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.
We genotyped a polymorphism (G-945C) in the promoter of the connective-tissue growth factor (CTGF) gene in 1000 subjects in two groups: group 1, consisting of 200 patients with systemic sclerosis and 188 control subjects; and group 2, consisting of 300 patients with systemic sclerosis and 312 control subjects.
Because hypoxia is associated with fibrosis in several profibrogenic conditions, we investigated whether CTGF expression in SSc fibroblasts is regulated by hypoxia.
Normal fibroblasts incubated with serum from an SSc-affected patient or with serum from her unaffected MZ twin sister developed the increased expression of COL1A2, SPARC, and CTGF typically seen in SSc fibroblasts.
This review discusses recent information regarding insights into connective tissue growth factor biology and, using scleroderma as a model system, the part connective tissue growth factor might play in fibrotic disease.
Based on these data, we hypothesize that a 2-step process of fibrosis occurs in SSc: that is, TGF-beta induces fibrosis in the early stage and afterwards CTGF acts to maintain tissue fibrosis.
These include the role of transforming growth factor-beta (TGF-beta) and connective tissue growth factor (CTGF) and their receptors in the fibrotic process in scleroderma and the overview of the transcription factors involved in regulation of the human alpha2 (I) collagen (COL1A2) gene.
However, mutation of the previously termed TGFbetaRE reduces ccn2 (ctgf) promoter activity in scleroderma fibroblasts to that seen in normal fibroblasts.
By sampling dermal interstitial fluid using a suction blister device, we show that CTGF levels are greatly elevated in the dermis of scleroderma patients compared with healthy controls and that Iloprost infusion causes a marked decrease in dermal CTGF levels.
Studies of mechanisms regulating constitutive expression of CTGF by SSc fibroblasts are currently being undertaken and indicate that a TGF-beta responsive element in the CTGF promoter is involved, although this appears to function independent of the Smad proteins, suggesting that other TGF-beta-regulated pathways may be involved.
Although TNFalpha was able to repress TGF-beta-induced CTGF and collagen synthesis both in normal and scleroderma skin fibroblasts, fibroblasts cultured from scleroderma patients were more resistant to TNFalpha as TNFalpha was unable to suppress the basal level of CTGF expression in scleroderma fibroblasts.
Connective tissue growth factor (CTGF) is a member of an emerging CCN gene family that is implicated in various diseases associated with fibro-proliferative disorder including scleroderma and atherosclerosis.
Connective tissue growth factor (CTGF), a cytokine of the family of growth regulators comprising sef10, cyr61, CTGF and nov, has recently been described in association with scleroderma and other scarring conditions.
Our findings indicate a correlation between CTGF gene expression and skin sclerosis and support the hypothesis that transforming growth factor-beta plays an important role in the pathogenesis of SSc, because transforming growth factor beta is the only inducer for CTGF identified to date.