Open AccessDecrease in matrix metalloproteinase‑3 activity in systemic sclerosis fibroblasts causes α2‑antiplasmin and extracellular matrix deposition, and contributes to fibrosis development
Author(s) -
Hitoshi Niwa,
Yosuke Kanno,
En Shu,
Mariko Seishima
Publication year - 2020
Publication title -
molecular medicine reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.727
H-Index - 56
eISSN - 1791-3004
pISSN - 1791-2997
DOI - 10.3892/mmr.2020.11358
Subject(s) - extracellular matrix , fibrosis , fibroblast , tissue inhibitor of metalloproteinase , matrix metalloproteinase , biology , type i collagen , myofibroblast , connective tissue , pathology , immunology , endocrinology , microbiology and biotechnology , medicine , biochemistry , in vitro
Systemic sclerosis (SSc) is a connective tissue disease of autoimmune origin characterized by fibrosis of the skin and visceral organs, and peripheral circulatory disturbance. α2‑antiplasmin (α2AP) is the major circulating inhibitor of plasmin and is a key regulator of fibrinolysis. It has been demonstrated that the expression of α2AP is elevated in dermal fibroblasts obtained from patients with SSc patients. It has also been determined that α2AP is associated with the development and progression of fibrosis in SSc. The present study assessed the relationship between α2AP and matrix metalloproteinase‑3 (MMP‑3), an extracellular matrix (ECM)‑degrading enzyme. Serum levels of α2AP and MMP‑3 were measured in healthy controls and patients with SSc using ELISA. No significant differences were determined between these two groups. α2AP, 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 α2AP expression increased in SSc dermal fibroblasts, while the ratio of MMP‑3/TIMP‑1 decreased. Additionally, incubation of recombinant α2AP with MMP‑3 caused α2AP degradation. The mixture of recombinant α2AP with MMP‑3 was subsequently added to normal fibroblasts prior to western blotting. The results revealed decreased α‑smooth muscle actin (α‑SMA; a marker of the myofibroblast phenotype) and type I collagen expression. The stimulation of SSc fibroblasts with MMP‑3 decreased protein levels of α2AP, α‑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 α2AP. The results indicated that MMP‑3 attenuated fibrosis progression by degrading α2AP and ECM, and might therefore contribute to a novel therapeutic approach for SSc treatment.