MMP9

What is MMP9?

Matrix metalloproteinase-9 (MMP9), also known as gelatinase B, is a crucial enzyme that plays a vital role in extracellular matrix remodeling. This protein is linked to the degradation of the extracellular matrix, which encompasses capillaries, influencing the mobility of cells. Alongside its prominent function, MMP9 also participates in many physiological and pathological processes, such as embryogenesis, tissue remodeling, inflammation, and cancer progression.

The MMP9 protein, encoded by the MMP9 gene, was first discovered in the 1970s. Studies delved into the mechanisms and potential therapeutic benefits of inhibiting MMP synthesis. The MMP9 gene maps to a specific section of chromosome 20q11.2-13.1, one of the numerous loci identified within the human genome. Structurally, the protein has four distinct domains: the pro-peptide domain, the catalytic domain, the fibronectin type II-like repeats, and the hemopexin-like domain. Each domain performs different roles, ensuring the functionality and stability of the synthesized MMP9 protein.

What Is The Function of MMP9 Protein?

Functionally, MMP9 is a multifaceted protein, involved in several normal physiological and pathological processes. In normal physiology, MMP9 maintains homeostasis by controlling the balance between matrix deposition and degradation. It plays a critical role in wound healing, tissue regeneration and remodeling, and many more cellular organization and restructuring. Moreover, MMP9 is actively involved in modeling the neural network, aiding in brain development and neuron migration.

MMP9 Protein Related Signal Pathway

The signaling pathway of the MMP9 protein has been a focus in understanding tumor progression, particularly its role in matrix degradation, which indirectly supports cancer cell invasion and metastasis. MMP9 is often secreted when tissue undergoes remodeling, such as during inflammation and tumorigenesis. Its involvement in the NF-kB signaling pathway can lead to the activation of pro-inflammatory genes, engaging in a positive feedback cycle that results in chronic inflammation and contributes to inflammation-associated diseases, including cancer.

MMP9 Protein Related Diseases

Beyond tumor progression, numerous diseases are associated with MMP9. It is involved in the pathogenesis of chronic obstructive pulmonary disease (COPD) and asthma, where excessive MMP9 produces fibrosis and tissue damage. MMP9 protein dysregulation is also seen in neurodegenerative diseases such as Alzheimer's, multiple sclerosis, and migraines. Further, its active role in plaque destabilization connects it with cardiovascular diseases, atherosclerosis specifically. Lastly, research has shown a correlation between elevated MMP9 levels and adverse pregnancy outcomes, suggesting its involvement in processes like preterm delivery and preeclampsia.

MMP9 Protein's Applications

Despite these concerning disease associations, MMP9's unique actions have yielded numerous biomedical applications. MMP9's wide-ranging roles allow it to potentially modify or arrest disease progression when appropriately regulated. Specifically, MMP9 has become a promising target in cancer biology, with several research studies aimed at developing inhibitors to halt tumor progression.

Moreover, the function of MMP9 in inflammation and wound healing has spurred research into its potential use in tissue engineering and regenerative medicine. Its role in degrading the extracellular matrix can facilitate the development of novel scaffolding for tissue regeneration. MMP9 can also change the inflammatory environment of wounds, potentially improving healing outcomes.

The connection of MMP9 with neurodegenerative diseases has also prompted investigations into its role in diagnosing and monitoring disease progression. It is potentially useful as a biomarker in diseases such as multiple sclerosis or Alzheimer's.

In conclusion, the MMP9 protein and its related enzymes undoubtedly have a profound impact on both normal physiology and disease states, making it an attractive target in biomedical research. Its multifarious roles, spanning inflammation, tissue remodeling, neurodevelopment, tumorigenesis, and more, suggest a promising future in the development of novel therapeutics and diagnostic tools. However, further studies are needed to better understand the complexities and nuances of MMP9 to fully leverage its biomedical potential.

Case 1: Eshwar AK, et al. Cell Microbiol. 2018.
Researchers provided evidence that Zpx induces the expression of the mmp-9 but also increases the levels of processed MMP-9 during infection. The involvement of the MMP-9 in induction of the expression of the bacterial Zpx was shown in zebrafish mmp-9 morphant experiments. This study identified MMP-9 as a substrate of Zpx and demonstrated yet-undescribed mutual cross-talk between these two proteases in infections mediated by C. turicensis LMG 23827T.

Fig1. Cronobacter turicensis and Escherichia coli cells expressing Zpx process and activating recombinant human pro-MMP-9. Gelatin zymography (a) and Western blot against the His-tag of the MMP-9. Processing with APMA serves as positive control. Proteolytic bands: intact pro-MMP-9 (92 kDa); processed/activated MMP-9: 83 kDa. DPBS, DMSO, and BHI medium serve as negative control. BHI, brain heart infusion; DMSO, dimethylsulfoxide; DPBS, Dulbecco's phosphate-buffered saline.

Fig2. Top panel: Western blot analysis to detect the presence of zebrafish pro-MMP-9 and processed/activated MMP-9 at several time points during infection with Cronobacter turicensis. Unprocessed pro-MMP-9: 92 kDa, processed/activated MMP-9: 77 kDa. Bottom panel: Western blot to detect β-actin (control, 42 kDa) serves as positive control. DPBS, Dulbecco's phosphate-buffered saline.

Case 2: Nandi SS, et al. Am J Physiol Heart Circ Physiol. 2020.
Increased matrix metalloprotease 9 (MMP9) after myocardial infarction (MI) exacerbates ischemia-induced chronic heart failure (CHF). Autophagy is cardioprotective during CHF; however, whether increased MMP9 suppresses autophagic activity in CHF is unknown. This study aimed to determine whether increased MMP9 suppressed autophagic flux and MMP9 inhibition increased autophagic flux in the heart of rats with post-MI CHF.
The novelty and highlights of this report are as follows:
1) MMP9 regulates cardiomyocyte and fibroblast autophagy;
2) MMP9 inhibition protects CHF after myocardial infarction (MI) via increased cardiac autophagic flux;
3) MMP9 inhibition increased cardiac autophagy via activation of AMP-activated protein kinase (AMPK)α, Beclin-1, Atg7 pathway and suppressed mechanistic target of rapamycin (mTOR) pathway.

Fig1. Increased matrix metalloprotease (MMP)9 activity during post-myocardial infarction (MI) induced chronic heart failure (CHF). A: representative in-gel gelatin zymography showing MMP9 and MMP2 activity in peri-infarct and remote areas of the myocardium. Sham, sham operated. B and C: bar graphs showing quantification of MMP9 activity (B) and MMP2 activity (C) in peri-infarct and remote areas of myocardium. Values are means ± SE of analyses on n = 6–8 rats in each group.

Case 3: Ringland C, et al. BMC Neurosci. 2021.
Matrix metallopeptidase 9 (MMP9) has been implicated in a variety of neurological disorders, including Alzheimer's disease (AD), where MMP9 levels are elevated in the brain and cerebrovasculature.
In the current studies, the authors evaluated the impact of MMP9 modulation on Aβ disposition and neurobehavior in AD using two approaches, (1) pharmacological inhibition of MMP9 with SB-3CT in apoE4 x AD (E4FAD) mice, and (2) gene deletion of MMP9 in AD mice (MMP9KO/5xFAD)
In conclusion, while MMP9 inhibition did improve specific neurobehavioral deficits associated with AD, such as anxiety and social recognition memory, modulation of MMP9 did not alter spatial learning and memory or Aβ tissue levels in AD animals.

Fig1. Analysis of MMP9 levels in SB-3CT and vehicle-treated E4FAD mice. A, B Levels of proMMP9 were examined in spleen samples from SB-3CT and vehicle-treated mice by zymography. A Zymography gel showing bands of proMMP9 in SB-3CT-treated and control animals. B Quantification of zymographic analysis. C, D Levels of total MMP9 as measured by ELISA analysis of the C cerebrovasculature and D the whole brain parenchyma of SB-3CT and vehicle-treated E4FAD mice.

MMP9 has several biochemical functions, for example, collagen binding,endopeptidase activity,identical protein binding. Some of the functions are cooperated with other proteins, some of the functions could acted by MMP9 itself. We selected most functions MMP9 had, and list some proteins which have the same functions with MMP9. You can find most of the proteins on our site.

MMP9 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with MMP9 here. Most of them are supplied by our site. Hope this information will be useful for your research of MMP9.

VCAN;MEP1A;MEP1B;TIMP1;SRGN;ELN;SCUBE3;TGFB1;q7cje7_yerpe;ITGA5