lastname: Chujo
authors.forename: Wataru
authors.initials: W
authors.lastname: Ishida
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Shirasaki
authors.forename: Manabu
authors.initials: M
authors.lastname: Fujimoto
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Takehara
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000378:metabolism*; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D055513:Connective Tissue Growth Factor; D005260:Female; D005355:Fibrosis / Q000139:chemically induced* / Q000473:pathology; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000276:immunology / Q000473:pathology; D012867:Skin / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D000911:Antibodies, Monoclonal; C526317:CCN2 protein, human; C526318:CCN2 protein, mouse; D024042:Collagen Type I; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor