학술논문
Decrease in matrix metalloproteinase-3 activity in systemic sclerosis fibroblasts causes [alpha]2-antiplasmin and extracellular matrix deposition, and contributes to fibrosis development
Document Type
Academic Journal
Author
Source
Molecular Medicine Reports. October 2020, Vol. 22 Issue 4, p3001, 7 p.
Subject
Language
English
ISSN
1791-2997
Abstract
Introduction Systemic sclerosis (SSc) is a chronic connective tissue disease that causes widespread microvascular damage and excessive collagen deposition in the skin and internal organs (1). However, the etiology, pathogenesis, [...]
Systemic sclerosis (SSc) is a connective tissue disease of autoimmune origin characterized by fibrosis of the skin and visceral organs, and peripheral circulatory disturbance. [alpha]2-antiplasmin ([alpha]2AP) is the major circulating inhibitor of plasmin and is a key regulator of fibrinolysis. It has been demonstrated that the expression of [alpha]2AP is elevated in dermal fibroblasts obtained from patients with SSc patients. It has also been determined that [alpha]2AP is associated with the development and progression of fibrosis in SSc. The present study assessed the relationship between [alpha]2AP and matrix metalloproteinase-3 (MMP-3), an extracellular matrix (ECM)-degrading enzyme. Serum levels of [alpha]2AP and MMP-3 were measured in healthy controls and patients with SSc using ELISA. No significant differences were determined between these two groups. [alpha]2AP, MMP-3 and tissue inhibitor of metalloproteinase-1 (TIMP-1) expression was subsequently evaluated in normal and SSc fibroblasts via western blotting. The results revealed that [alpha]2AP expression increased in SSc dermal fibroblasts, while the ratio of MMP-3/TIMP-1 decreased. Additionally, incubation of recombinant [alpha]2AP with MMP-3 caused [alpha]2AP degradation. The mixture of recombinant [alpha]2AP with MMP-3 was subsequently added to normal fibroblasts prior to western blotting. The results revealed decreased [alpha]-smooth muscle actin ([alpha]-SMA; a marker of the myofibroblast phenotype) and type I collagen expression. The stimulation of SSc fibroblasts with MMP-3 decreased protein levels of [alpha]2AP, [alpha]-SMA and type I collagen, thus reversing the pro-fibrotic phenotype of SSc fibroblasts. SSc fibroblast transfection with microRNA-29a resulted in a decreased TIMP-1 expression, but also decreased the protein expression of [alpha]2AP. The results indicated that MMP-3 attenuated fibrosis progression by degrading [alpha]2AP and ECM, and might therefore contribute to a novel therapeutic approach for SSc treatment. Key words: alpha2-antiplasmin, Systemic sclerosis, Fibrosis, matrix metallopeptidase-3, tissue inhibitor of metalloproteinase-1
Systemic sclerosis (SSc) is a connective tissue disease of autoimmune origin characterized by fibrosis of the skin and visceral organs, and peripheral circulatory disturbance. [alpha]2-antiplasmin ([alpha]2AP) is the major circulating inhibitor of plasmin and is a key regulator of fibrinolysis. It has been demonstrated that the expression of [alpha]2AP is elevated in dermal fibroblasts obtained from patients with SSc patients. It has also been determined that [alpha]2AP is associated with the development and progression of fibrosis in SSc. The present study assessed the relationship between [alpha]2AP and matrix metalloproteinase-3 (MMP-3), an extracellular matrix (ECM)-degrading enzyme. Serum levels of [alpha]2AP and MMP-3 were measured in healthy controls and patients with SSc using ELISA. No significant differences were determined between these two groups. [alpha]2AP, MMP-3 and tissue inhibitor of metalloproteinase-1 (TIMP-1) expression was subsequently evaluated in normal and SSc fibroblasts via western blotting. The results revealed that [alpha]2AP expression increased in SSc dermal fibroblasts, while the ratio of MMP-3/TIMP-1 decreased. Additionally, incubation of recombinant [alpha]2AP with MMP-3 caused [alpha]2AP degradation. The mixture of recombinant [alpha]2AP with MMP-3 was subsequently added to normal fibroblasts prior to western blotting. The results revealed decreased [alpha]-smooth muscle actin ([alpha]-SMA; a marker of the myofibroblast phenotype) and type I collagen expression. The stimulation of SSc fibroblasts with MMP-3 decreased protein levels of [alpha]2AP, [alpha]-SMA and type I collagen, thus reversing the pro-fibrotic phenotype of SSc fibroblasts. SSc fibroblast transfection with microRNA-29a resulted in a decreased TIMP-1 expression, but also decreased the protein expression of [alpha]2AP. The results indicated that MMP-3 attenuated fibrosis progression by degrading [alpha]2AP and ECM, and might therefore contribute to a novel therapeutic approach for SSc treatment. Key words: alpha2-antiplasmin, Systemic sclerosis, Fibrosis, matrix metallopeptidase-3, tissue inhibitor of metalloproteinase-1