Abstract
Matrix metalloproteinase-9 (MMP-9) has been implicated in the pathogenesis of cancer, autoimmune disease, and various pathologic conditions characterized by excessive fibrosis. In this study, we investigated the expression of MMP-9 and its clinical significance in systemic sclerosis (SSc). The patients (n = 42) with SSc had higher concentrations of MMP-9 and of tissue inhibitor of metalloproteinase-1 (TIMP-1) and a higher ratio of MMP-9 to TIMP-1 in sera than healthy controls (n = 32). Serum MMP-9 concentrations were significantly higher in the diffuse type (n = 23) than the limited type of SSc (n = 19). Serum concentrations of MMP-9 correlated well with the degree of skin involvement, as determined by the Rodnan score and with serum concentrations of transforming growth factor β. Moreover, dermal fibroblasts from patients with SSc produced more MMP-9 than those from healthy controls when they were stimulated with IL-1β, tumor necrosis factor α, or transforming growth factor β. Such an increase in MMP-9 production was partially blocked by treatment with cyclosporin A. In summary, the serum MMP-9 concentrations were elevated in SSc patients and correlated well with skin scores. The increased MMP-9 concentrations may be attributable to overproduction by dermal fibroblasts in SSc. These findings suggest that the enhanced production of MMP-9 may contribute to fibrogenic remodeling during the progression of skin sclerosis in SSc.
Highlights
Systemic sclerosis (SSc) is a generalized disorder of connective tissue characterized by microvacular damage and excessive fibrosis in the skin and internal organs, including the heart, lungs, and gastrointestinal tract
Elevated serum Matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) concentrations in systemic sclerosis (SSc) patients The serum concentrations of matrix metalloproteinases (MMPs)-9 were significantly higher in patients with SSc (n = 42) than in healthy controls (n = 32) (317.6 ± 33.5 ng/ml versus 81.2 ± 6.8 ng/ml, P < 0.001) (Fig. 1)
This study has shown that SSc fibroblasts produced more MMP-9 after stimulation with IL-1β, tumor necrosis factor (TNF)-α, and transforming growth factor β (TGFβ) than fibroblasts of healthy controls
Summary
Systemic sclerosis (SSc) is a generalized disorder of connective tissue characterized by microvacular damage and excessive fibrosis in the skin and internal organs, including the heart, lungs, and gastrointestinal tract. One of the major hallmarks of the disease is an increased amount of collagen deposits in the affected tissue. The relative proportion of two major types of skin procollagen, types I and III, is higher in SSc lesions than in healthy controls [1,2]. This increase in collagen deposits may be associated with changes in the dermal microvasculature in SSc. In particular, alterations in the structure of the basement membrane, a critical component of the vessel, may lead to changes in the surrounding tissue and to subsequent development of fibrosis in SSc [3]. The finding that the synthesis of type IV collagen, a major collagen type in basement membrane, is disproportionately increased in the dermal fibroblasts and sera of patients with SSc supports this notion [4,5]
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