MMP9

Matrix metallopeptidase 9 (MMP-9), also known as 92 kDa type IV collagenase, 92 kDa gelatinase or gelatinase B (GELB), is a matrixin, a class of is_associated_with::enzymes that belong to the is_associated_with::zinc-is_associated_with::metalloproteinases family involved in the degradation of the is_associated_with::extracellular matrix. In humans the MMP9 is_associated_with::gene. encodes for a is_associated_with::signal peptide, a is_associated_with::propeptide, a is_associated_with::catalytic domain with inserted three repeats of is_associated_with::fibronectin type II domain followed by a C-terminal hemopexin-like domain.

Function
Proteases of the is_associated_with::matrix metalloproteinase (MMP) family are involved in the breakdown of is_associated_with::extracellular matrix in normal physiological processes, such as is_associated_with::embryonic development, is_associated_with::reproduction, is_associated_with::angiogenesis, is_associated_with::bone development, is_associated_with::wound healing, cell migration, is_associated_with::learning and is_associated_with::memory, as well as in pathological processes, such as is_associated_with::arthritis, is_associated_with::intracerebral hemorrhage, and is_associated_with::metastasis. Most MMPs are secreted as inactive is_associated_with::proproteins which are activated when cleaved by extracellular is_associated_with::proteinases. The enzyme encoded by this gene degrades type IV and V is_associated_with::collagens and other extracellular matrix proteins. Studies in rhesus monkeys suggest that the enzyme is involved in IL-8-induced mobilization of is_associated_with::hematopoietic progenitor cells from bone marrow, and murine studies suggest a role in tumor-associated tissue remodeling.

is_associated_with::Thrombospondins, intervertebral disc proteins, regulate the effective levels of matrix metalloproteinases (MMPs) 2 and 9, which are key effectors of ECM remodeling.

Neutrophil action
MMP9, along with elastase, appears to be a regulatory factor in is_associated_with::neutrophil migration across the is_associated_with::basement membrane.

MMP9 plays several important functions within neutrophil action, such as degrading extracellular matrix, activation of is_associated_with::IL-1β, and cleavage of several is_associated_with::chemokines. In a mouse model, MMP9 deficiency resulted in resistance to endotoxin shock, suggesting that MMP9 is important in is_associated_with::sepsis.

Angiogenesis
MMP9 may play an important role in angiogenesis and neovascularization. For example, MMP9 appears to be involved in the remodeling associated with malignant is_associated_with::glioma neovascularization. It is also a key regulator of growth plate formation- both growth plate is_associated_with::angiogenesis and the generation of hypertrophic is_associated_with::chondrocytes. Knock-out models of MMP9 result in delayed apoptosis, vascularization, and ossification of hypertrophic chondrocytes. Lastly, there is significant evidence that Gelatinase B is required for the recruitment of endothelial stem cells, a critical component of angiogenesis

Wound repair
MMP9 is greatly upregulated during human respiratory is_associated_with::epithelial healing. Using a MMP9 deficient mouse model, it was seen that MMP9 coordinated epithelial wound repair and deficient mice were unable to remove the fibrinogen matrix during wound healing. When interacting with TGF-ß1, Gelatinase B also stimulates collagen contraction, aiding in wound closure.

Structure
MMP9 is synthesized as is_associated_with::preproenzyme of 707 amino-acid residues, including a 19 is_associated_with::amino acid is_associated_with::signal peptide and secreted as an inactive pro-MMP. The human MMP9 is_associated_with::proenzyme consists of five domains. The amino-terminal is_associated_with::propeptide, the zinc-binding is_associated_with::catalytic domain and the carboxyl-terminal hemopexin-like domain are conserved. Its primary structure comprises several domain motifs. The propeptide domain is characterized by a conserved PRCGVPD sequence. The Cys within this sequence is known as the “cysteine switch”. It ligates the is_associated_with::catalytic is_associated_with::zinc to maintain the is_associated_with::enzyme in an inactive state. Activation is achieved through an interacting protease cascade involving plasmin and stromelysin 1 (MMP-3). Plasmin generates active MMP-3 from its zymogen. Active MMP-3 cleaves the propeptide from the 92-kDa pro-MMP-9, yielding an 82-kDa enzymatically active enzyme. In the active enzyme a substrate, or a fluorogenic activity probe., replaces the propetide in the enzyme active site where it is cleaved. The catalytic domain contains two zinc and three calcium atoms. The catalytic zinc is coordinated by three histidines from the conserved HEXXHXXGXXH binding motif. The other zinc atom and the three calcium atoms are structural. A conserved methionine, which forms a unique “Met-turn” structure categorizes MMP9 as a metzincin. Three type II fibronectin repeats are inserted in the catalytic domain, although these domains are omitted in most crystallographic structures of MMP9 in complex with inhibitors.The active form of MMP9 also contains a C-terminal hemopexin-like domain. This domain is ellipsoidal in shape, formed by four β-propeller blades and an is_associated_with::α-helix. Each blade consists of four antiparallel is_associated_with::β-strands arranged around a funnel-like tunnel that contains two calcium and two chloride ions. The hemopexin domain is important to facilitate the cleavage of triple helical interstitial collagens. .

Clinical significance
MMP9 has been found to be associated with numerous pathological processes, including cancer, immunologic and cardiovascular diseases.

Arthritis
Elevated MMP9 levels can be found in the cases of is_associated_with::rheumatoid arthritis and focal brain ischemia.

Cancer
One of MMP9's most widely-associated pathologies is the relationship to cancer, due to its role in extracellular matrix remodeling and angiogenesis. For example, its increased expression was seen in a metastatic mammary cancer cell line. Gelatinase B plays a central role in tumor progression, from angiogenesis, to stromal remodeling, and ultimately metastasis. However, because of its physiologic function, it may be difficult to leverage Gelatinase B inhibition into cancer therapy modalities. However, Gelatinase B has been investigated in tumor metastasis diagnosis- Complexes of Gelatinase B/Tissue Inhibitors of Metalloproteinases are seen to be increased in gastrointestinal cancer and gynecologic malignancies

MMPs such as MMP9 can be involved in the development of several human malignancies, as degradation of collagen IV in basement membrane and extracellular matrix facilitates tumor progression, including invasion, metastasis, growth and angiogenesis.

Cardiovascular
MMP9 levels increase with the progression of idiopathic is_associated_with::atrial fibrillation.

MMP9 has been found to be associated with the development of aortic aneurysms, and its disruption prevents the development of aortic aneurysms. is_associated_with::Doxycycline suppresses the growth of aortic aneurysms through its inhibition of MMP9.