This study was conducted in accordance with the principles embodied in the Declaration of Helsinki and was approved by the Ethical Committees in the Catholic Research Institutes of Medical Sciences. In the present study, we measured the expression of MMP-9 and tissue inhibitor of metalloproteinase-1 (TIMP-1), an inhibitor of MMP-9, in the sera and culture supernatants of dermal fibroblasts from SSc patients and compared them with serum concentrations of transforming growth factor β (TGFβ) and with clinical and laboratory parameters of SSc. Moreover, the overexpression of MMP-9 has been reported in various pathologic conditions characterized by excessive fibrosis, including idiopathic pulmonary fibrosis, bronchial asthma, experimental biliary cirrhosis, and chronic pancreatitis, suggesting that elevated MMP-9 is closely linked to fibrogenic remodeling in target organs. MMP-9 has been associated with chronic inflammatory autoimmune diseases, including rheumatoid arthritis, Sjögren's syndrome, idiopathic uveitis, and systemic lupus erythematosus. T cells, mononuclear phagocytes, synovial fibroblasts, and metastatic tumor cells). Of these, MMP-9 (92–96 kD gelatinase B), whose substrates include type IV collagen in basement membrane, has been thought to be involved in the cellular invasion of the basement membrane by cells involved in arthritis and cancer (e.g. The matrix metalloproteinases (MMPs) are a family of extracellular endopeptidases that selectively degrade the components of various extracellular matrixes. The excessive production of type IV collagen and subsequent autoimmune T-cell responses to type IV collagen may set off a self-perpetuating cycle in SSc through the interaction between lymphocytes and fibroblasts. Furthermore, type IV collagen activates T cells from patients with SSc, suggesting that the selective immunity to type IV collagen may influence the clinical expression of SSc. Immunization of mice with autologous type IV collagen leads to the activation of fibroblasts and to fibrosis. For example, autoantibodies to type IV collagen have been observed in some SSc patients and may be involved in endothelial injury. The enhanced expression of matrix collagen is presumably associated with abnormal immune responses to collagen in SSc. 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. 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. This increase in collagen deposits may be associated with changes in the dermal microvasculature in SSc. The relative proportion of two major types of skin procollagen, types I and III, is higher in SSc lesions than in healthy controls. One of the major hallmarks of the disease is an increased amount of collagen deposits in the affected tissue. 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. These findings suggest that the enhanced production of MMP-9 may contribute to fibrogenic remodeling during the progression of skin sclerosis in SSc. The increased MMP-9 concentrations may be attributable to overproduction by dermal fibroblasts in SSc. In summary, the serum MMP-9 concentrations were elevated in SSc patients and correlated well with skin scores. Such an increase in MMP-9 production was partially blocked by treatment with cyclosporin A. 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. 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. Serum MMP-9 concentrations were significantly higher in the diffuse type ( n = 23) than the limited type of SSc ( n = 19). 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). In this study, we investigated the expression of MMP-9 and its clinical significance in systemic sclerosis (SSc). Matrix metalloproteinase-9 (MMP-9) has been implicated in the pathogenesis of cancer, autoimmune disease, and various pathologic conditions characterized by excessive fibrosis.
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