Distinct Metalloproteinase Expression and Functions in Systemic Sclerosis and Fibrosis: What We Know and the Potential for Intervention

Abstract

Systemic sclerosis (SSc) is a chronic debilitating idiopathic disorder, characterized by deposition of excessive extracellular matrix (ECM) proteins such as collagen which leads to fibrosis of the skin and other internal organs. During normal tissue repair and remodeling, the accumulation and turnover of ECM proteins are tightly regulated by the interaction of matrix metalloproteinases (MMPs) and endogenous tissue inhibitors of metalloproteinases (TIMPs). SSc is associated with dysregulation of the activity of these proteolytic and inhibitory proteins within the tissue microenvironment, tipping the balance toward fibrosis. The resultant ECM accumulation further perpetuates tissue stiffness and decreased function, contributing to poor clinical outcomes. Understanding the expression and function of these endogenous enzymes and inhibitors within specific tissues is therefore critical to the development of therapies for SSc. This brief review describes recent advances in our understanding of the functions and mechanisms of ECM remodeling by metalloproteinases and their inhibitors in the skin and lungs affected in SSc. It highlights recent progress on potential candidates for intervention and therapeutic approaches for treating SSc fibrosis.

Matrix Metalloproteinases: From Molecular Mechanisms to Physiology, Pathophysiology, and Pharmacology

“…Once the fibrosis is resolved, the patient stops taking veledimex (INXN-1001), which stops MMP1 production. Therefore, the biologic activity of certain MMPs could also potentially be used as a therapeutic to resolve fibrosis in specific diseases (Leong et al, 2021). This approach further supports that a better characterization of the roles of individual MMPs in inflammation and fibrosis could result in the development of novel therapeutics.…”

MS-proteomics provides insight into the host responses towards alginate microspheres

“…The significantly enriched heparin-binding proteins which were unique for the anti-fibrotic SA include the matrix metalloproteinases (MMPs [MMP2, MMP9]), neutrophil elastase (ELANE) and tenascin-X (TNXB). The ECM degrading enzymes MMP2 and MMP9 have been found to inhibit, and also promote, fibrosis in different fibrotic disease models [ 95 , 96 ]. Interestingly, the MMPs and their regulators (TIMPs) were enriched on SA, while only the latter was enriched on HiG.…”

Current Trends in Vascular Biomarkers for Systemic Sclerosis: A Narrative Review

“…Connective tissue turnover strictly depends on the balance between ECM synthesis and degradation. ECM breakdown is mainly regulated by MMPs (MMP-1 to MMP-28), whose activity is in turn controlled by a family of homologous proteins, the tissue inhibitors of MMPs (TIMP-1 to TIMP-4) [ 109 , 110 ]. MMPs are essential for various physiological processes such as embryonic development, morphogenesis, angiogenesis, and cell migration, and they have been implicated in a number of key pathologic processes, including inflammation, fibrosis, arthritis, pulmonary diseases, and cancer [ 109 , 110 ].…”