Matrix Metalloproteinases and Tissue Inhibitor of Metalloproteinases in Inflammation and Fibrosis of Skeletal Muscles

Abstract

In skeletal muscles, levels and activity of Matrix MetalloProteinases (MMPs) and Tissue Inhibitors of MetalloProteinases (TIMPs) have been involved in myoblast migration, fusion and various physiological and pathological remodeling situations including neuromuscular diseases. This has opened perspectives for the use of MMPs’ overexpression to improve the efficiency of cell therapy in muscular dystrophies and resolve fibrosis. Alternatively, inhibition of individual MMPs in animal models of muscular dystrophies has provided evidence of beneficial, dual or adverse effects on muscle morphology or function. We review here the role played by MMPs/TIMPs in skeletal muscle inflammation and fibrosis, two major hurdles that limit the success of cell and gene therapy. We report and analyze the consequences of genetic or pharmacological modulation of MMP levels on the inflammation of skeletal muscles and their repair in light of experimental findings. We further discuss how the interplay between MMPs/TIMPs levels, cytokines/chemokines, growth factors and permanent low-grade inflammation favor cellular and molecular modifications resulting in fibrosis.

Modulation of Monocyte-Driven Myositis in Alphavirus Infection Reveals a Role for CX 3 CR1 + Macrophages in Tissue Repair

“…In contrast, the effect of IMP modulation was milder on the local production of proinflammatory CCL2 and TNF-␣, suggesting that infiltrating cells other than those targeted by IMP may be contributing to the proinflammatory environment. IMP treatment lead to an upregulation of matrix metalloproteinase (MMP) Mmp2, Mmp9 and Mmp12; MMPs are essential for tissue remodeling and are activated at different stages following tissue injury (43)(44)(45), suggesting that the reduction in IM infiltration as a result of IMP modulation in turn helps local tissue microenvironment regulate transcriptional activity to promote tissue repair. CX 3 CR1 expression regulates all stages of macrophage development and is a classical marker for patrolling monocytes, intestinal macrophages, and microglia (46,47).…”

Inflammation by activated macrophage‐like THP‐1 cells increases human dura mater cell adhesion with alteration of integrin α2β1 and matrix metalloproteinase

“…As both MMPs and growth factors affect ECM degradation and cell migration, we also evaluated environmental factors produced by hDMCs. Of the various MMPs, MMP‐1 (collagenase‐1), MMP‐2 (gelatinase A), MMP‐3 (stromelysin‐1), and MMP‐9 (gelatinase B) were assayed, because they regulate chemokine activity and the chemotactic gradients that form during inflammation .…”

“…The TIMPs (TIMP‐1, ‐2, ‐3, and ‐4) are specific endogenous inhibitors of MMPs and also regulators of cell proliferation and apoptosis . TIMP‐1 preferentially inhibits MMP‐7, MMP‐9, MMP‐1, and MMP‐3; TIMP‐2 is a more effective inhibitor of MMP‐2; TIMP‐3 inhibits MMP‐2 and MMP‐9; and TIMP‐4 inhibits membrane‐type MMP‐1 and MMP‐2 .…”

“…Since the decrease in adhesion after inhibitor treatment was higher than the decrease in cell viability, this result suggested that integrin subtype a 2 b 1 inhibition reduced adhesion of hDMCs in inflammatory conditions. As both MMPs and growth factors affect ECM degradation and cell migration, 36,37 we also evaluated environmental factors produced by hDMCs. Of the various MMPs, MMP-1 (collagenase-1), MMP-2 (gelatinase A), MMP-3 (stromelysin-1), and MMP-9 (gelatinase B) were assayed, because they regulate chemokine activity and the chemotactic gradients that form during inflammation.…”

“…The TIMPs (TIMP-1, -2, -3, and -4) are specific endogenous inhibitors of MMPs and also regulators of cell proliferation and apoptosis. 36,38,44 TIMP-1 preferentially inhibits MMP-7, MMP-9, MMP-1, and MMP-3; TIMP-2 is a more effective inhibitor of MMP-2; TIMP-3 inhibits MMP-2 and MMP-9; and TIMP-4 inhibits membrane-type MMP-1 and MMP-2. 45 The observed increases in MMP-1 and MMP-3 levels in co-cultured cells, in the absence of changes in TIMP-1 levels, imply that the MMP changes were caused by interactions between hDMCs and Mfs.…”