Transforming growth factor beta, collagenase-1 and TIMP-1: Possible role as key mediators in scieroderma pathogenesis

ABSTRACT

Systemic sclerosis is a multisystem disease affecting the skin, dermal blood vessels and internal organs. It is characterized pathologically by the overproduction of connective tissue notably collagen. Scleroderma fibroblasts exhibit numerous phenotypic differences when compared with healthy skin fibroblasts; some of these differences in particular are over-expression of collagen and extracellular matrix [ECM] proteins. The fibroblasts produce enzymes as collagenase and other matrix metalloproteinases which can collectively digest all matrix components. Although the pathogenesis of scieroderma is still poorly understood, there is an increasing evidence that transforming growth factor beta is a key mediator of tissue fibrosis as a result of ECM accumulation in pathological states as systemic sclerosis. Also there is evidence of disturbed balance between collagenase-l and its inhibitor TIMP-1 in SSc patients leading to ECM accumulation. The aim of this study was to investigate the serum levels of TGF-beta1, TGF-beta2, collagenase-l and TIMP-l in patients with scleroderma in an attempt to throw lights on different factors which may represent an important clue for understanding the pathogenesis of sclerodernia and thus will probably help in the development of targeted drug therapy aiming at interrupting the abnormal fibrogenic process in this disease. The serum levels of TGF-beta1, TGF-beta2, collagenase-l and TIMP-l were measured in 20 patients with scleroderma [13 females and 7 males], and 15 healthy controls [9 females and 6 males]. The serum levels of TGF-beta1, TGF-beta2 and TIMP-l were found to be significantly higher in scieroderma patients compared with the control group [p<0.01] Meanwhile, the collagenase-l serum levels in SSc patients did not differ significantly from those of normal controls [p<0.05]. No significant correlation was found between either TGF-beta1 or TGF-beta2 serum levels in SSc patients and TIMP-l serum levels, disease duration, scl-70 or ESR [as an indicator of disease activity]. In TGF-beta1 TGF-beta2 andi-IMP-l are probably key mediators underlying the process of fibrosis in patients with SSc as a consequence of ECM accumulation. TGF-beta play a crucial role in the pathogenesis of SSc as it is the most potent inducer of collagen and connective tissue accumulation. The study of TGF-beta and TIMP-l and their biologic effects provides important clues to understanding the pathogenesis of SSc and to the development of new therapies acting directly on the causative factors underlying the pathogenesis of SSc as gene therapy or monoclonal antibodies to TGF-beta or the use of other cytokines as TNF-alpha aiming at interrupting the abnormal fibrogenic process in this disease