Transforming growth factor-beta and connective tissue growth factor: key cytokines in scleroderma pathogenesis

Evidence for a role for members of the transforming growth factor beta (TGF -beta) family of cytokines in the pathogenesis of systemic sclerosis and ot her fibrotic conditions is provided from studies of TGF-beta protein and ge ne expression in lesional biopsy specimens, from altered responses of expla nted fibroblasts to TGF-beta stimulation which are associated with increase d receptor expression on these cells and from genetic data linking TGF-beta gene loci to the disease. Of the many effects of TGF-beta on fibroblast pr operties induction of the connective tissue growth factor/Cyr61/NOV (CCN) f amily members, connective tissue growth factor (CTGF) may be particularly r elevant to fibrosis. Moreover, systemic sclerosis (SSc) fibroblasts demonst rate constitutive over expression of CTGF that promotes migration, prolifer ation and matrix production. Studies of mechanisms regulating constitutive expression of CTGF by SSc fibroblasts are currently being undertaken and in dicate that a TGF-beta responsive element in the CTGF promoter is involved, although this appears to function independent of the Smad proteins, sugges ting that other TGF-beta -regulated pathways may be involved. TGF-neutraliz ing strategies have now been shown to abrogate many animal models of fibros is, and will soon reach the clinical arena for SSc. These agents will furth er clarify the role of this ligand in initiating or sustaining fibrosis and offer the exciting possibility of targeted therapy for this disease. Curr Opin Rheumatol 2001, 13:505-511 (C) 2001 Lippincott Williams & Wilkins, Inc .