Biochemical and Biological Attributes of Matrix Metalloproteinases

Abstract

Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that are involved in the degradation of various proteins in the extracellular matrix (ECM). Typically, MMPs have a propeptide sequence, a catalytic metalloproteinase domain with catalytic zinc, a hinge region or linker peptide, and a hemopexin domain. MMPs are commonly classified on the basis of their substrates and the organization of their structural domains into collagenases, gelatinases, stromelysins, matrilysins, membrane-type (MT)-MMPs, and other MMPs. MMPs are secreted by many cells including fibroblasts, vascular smooth muscle (VSM) and leukocytes. MMPs are regulated at the level of mRNA expression and by activation of their latent zymogen form. MMPs are often secreted as inactive proMMP form which is cleaved to the active form by various proteinases including other MMPs. MMPs cause degradation of ECM proteins such as collagen and elastin, but could influence endothelial cell function as well as VSM cell migration, proliferation, Ca2+ signaling and contraction. MMPs play a role in tissue remodeling during various physiological processes such as angiogenesis, embryogenesis, morphogenesis and wound repair, as well as in pathological conditions such as myocardial infarction, fibrotic disorders, osteoarthritis, and cancer. Increases in specific MMPs could play a role in arterial remodeling, aneurysm formation, venous dilation and lower extremity venous disorders. MMPs also play a major role in leukocyte infiltration and tissue inflammation. MMPs have been detected in cancer, and elevated MMP levels have been associated with tumor progression and invasiveness. MMPs can be regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs), and the MMP/TIMP ratio often determines the extent of ECM protein degradation and tissue remodeling. MMPs have been proposed as biomarkers for numerous pathological conditions and are being examined as potential therapeutic targets in various cardiovascular and musculoskeletal disorders as well as cancer.

Green tea–induced epigenetic reactivation of tissue inhibitor of matrix metalloproteinase‐3 suppresses prostate cancer progression through histone‐modifying enzymes

“…Our studies show the reactivation of epigenetically silenced TIMP‐3 by GTPs in prostate cancer cells and in prostate tissue obtained from patients with short‐term supplementation of Polyphenon E. These results also provide convincing evidence that induction of TIMP‐3 expression suppresses MMP‐2/MMP‐9 activity and tumor invasion in cell culture and clinical specimens. TIMPs are involved in the regulation of ECM and a balance between TIMPs and MMPs is critical for ECM degradation, a crucial step for tumor invasion and metastasis . Absence of TIMP‐3 has been shown to accelerate prostate tumor growth, proliferation, angiogenesis, and invasion in a murine model .…”

“…MMPs are key regulators of migration, invasion, metastasis, and classic hallmarks of cancer . MMPs are a specific group of 24 enzymes whose catalytic activity is dependent on metal ions with potent ability to degrade structural proteins of the ECM .…”

“…The balance between MMPs and TIMPs plays a critical role in ECM remodeling and turnover. Studies suggest that during tumorigenesis, the expression of TIMPs is downregulated, which ultimately results in an increase in MMP activity, facilitating cancer progression . Given the importance of MMPs and TIMPs in regulating tumor progression, in recent years, intensive efforts have been taken to develop therapeutic strategies designed to inhibit MMP activity.…”

Phenethyl Isothiocyanate (PEITC) and Benzyl Isothiocyanate (BITC) Inhibit Human Melanoma A375.S2 Cell Migration and Invasion by Affecting MAPK Signaling Pathway In Vitro

“…Therefore, the inhibition of MMPs has been recognized to lead in suppression of cancer cell metastasis (28,29) and MMPs have been shown to be present in melanoma (39) and many cancer cells express high levels of MMPs that facilitate cancer invasion and metastasis (40). We evaluated MMP-2 and MMP-9 activities and the levels of both proteins which are associated with reduced survival in human malignancies (41,42) and with metastatic cancer and tumor-induced angiogenesis (43).…”

Generation of bioactive prolyl‐hydroxyproline (Pro‐Hyp) by oral administration of collagen hydrolysate and degradation of endogenous collagen

“…Collagen with a triple helical structure resists most of the protease digestion except for collagenases such as matrix metalloproteinases (MMPs)-1, -8, etc. (Cui et al, 2017). The triple helical structure of collagen collapses into a random coil structure, when heated in water.…”