Matrix Metalloproteinases (MMPs)

Matrix metalloproteinases (MMPs) are a family of Zinc-dependent endopeptidase that degrade various proteins of the extracellular matrix (ECM). As members of the metzincin group of proteases, they share the conserved zinc-binding motif in their catalytic active site. Initially, MMPs were thought to function mainly in degrading ECM, but recent studies has shown that they also function significantly as regulators of extracellular tissue signaling networks.

MMPs are defined by the presence of two conserved zinc-binding motifs. One motif is a cysteine-containing pro-domain, whose function is partly to restrain catalytic; whereas the other motif is a histidine-rich catalytic domain, responsible for the endopeptidase activity.

MMPs Are Involved in Various Physiological and Pathological Processes.

MMPs are involved in numerous physiological and pathological processes. In physiological process, MMPs are involved in embryonic development, wound repair, ovulation, bone remodeling, macrophage function and in neutrophil function. They are also involved in pathological processes such as inflammation, tumor metastasis, rheumatoid arthritis, gastric ulcer, among others.

 Matrix Metalloproteinases and EMT in Tumor Metastasis

Epithelia-mesenchymal transition (EMT) plays its central role in normal embryonic development. But recent studies have shown its roles in pathological processes, such as cancer progression, fibrosis, and chronic inflammation.

MMPs associate with EMT in cancer progression through three mechanisms:

  • Elevated levels of MMPs in the tumor microenvironment induce EMT in epithelia cells.
  • EMT in cancer then produces more MMPs, thereby facilitating cell invasion and metastasis.
  • EMT can generate activated stromal-like cells that drive cancer progression through further MMPs production.

Role of MMPs in Tumor Metastasis

The role of MMPs in tumor metastasis was initially believed to be limited to the degradation of ECM and basement membrane collagen. But now, we know that MMPs paly critical roles at every step of tumor progression. MMPs influence several biological functions, such as modification of signaling pathways, regulation of cytokines involved in immune responses, and tumor growth by stimulating angiogenesis, which leads to the spread of cancer.

MMP-11 Plays Dual Roles in Tumors

Unlike many members of MMPs, MMP-8 and MMP-12 were reported to exert antitumor effects, thereby suppressing tumor growth. MMP-11 on the other hand plays a dual role in cancer progression. In one hand, MMP-11 promotes cancer development by inhibiting apoptosis and enhancing the invasion of cancer cells; on the other hand, however, MMP-11 plays a negative role against cancer development through the suppression of metastasis.

MMPs play Major Roles In Rheumatoid Arthritis

Rheumatoid arthritis (RA) is characterized by progressive joint destruction with loss of bone and cartilage as well as the aggressive activation of synovian fibroblasts (SFs) bearing a tumor-like appearance.

During joint destruction, RASFs secrete various proteases, including MMPs that degrade ECM
components, mainly proteoglycans and collagens, of articular cartilage in the affected joints.

However, among the various MMPs involved in articular degradation, MMP-1 and MMP-13 cleave collagens, whereas MMP-3 and MMP-9 target proteoglycans which are comprised of aggrecan.

This way, the degradation of proteoglycans at the surface and the subsequent degradation of collagen fibrils in the deep zone together result in the destruction of articular cartilage.

MMPs Play Major Roles In Infectious Diseases

In a normal immune responses, when the host immune system is challenged by an invading
organism, it must first recruit leucocytes to the site of infection, eradicate the pathogen and then dampen the response to allow the resolution of inflammation.

Matrix metalloproteinases play an important role in this process both by degrading components of the extracellular matrix and by modulating cytokine and chemokine activity.

 

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Araki, Y., & Mimura, T. (2017). Matrix Metalloproteinase Gene Activation Resulting from Disordred Epigenetic Mechanisms in Rheumatoid Arthritis. International journal of molecular sciences, 18(5), 905. https://doi.org/10.3390/ijms18050905

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What is Angiogenesis?

Angiogenesis is the formation of new blood vessels. It is the process by which the body forms new blood vessels from existing ones. This process occurs throughout the life of an individual, starting in the uterus and continuing to old age. Angiogenesis occurs both in healthy tissues as well as in diseased ones, such as in cancer cell growths.

Why Does Angiogenesis Occur in the Body?

Angiogenesis takes place when a particular body part or tissue requires the supply of nutrients and to it. In hypoxia tissues, the need for oxygen supply to the parenchymal cells is detected by the oxygen sensing mechanisms, which then demands the formation of new blood vessels to meet this need.

Types of Angiogenesis

There are two types of angiogenesis, they are:

  1. Sprouting angiogenesis
  2. Intrussusceptive angiogenesis

Both sprouting and intrussusceptive angiogenesis, occur in the uterus and in adults.

Sprouting Angiogenesis (SA)

Sprouting angiogenesis is the process of growing new blood capillary vessels from pre-existing ones. When this occurs, the new blood vessels shall provide oxygen to expanding tissues and organs.

Sprouting angiogenesis plays important roles in many diseases, such as diabetes, rheumatoid arthritis, cardiovascular ischemic complications and cancer. In cancer, SA is involved not only in primary tumor but also in metastasis formation and further outgrowth of metastasis.

Steps in Sprouting Angiogenesis

Sprouting angiogenesis involves several steps, which include:

  1. Initiation of growth factors responsible for angiogenesis by low oxygen tension, low pH and high lactate levels.
  2. Expression of a transcription factor, hypoxia-inducible factor (HIF), by endothelia cells, which regulates expression of vascular endothelia growth factor (VEGF) and stimulates angiogenesis.
  3. Binding of growth factors to their receptors on endothelia cells and activating them. This is followed by detachment of pericytes.
  4. Binding of VEGF to its receptors and inducing a signaling cascades which enables one endothelia cell to form a tip cell while adjacent cells form stalk cells.
  5. Tip cells express VEGFR, delta-like ligand-4 (DLL-4), and matrix metalloproteinases (MMPs). They form filopodia, which are slender protrusions of the plasma membrane containing parallel bundles of actin filaments.
  6. Rhoa, Racl and Cdc42, members of Rho small GTPases, regulate the formation of filopodia.
  7. Activation of VEGFR leads to the extension of filopodia and migration of the tip cells forward.
  8. Activated endothelia cells secrete proteases, which are essential for the degradation of basement membrane. They allow tip cells to escape from the parent vessels and allow formation of sprouts and guidance of sprouts through the extracellular matrix (ECM).

Intrussusceptive Angiogenesis (IA)

In intrussusceptive angiogenesis, also called splitting angiogenesis, the blood vessel wall extends into the lumen, thereby causing a single vessel to split into two. It is fast and efficient compared to SA. This is because IA only requires reorganization of the existing endothelia cells; it does not rely on endothelia proliferation and migration. Like SA, however, IA also occur throughout the life of an individual, but it plays prominent roles in vascular development in embryos, where growth is fast with limited resources.

Promoters of Angiogenesis

Angiogenesis is regulated by a balance between pro-angiogenic and anti-angiogenic factors. The promoters include, HIF-1, VEGF, FGF, PDGE, TGF-β and angiopoietin and proteases.

Hypoxia-induced Factor-1 (HIF-1)

This is the most potent inducer of the expression of genes such as those encoding for glycolytic enzymes, VEGF and erythropoietin. HIF-1 is upregulated in hypoxia tumor cells; it activates transcription of target genes by binding to Cis-actin enhancers, hypoxia response element (HRE) close to the promoters of those genes.

Vascular Endothelia Growth factor (VEGF)

VEGF functions in angiogenesis by inducing the expression of DLL-4 in tip cells. It promotes the migration of endothelia cells by inducing expression of intergrins. It also stimulates production of MMPs, plasminogen activator and proteolytic enzymes by endothelia cells, which in turn promote the degradation of ECM.

Fibroblast Growth Factor (FGF)

FGF promotes proteases production and upregulates VEGF expression by endothelia cells. It also stimulates endothelia cells proliferation and migration.

Inhibition of Angiogenesis by Thymoquinone

Thymoquinone exerts its inhibitory effects on VEGF, FGF, PIGF, PDGF, which are pro-angiogenic factors, by suppressing the Akt/ERK signaling pathway.

 

REFERENCES

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