Details for: MMP8

Gene ID: 4317

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: MMP8

Ensembl ID: ENSG00000118113

Description: matrix metallopeptidase 8

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • granulocyte CL0000094
    CSI 3.52
    rCSI 5.38%
    PRS 99.98
  • neutrophil CL0000775
    CSI 1.8
    rCSI 10.08%
    PRS 99.66

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [MMP8](/details-gene/4317) (Matrix Metallopeptidase 8), also known as neutrophil collagenase, is a zinc-dependent endopeptidase that plays a crucial role in the breakdown of extracellular matrix (ECM) components, particularly fibrillar collagens. As its name implies, expression analysis shows that [MMP8](/details-gene/4317) is a highly specific gene product of the myeloid lineage, with its most significant expression observed in [granulocytes](/details-cell/CL0000094), and specifically [neutrophils](/details-cell/CL0000775). Functionally, it is integral to processes involving tissue remodeling, such as would occur during immune responses, inflammation, and wound healing. Its activity is tightly linked to the innate immune system, particularly through its storage in and release from neutrophil granules. The gene is clinically associated with a susceptibility to periodontitis, as documented in OMIM ([120355](https://omim.org/entry/120355)). ## Cellular Roles and Expression Landscape The expression profile of [MMP8](/details-gene/4317) establishes it as a key functional marker for specific cells of the innate immune system. **Overall**, the gene's significance is overwhelmingly concentrated in the granulocytic lineage. It is most prominently expressed in [granulocytes](/details-cell/CL0000094) (CSI: 3.52) and their most abundant subset, [neutrophils](/details-cell/CL0000775) (CSI: 1.80). This highly restricted expression pattern suggests that [MMP8](/details-gene/4317) is not a general lineage marker but rather a specialized effector molecule used by these phagocytes. Its presence within neutrophil-specific granules, as suggested by functional annotations, allows for its rapid deployment at sites of inflammation or infection, where it can remodel tissue barriers to facilitate neutrophil migration and clear debris. ## Pathways and Molecular Function The molecular functions and biological roles of [MMP8](/details-gene/4317) are centered on proteolysis and extracellular matrix organization, which are consistent with its discovery as a collagen-degrading enzyme from human neutrophils [Link](https://doi.org/10.1016/s0021-9258(19)38413-3). * **Molecular Function:** At its core, [MMP8](/details-gene/4317) exhibits `metalloendopeptidase activity` ([GO:0004222](https://www.ebi.ac.uk/QuickGO/term/GO:0004222)) that is dependent on `zinc ion binding` ([GO:0008270](https://www.ebi.ac.uk/QuickGO/term/GO:0008270)) for catalysis. Its primary substrates are collagens, underpinning its critical role in the `collagen catabolic process` ([GO:0030574](https://www.ebi.ac.uk/QuickGO/term/GO:0030574)). * **Biological Process:** The enzymatic activity of [MMP8](/details-gene/4317) is integral to the broader process of `extracellular matrix disassembly` ([GO:0022617](https://www.ebi.ac.uk/QuickGO/term/GO:0022617)), a key step in both physiological and pathological tissue remodeling. This function is highlighted in Reactome pathways such as `Collagen degradation` ([R-HSA-1442490](https://reactome.org/content/detail/R-HSA-1442490)) and `Degradation of the extracellular matrix` ([R-HSA-1474228](https://reactome.org/content/detail/R-HSA-1474228)). * **Immune System Context:** The gene's function is tightly integrated with the `Innate immune system` ([R-HSA-168249](https://reactome.org/content/detail/R-HSA-168249)). Its localization to the `specific granule lumen` ([GO:0035580](https://www.ebi.ac.uk/QuickGO/term/GO:0035580)) and `tertiary granule lumen` ([GO:1904724](https://www.ebi.ac.uk/QuickGO/term/GO:1904724)) is consistent with its role in `Neutrophil degranulation` ([R-HSA-6798695](https://reactome.org/content/detail/R-HSA-6798695)). Furthermore, it is involved in modulating inflammation through pathways like `cellular response to lipopolysaccharide` ([GO:0071222](https://www.ebi.ac.uk/QuickGO/term/GO:0071222)) and `positive regulation of neuroinflammatory response` ([GO:0150078](https://www.ebi.ac.uk/QuickGO/term/GO:0150078)). ## Research Directions The highly specific expression of [MMP8](/details-gene/4317) in [neutrophils](/details-cell/CL0000775) and its potent collagenolytic activity make it a subject of interest for understanding tissue damage in inflammatory diseases and its role in the tumor microenvironment. **Proposed Hypotheses:** 1. Given its function in collagen breakdown and its role in modulating neuroinflammation ([GO:0150078](https://www.ebi.ac.uk/QuickGO/term/GO:0150078)), excessive activity of [MMP8](/details-gene/4317) released from infiltrating [neutrophils](/details-cell/CL0000775) may be a direct contributor to blood-brain barrier disruption and neuronal damage in acute neurological injuries such as ischemic stroke or traumatic brain injury. 2. In the context of cancer, the activity of [MMP8](/details-gene/4317) from tumor-associated [neutrophils](/details-cell/CL0000775) could be dichotomous. It may promote metastasis by degrading the ECM basement membrane, but alternatively, it could process other ECM or signaling proteins into fragments that inhibit angiogenesis or promote anti-tumor immunity. The net effect is likely highly dependent on the specific tumor type and microenvironment. **Key Experimental Approach:** To test the hypothesis that neutrophil-derived [MMP8](/details-gene/4317) exacerbates tissue damage in ischemic stroke, a suitable experiment would involve the middle cerebral artery occlusion (MCAO) mouse model. A conditional knockout mouse line, where *Mmp8* is specifically deleted in the myeloid lineage (e.g., *Mmp8*fl/fl;Lyz2-Cre), would be compared to control littermates. Following MCAO, key endpoints would include infarct volume measurement (via MRI or histology), assessment of blood-brain barrier integrity (e.g., Evans blue dye extravasation), and quantification of neuronal apoptosis and neurological deficits. A significant reduction in infarct size and improved neurological outcomes in the knockout mice would strongly support the hypothesis that neutrophil-derived [MMP8](/details-gene/4317) is a key driver of pathology in this context. **Therapeutic Potential:** [MMP8](/details-gene/4317) represents a compelling target for therapeutic **inhibition** in acute and chronic inflammatory diseases characterized by excessive neutrophil infiltration and tissue destruction (e.g., acute respiratory distress syndrome, rheumatoid arthritis, periodontitis). While broad-spectrum MMP inhibitors have faced challenges with toxicity and lack of efficacy, the highly restricted expression of [MMP8](/details-gene/4317) to [neutrophils](/details-cell/CL0000775) offers a distinct advantage. A highly selective small-molecule inhibitor of [MMP8](/details-gene/4317) could potentially dampen pathological collagenolysis at sites of inflammation with a much-improved safety profile, representing a refined strategy for targeting MMPs in disease.

Genular Protein ID: 1051068842

Symbol: MMP8_HUMAN

Name: Neutrophil collagenase

UniProtKB Accession Codes:

P22894 Q45F99

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BRENDA 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 2 CTD 1 ChEBI 23 ChEMBL 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 15 DrugCentral 1 EC 2 EMBL 4 Ensembl 1 EvolutionaryTrace 1 ExpressionAtlas 1 GO 21 Gene3D 2 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 GuidetoPHARMACOLOGY 1 HGNC 1 HPA 1 InParanoid 1 IntAct 1 InterPro 12 KEGG 1 MANE-Select 1 MEROPS 1 MIM 1 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 25 PDBsum 25 PIR 1 PIRSF 1 PRIDE 1 PRINTS 1 PRO 1 PROSITE 4 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 3 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 Reactome 4 RefSeq 3 SIGNOR 1 SMART 2 SMR 1 STRING 1 SUPFAM 3 SignaLink 1 TopDownProteomics 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 2164002

Title: Human neutrophil collagenase. A distinct gene product with homology to other matrix metalloproteinases.

PubMed ID: 2164002

DOI: 10.1016/s0021-9258(19)38413-3

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 2159879

Title: Characterization and activation of procollagenase from human polymorphonuclear leucocytes. N-terminal sequence determination of the proenzyme and various proteolytically activated forms.

PubMed ID: 2159879

DOI: 10.1111/j.1432-1033.1990.tb15489.x

PubMed ID: 1662606

Title: Mercurial activation of human polymorphonuclear leucocyte procollagenase.

PubMed ID: 1662606

DOI: 10.1111/j.1432-1033.1991.tb16494.x

PubMed ID: 2176876

Title: Characterization of 58-kilodalton human neutrophil collagenase: comparison with human fibroblast collagenase.

PubMed ID: 2176876

DOI: 10.1021/bi00499a008

PubMed ID: 2169256

Title: Partial amino acid sequence of human PMN leukocyte procollagenase.

PubMed ID: 2169256

PubMed ID: 2169766

Title:

PubMed ID: 2169766

DOI: 10.1515/bchm3.1990.371.2.733

PubMed ID: 1330697

Title: Formation of a covalent Hg-Cys-bond during mercurial activation of PMNL procollagenase gives evidence of a cysteine-switch mechanism.

PubMed ID: 1330697

DOI: 10.1016/0014-5793(92)81184-n

PubMed ID: 8137810

Title: The X-ray crystal structure of the catalytic domain of human neutrophil collagenase inhibited by a substrate analogue reveals the essentials for catalysis and specificity.

PubMed ID: 8137810

DOI: 10.1002/j.1460-2075.1994.tb06378.x

PubMed ID: 8307185

Title: Structural implications for the role of the N-terminus in the 'superactivation' of collagenases. A crystallographic study.

PubMed ID: 8307185

DOI: 10.1016/0014-5793(94)80370-6

PubMed ID: 7656015

Title: Structure of human neutrophil collagenase reveals large S1' specificity pocket.

PubMed ID: 7656015

DOI: 10.1038/nsb0294-119

PubMed ID: 9249047

Title: 1.8-A crystal structure of the catalytic domain of human neutrophil collagenase (matrix metalloproteinase-8) complexed with a peptidomimetic hydroxamate primed-side inhibitor with a distinct selectivity profile.

PubMed ID: 9249047

DOI: 10.1111/j.1432-1033.1997.00356.x

PubMed ID: 9655333

Title: Structure of malonic acid-based inhibitors bound to human neutrophil collagenase. A new binding mode explains apparently anomalous data.

PubMed ID: 9655333

DOI: 10.1002/pro.5560070605

Sequence Information:

  • Length: 467
  • Mass: 53412
  • Checksum: 4D4602A53AD7F8BC
  • Sequence:
    • MFSLKTLPFL LLLHVQISKA FPVSSKEKNT KTVQDYLEKF YQLPSNQYQS TRKNGTNVIV 
EKLKEMQRFF GLNVTGKPNE ETLDMMKKPR CGVPDSGGFM LTPGNPKWER TNLTYRIRNY 
TPQLSEAEVE RAIKDAFELW SVASPLIFTR ISQGEADINI AFYQRDHGDN SPFDGPNGIL 
AHAFQPGQGI GGDAHFDAEE TWTNTSANYN LFLVAAHEFG HSLGLAHSSD PGALMYPNYA 
FRETSNYSLP QDDIDGIQAI YGLSSNPIQP TGPSTPKPCD PSLTFDAITT LRGEILFFKD 
RYFWRRHPQL QRVEMNFISL FWPSLPTGIQ AAYEDFDRDL IFLFKGNQYW ALSGYDILQG 
YPKDISNYGF PSSVQAIDAA VFYRSKTYFF VNDQFWRYDN QRQFMEPGYP KSISGAFPGI 
ESKVDAVFQQ EHFFHVFSGP RYYAFDLIAQ RVTRVARGNK WLNCRYG

Genular Protein ID: 1277212518

Symbol: B4E0I2_HUMAN

Name: N/A

UniProtKB Accession Codes:

B4E0I2

Database IDs:

ARBA 10 AlphaFoldDB 1 BioGRID-ORCS 1 CDD 2 CTD 1 ChEBI 25 DNASU 1 DisGeNET 1 EMBL 2 GO 5 Gene3D 2 InterPro 12 MEROPS 1 NCBI Taxonomy 1 OrthoDB 1 PANTHER 2 PIRSF 1 PIRSR 4 PRINTS 1 PROSITE 3 PROSITE-ProRule 1 PeptideAtlas 1 Pfam 3 RefSeq 1 SMART 3 SUPFAM 3

Sequence Information:

  • Length: 426
  • Mass: 48694
  • Checksum: E9A5C17331004EAD
  • Sequence:
    • MQQIPQEKSI NDYLEKFYQL PSNQYQSTRK NGTNVIVEKL KEMQRFFGLN VTGKPNEETL 
DMMEKPRCGV PDSGGFMLTP GNPKWERTNL TYRIRNYTPQ LSEAEVERAI KDAFELWSVA 
SPLIFTRISQ GEADINIAFY QRDHGDNSPF DGPNGILAHA FQPGQGIGGD AHFDAEETWT 
NTSANYNLFL VAAHEFGHSL GLAHSSDPGA LMYPNYAFRE TSNYSLPQDD IDGIQAIYGL 
SSNPIQPTGP STPKPCDPSL TFDAITTLRG EILFFKDRYF WRRHPQLQRV EMNFISLFWP 
SLPTGIQAAY EDFDRDLIFL FKGNQYWALS GYDILQGYPK DISNYGFPSS VQAIDAAVFY 
RSKTYFFVND QFWRYDNQRQ FMEPGYPKSI SGAFPGIESK VDAVFQQEHF FHVFSGPRYY 
AFDLIA