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 pathogensis of systemic sclerosis and other fibrotic conditions is provided from studies of TGF-beta protein and gene expression in lesional biopsy specimens, from altered responses of explanted fibroblasts to TGF-beta stimulation which are associated with increased 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 properties induction of the connective tissue growth factor/Cyr61/NOV (CCN) family members, connective tissue growth factor (CTGF) may be particularly relevant to fibrosis. Moreover, systemic sclerosis (SSc) fibroblasts demonstrate constitutive over expression of CTGF that promotes migration, proliferation and matrix production. 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. TGF-neutralizing strategies have now been shown to abrogate many animal models of fibrosis, and will soon reach the clinical arena for SSc. These agents will further clarify the role of this ligand in initiating or sustaining fibrosis and offer the exciting possibility of targeted therapy for this disease.
Denton
C P
CP
Centre for Rheumatology, Royal Free and University College Medical School, London, United Kingdom. c.denton@rfc.ucl.ac.uk
Abraham
D J
DJ
D055513:Connective Tissue Growth Factor; D004268:DNA-Binding Proteins / Q000502:physiology; D006133:Growth Substances / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins; D005810:Multigene Family; D055514:Nephroblastoma Overexpressed Protein; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000188:drug therapy / Q000209:etiology*; D051900:Smad3 Protein; D015534:Trans-Activators / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*
C526317:CCN2 protein, human; C526319:CCN3 protein, human; D004268:DNA-Binding Proteins; D006133:Growth Substances; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D055514:Nephroblastoma Overexpressed Protein; D018125:Receptors, Transforming Growth Factor beta; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor