Matrix Metalloproteinases (MMPs) - Structure, Sources and Functions

Structure of Matrix Metalloproteinase (MMP) Family

In vertebrates, the MMP family consists of 28 members, at least 23 of which are expressed in human tissues, 14 of which are expressed in the vascular system. MMPs are usually classified into collagenases, gelatinases, stromelysins, matrilysins, membrane-type (MT)-MMPs, and other MMPs based on their substrates and the organization of their structural domains.

The MMP family has a common core structure. Typical MMPs consist of a pro-peptide of approximately 80 amino acids, a metalloproteinase catalytic structural domain of 170 amino acids, a variable length linker peptide or hinge region, and a heme protein structural domain of approximately 200 amino acids.MT-MMPs typically have both a transmembrane structural domain and a cytoplasmic structural domain. MMP-17 and -25 have a glycosylphosphatidylinositol (GPI) anchor. mmp-23 can be in a potentially inactive form via its type II signaling anchor and has regions rich in cysteine and immunoglobulin-like proline.

Cellular Sources of MMPs

MMPs are produced by a variety of tissues and cells. MMPs are secreted by pro-inflammatory cells and uteroplacental cells, including fibroblasts, osteoblasts, endothelial cells, vascular smooth muscle, macrophages, neutrophils, lymphocytes, and cytotrophoblasts. Dermal fibroblasts and leukocytes are the main sources of MMP, especially MMP-2. Platelets are an important source of MMP-1, MMP-2, MMP-3 and MMP-14.

They are present in most connective tissues. MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-12, MMP-13, and MT1-MMP and MT3-MMP are expressed in various vascular tissues and cells.

Function of MMPs

MMPs are usually secreted as inactive proMMPs, which are cleaved to the active form by various proteases including other MMPs. MMPs degrade various protein substrates in the ECM, including collagen and elastin. MMPs promote cell proliferation, migration and differentiation, and play a role in angiogenesis, apoptosis and tissue repair. They affect endothelial cell function as well as migration, proliferation, Ca²⁺ signaling, and contraction of vascular smooth muscle cells. MMPs can also affect cell surface bioactive molecules and regulate various cellular and signaling pathways.

Biological Processes and Pathological Processes Involved in MMPs

MMPs play a role in many biological processes, such as tissue remodeling and growth, trauma repair, tissue defense mechanisms and immune response. Increased expression of MMPs is detected at different stages of mammalian development, from embryonic implantation to morphogenesis of different tissues and organs, including lung, bone and blood vessels.

MMPs are involved in vascular smooth muscle growth, proliferation, migration, and relaxation. They are involved in endothelial cell function, angiogenesis, apoptosis, tissue repair, wound healing, embryonic implantation during gestation and trophoblast invasion.

MMPs are involved in pathological processes such as hypertension, eclampsia, vascular inflammation, atherosclerosis, coronary syndromes and myocardial infarction, cerebral ischemia and ischemic stroke, peripheral arterial disease, aneurysms, chronic venous disease, etc. MMPs can be used as biomarkers and potential therapeutic targets for certain vascular diseases.

The induction of MMPs activity contributes to the disassembly of intercellular junctions and the degradation of ECM, thus overcoming the physical limitations of cell motility and participating in tumor invasion. Thus, they are also targets of antitumor drugs.

MMPs are involved in processes such as osteoblast/osteoclast differentiation, bone formation, osteolysis of osteoid during bone resorption, osteoclast recruitment and migration. They act as coupling factors for bone remodeling under physiological conditions. MMP overexpression and ECM abnormalities may lead to unbalanced bone remodeling-related pathological changes in osteolysis or bone formation.

MMP-2 and MMP-9 play a role in chronic kidney disease. MMP-9 has also been proposed as a therapeutic target for Alzheimer's disease and type 2 diabetes. Neuronal MMP-9 is involved in synaptic plasticity by controlling the shape of dendritic spines and the function of excitatory synapses, thus playing a key role in learning, memory and cortical plasticity. If not released properly, MMP-9 can lead to a variety of brain disorders including epilepsy, schizophrenia, autism, brain injury, stroke, neurodegeneration, pain, and brain tumors. The most important mechanism of action of MMP-9 in brain disorders appears to be the involvement of immune/inflammatory responses. MMP-1 and MMP-12 gene polymorphisms are associated with ischemic stroke.

Cytokines are involved in the immune response and inflammatory response of the body and are very sensitive indicators of inflammation. Dynamic monitoring of cytokine levels during disease progression can detect the tendency of disease to turn serious in time, and treat, avoid or reduce the risk of disease deterioration in a timely manner. In addition, cytokine analysis is also required for disease mechanism analysis, drug development and treatment method development. Creative Proteomics provides MMP Panel Service based on Luminex multiplex assay technology to help your project research.

References:

1. Löffek, S., Schilling, O., & Franzke, C. W. (2011). Series 'matrix metalloproteinases in lung health and disease'edited by J. Müller-Quernheim and O. Eickelberg number 1 in this series: Biological role of matrix metalloproteinases: A critical balance. Eur. Respir. J, 38(1), 191-208.
2. Schuppan, D., & Hahn, E. G. (2000). MMPs in the gut: inflammation hits the matrix. Gut, 47(1), 12-14.
3. Cabral-Pacheco, G. A., Garza-Veloz, I., et al. (2020). The roles of matrix metalloproteinases and their inhibitors in human diseases. International journal of molecular sciences, 21(24), 9739.