Metalloproteinases in the pathogenesis and progression of metabolic syndrome: potential targets for improved outcomes

Abstract

Matrix metalloproteinases (MMPs) constitute a family of more than 25 calciumdependent, zinc-containing endopeptidases, synthesized by multiple cell types. These enzymes play an important role during physiological tissue development and remodeling and angiogenesis, as well as in pathophysiological conditions such as obesity and atherosclerotic process. Moreover, circulating levels of MMPs have emerged as potential biomarkers of cardiovascular disease. MMPs are regulated by different factors such as insulin resistance and obesity. Different components of the metabolic syndrome have been identified as possible stimulus for the synthesis and activity of MMPs. On the other hand, pro-inflammatory and anti-inflammatory cytokines, such as leptin and adiponectin, respectively, are associated with the regulation of MMPs. Leptin induces expression of MMP-2 activators as well as expression of MMP-2, MMP-9, and tissue inhibitor of metalloproteinase (TIMP)-1 in different human cells. Adiponectin may play a protective role in plaque rupture through selectively increasing TIMP expression. The hepatic manifestation of metabolic syndrome is nonalcoholic fatty liver disease (NAFLD). MMPs may remodel the liver parenchyma during the process of liver fibrosis. MMP-2 and MT1-MMP have been considered to be fibrogenic enzymes.There are few studies analyzing the role of MMPs in NAFLD, and most of them include study on mRNA expression, but even the results on their expression pattern remains controversial. MMPs could be considered as possible therapeutic targets. Different studies demonstrated that metformin, thiazolidinediones, and antibiotics could have inhibitory effects on the expression of MMPs; however, a rational study of lifestyle modifications as well as further studies of pharmacological therapies that influence MMPs are necessary to generate the information that physicians will probably need to improve the treatment of patients. The aim of this revision is to update the data about MMPs in the pathogenesis and progression of metabolic syndrome and the possible effect of different drugs on the behavior of these enzymes.

Behavior of Metalloproteinases in Adipose Tissue, Liver and Arterial Wall: An Update of Extracellular Matrix Remodeling

“…The local balance between activated MMPs and TIMPs determines the net result of MMPs activity in tissues. In pathological situations, this balance might be disrupted leading to the uncontrolled activation of the MMPs [13].…”

“…Little is known about the direct effect of adiponectin on MMPs from AT. It has been suggested that adiponectin could directly affect the balance of MMP/TIMP expression in macrophages from AT [13]; however, further studies are necessary to elucidate the role of this cytokine in MMPs behavior in this tissue.…”

Metalloproteinases in non-alcoholic fatty liver disease and their behavior in liver fibrosis

“…The balance between activated MMPs and TIMPs determines the net result of MMPs activity in tissues. However, in pathological situations, this balance might be disrupted leading to MMPs uncontrolled activation [10].…”

Serum MMP3 Correlates with Renal Function Tests and Insulin Resistance Parameters in Patients with End-stage Renal Disease

“…On the other hand, hyperinsulinemia stimulates the degradation of these MMPs [40]. MMPs and IR have a reciprocal relationship in that IR increases the production and activation of MMPs via various signaling pathways, and MMPs contribute to the growth of adipose tissue with a surge in the IR state [41].…”