* 120361

MATRIX METALLOPROTEINASE 9; MMP9


Alternative titles; symbols

COLLAGENASE TYPE IV-B; CLG4B
COLLAGENASE TYPE IV, 92-KD
COLLAGENASE TYPE V
GELATINASE, 92-KD
GELATINASE B; GELB


HGNC Approved Gene Symbol: MMP9

Cytogenetic location: 20q13.12     Genomic coordinates (GRCh38): 20:46,008,908-46,016,561 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
20q13.12 Metaphyseal anadysplasia 2 613073 AR 3

TEXT

Description

The 72- and 92-kD type IV collagenases are members of a group of secreted zinc metalloproteases which, in mammals, degrade the collagens of the extracellular matrix. Other members of this group include interstitial collagenase (MMP1; 120353) and stromelysin (MMP3; 185250). The 72-kD type IV collagenase (MMP2, or CLG4A; 120360) is secreted from normal skin fibroblasts, whereas the 92-kD collagenase (CLG4B) is produced by normal alveolar macrophages and granulocytes. The 92-kD type IV collagenase is also known as 92-kD gelatinase, type V collagenase, or matrix metalloproteinase-9 (MMP9); see the glossary of matrix metalloproteinases provided by Nagase et al. (1992).


Gene Structure

Both CLG4A and CLG4B have 13 exons and similar intron locations (Huhtala et al., 1991). The 13 exons of both CLG4A and CLG4B are 3 more than have been found in other members of this gene family. The extra exons encode the amino acids of the fibronectin-like domain, which has been found only in the 72- and 92-kD type IV collagenases.


Mapping

By hybridization to somatic cell hybrid DNAs, Collier et al. (1991) demonstrated that both CLG4A and CLG4B are situated on chromosome 16. However, St Jean et al. (1995) assigned CLG4B to chromosome 20. They did linkage mapping of the CLG4B locus in 10 CEPH reference pedigrees using a polymorphic dinucleotide repeat in the 5-prime flanking region of the gene. St Jean et al. (1995) observed lod scores of between 10.45 and 20.29 with markers spanning chromosome region 20q11.2-q13.1. Further support for assignment of CLG4B to chromosome 20 was provided by analysis of human/rodent somatic cell hybrids. Due to their similar gene structures, the CLG4B cDNA clone used in the mapping to chromosome 16 may have hybridized to CLG4A rather than to CLG4B on chromosome 20.

Linn et al. (1996) reassigned MMP9 (referred to as CLG4B by them) to chromosome 20 based on 3 different lines of evidence: screening of a somatic cell hybrid mapping panel, fluorescence in situ hybridization, and linkage analysis using a newly identified polymorphism. They also mapped mouse Clg4b to mouse chromosome 2, which has no known homology to human chromosome 16 but large regions of homology with human chromosome 20.


Gene Function

Laterveer et al. (1996) demonstrated that interleukin-8 (IL8; 146930) induces rapid mobilization of hematopoietic progenitor cells (HPCs) from the bone marrow of rhesus monkeys. Because activation of neutrophils by IL8 induces the release of MMP9, which is involved in the degradation of extracellular matrix molecules, Opdenakker et al. (1998) and Pruijt et al. (1999) hypothesized that MMP9 release might induce stem cell mobilization by cleaving matrix molecules to which stem cells are attached. Pruijt et al. (1999) showed that the mobilization of HPCs could be prevented by pretreatment with an inhibitory anti-gelatinase B antibody, indicating that MMP9 is involved as a mediator of the IL8-induced mobilization of HPCs. Van den Steen et al. (2000) showed that MMP9-mediated N-terminal cleavage of IL8 potentiates IL8 activation of neutrophils, as measured by increased intracellular calcium, MMP9 secretion, and neutrophil chemotaxis.

Yu and Stamenkovic (2000) identified a functional relationship between the hyaluronan receptor CD44 (107269), MMP9, and transforming growth factor-beta (TGFB; see 190180) in the control of tumor-associated tissue remodeling. They showed that several isoforms of CD44 expressed on murine mammary carcinoma cells provide cell surface docking receptors for proteolytically active MMP9. Localization of MMP9 to the cell surface is required to promote tumor invasion and angiogenesis. Cell surface expression of MMP9 stimulated the formation of capillary tubes by bovine microvascular endothelial cells. Yu and Stamenkovic (2000) demonstrated that MMP9 and MMP2 proteolytically cleave latent TGFB2 (190220), a mechanism required to activate TGFB. The authors suggested that the activation of TGFB may be part of the mechanism by which MMP9 activity induces or promotes angiogenesis.

Using substrate conversion assays, Opdenakker et al. (1991) and Gijbels et al. (1992) detected increased levels of MMP9 in arthritis patient synovial fluid and in multiple sclerosis patient cerebrospinal fluid, respectively. Price et al. (2001) detected a significantly higher concentration of MMP9 per leukocyte in cerebrospinal fluid from adult tuberculous meningitis patients than in patients with bacterial or viral meningitis. In vitro studies indicated that viable bacilli were not required to stimulate MMP9 production. In contrast to the changes in MMP9 expression, MMP2 and tissue inhibitor of metalloproteinase-1 (TIMP1; 305370) were constitutively expressed, and the latter did not oppose the MMP9 activity. Elevated MMP9 activity was related to unconsciousness, confusion, focal neurologic damage, and death in the tuberculous meningitis patients.

Using RT-PCR, gelatin zymography, and Western blot analysis, Kanbe et al. (1999) showed that cultured human mast cells expressed MMP9 mRNA following activation, and that culture supernatants produced a 92-kD MMP9 protein with gelatinolytic activity. Immunohistochemical analysis detected MMP9 in mast cells in human skin, lung, and synovial tissue. Kanbe et al. (1999) concluded that mast cells produce MMP9, which might contribute to extracellular matrix degradation and absorption in the process of allergic and nonallergic responses.

Using a monoclonal antibody on a series of well-characterized paraffin-embedded sections of pituitary tumors, Turner et al. (2000) investigated whether expression of MMP9 plays a role in allowing angiogenesis and invasion by different pituitary tumor types. They found that invasive macroprolactinomas were significantly more likely to express MMP9 than noninvasive macroprolactinomas. Invasive macroprolactinomas showed higher-density MMP9 staining than noninvasive tumors and normal pituitary gland, or between different sized prolactinomas. MMP9 expression was related to aggressive tumor behavior. The authors concluded that MMP9 expression is present in some invasive and recurrent pituitary adenomas and in the majority of pituitary carcinoma. While the mechanisms whereby MMP9 expression influences tumor recurrence and invasiveness, and its association with angiogenesis, remained to be elucidated, these observations suggested that a future potential therapeutic strategy for some pituitary tumors may be administration of a synthetic MMP9 inhibitor.

Concentrations of MMP9 are increased in the bronchoalveolar lavage fluid (BAL), sputum, bronchi, and serum of asthmatic subjects compared with normal individuals. Using segmental bronchoprovocation (SBP) and ELISA analysis of BAL from allergic subjects, Kelly et al. (2000) detected increased MMP9 48 hours after SBP in antigen-challenged patients compared with saline-challenged patients. TIMP1 inhibitor was also increased in all subjects, but the ratio of MMP9 to TIMP1 was significantly higher in the antigen-challenged group. No differences were found in serum. Immunocytochemical analysis demonstrated MMP9 expression primarily in neutrophils. Kelly et al. (2000) concluded that antigen may contribute not only to inflammation but also to eventual airway remodeling in asthma.

Osman et al. (2002) showed that mature dendritic cells (DCs) produce more MMP9 than do immature DCs, facilitating their hydroxaminic acid-inhibitable migration through gel in vitro and, presumably, through the extracellular matrix to monitor the antigenic environment in vivo. RT-PCR analysis indicated that the enhanced expression of MMP9 is correlated with a downregulation of TIMP1 and, particularly, TIMP2 (188825), while expression of TIMP3 (188826) is upregulated. The authors concluded that the balance of MMP and TIMP determines the net migratory capacity of DCs. They proposed that TIMP3 may be a marker for mature DCs.

Ueda et al. (2002) investigated survivin (603352) gene and protein expression in a tumor-like benign disease, endometriosis, and correlated them with apoptosis and invasive phenotype of endometriotic tissues. Gene expression levels of survivin, MMP2, MMP9, and MMP14 (600754) in 63 pigmented or nonpigmented endometriotic tissues surgically obtained from 35 women with endometriosis were compared with those in normal eutopic endometrium obtained from 12 women without endometriosis. Survivin, MMP2, MMP9, and MMP14 mRNA expression levels in clinically aggressive pigmented lesions were significantly higher than those in normal eutopic endometrium, and survivin gene expression in pigmented lesions was also higher than that in nonpigmented lesions (P less than 0.05). There was a close correlation between survivin and MMP2, MMP9, and MMP14 gene expression levels in 63 endometriotic tissues examined (P less than 0.01). The authors concluded that upregulation of survivin and MMPs may cooperatively contribute to survival and invasion of endometriosis.

Following enforced expression in a fibrosarcoma cell line, Yan et al. (2003) found that MTA1 (603526) repressed MMP9 expression. MTA1 directly bound the MMP9 promoter and repressed expression via both histone-dependent and -independent mechanisms.

Wang et al. (2003) demonstrated that tissue plasminogen activator (TPA; 173370) upregulates MMP9 in cell culture and in vivo. MMP9 levels were lower in TPA knockout compared with wildtype mice after focal cerebral ischemia. In human cerebral microvascular endothelial cells, MMP9 was upregulated when recombinant TPA was added. RNA interference suggested that this response was mediated by the LDL receptor-related protein (LRP1; 107770), which avidly binds TPA and possesses signaling properties.

Matsuyama et al. (2003) measured circulating levels of MMP2, MMP3, and MMP9 in 25 patients with Takayasu arteritis (207600) and 20 age- and sex-matched healthy controls. Levels of all 3 metalloproteinases were higher in patients with active disease than in controls (p less than 0.0001 for each), and MMP2 levels remained elevated even in remission. In contrast, an improvement in clinical signs and symptoms was associated with a marked reduction in circulating MMP3 and MMP9 levels in all patients (p less than 0.05). Matsuyama et al. (2003) concluded that MMP2 could be helpful in diagnosing Takayasu arteritis and that MMP3 and MMP9 could be used as activity markers for the disease.

In a study of 699 Framingham Study participants who had no history of heart failure or myocardial infarction and who underwent routine echocardiography, Sundstrom et al. (2004) found that detectable plasma MMP9 levels were associated with increased left ventricular dimensions and increased wall thickness in men. Sundstrom et al. (2004) suggested that plasma MMP9 level may be a marker for cardiac extracellular matrix degradation, a process involved in left ventricular remodeling.

Using an expression cloning strategy with HT1080 human fibrosarcoma cells, Nair et al. (2006) identified SM22 (TAGLN; 600818) as a regulator of MMP9 expression. Stable expression of SM22 in HT1080 cells repressed MMP9 expression, whereas suppression of SM22 via small interfering RNA in human lung fibroblasts enhanced MMP9 expression and enzymatic activity. Mmp9 expression was weak in wildtype mouse uterine tissue, which constitutively expresses Sm22, but it was strong in uterine tissue from Sm22 -/- mice. Mutation analysis indicated that the N-terminal calponin homology domain of SM22, but not the actin-binding domain, mediated MMP9 repression, probably through interference with ERK1 (MAPK3; 601795) and ERK2 (MAPK1; 176948) signaling. Nair et al. (2006) concluded that SM22, which often exhibits diminished expression in cancer, regulates MMP9 expression.

Using a modified angiogenic model, Ardi et al. (2007) demonstrated that intact human neutrophils, their granule contents, and, specifically, neutrophil MMP9 had potent proangiogenic activity in the absence of TIMP1.

Gong et al. (2008) found that Plg (173350) -/- mice displayed diminished macrophage trans-extracellular matrix (ECM) migration and decreased Mmp9 activation following induction of peritonitis. Injection of active Mmp9 rescued macrophage migration in Plg -/- mice. Macrophage migration and aneurysm formation were also reduced in Plg -/- mice induced to undergo abdominal aortic aneurysm (AAA). Administration of active Mmp9 to Plg -/- mice promoted macrophage infiltration and development of AAA. Gong et al. (2008) concluded that PLG regulates macrophage migration in inflammation via activation of MMP9, which in turn regulates the ability of macrophages to migrate across ECM.

Lausch et al. (2009) suggested that there is a functional link between MMP13 (600108) and MMP9 in the endochondral ossification, as impaired MMP9 protein function, caused by direct inactivation (in recessive disease due to MMP9 loss of function), impaired activation (in recessive disease due to MMP13 loss of function), or transcatalytic degradation (in dominant disease caused by MMP13 gain of function) appears to be a common downstream step in the pathogenesis of metaphyseal anadysplasia (MANDP1, 602111; MANDP2, 613073).

Pathak et al. (2011) studied plasma and peripheral blood cell expression of IL1B (147720), MMP9, soluble IL1R2 (147811), and IL17 (see 603149) in 47 patients with either autoimmune inner ear disease or sensorineural hearing loss of likely immunologic origin who were treated with corticosteroids. They found that 18 corticosteroid nonresponder patients expressed significantly higher levels of IL1B and MMP9, but not IL17 or soluble IL1R2, compared with clinically responsive patients. RT-PCR analysis showed that treating control blood cells with IL1B induced expression of MMP9. Treatment with the MMP9 catalytic domain plus dexamethasone, but not MMP9 alone, reciprocally induced IL1B expression. Treatment of cells with dexamethasone alone increased IL1R2 expression in cells and plasma, and IL1R2 expression was further increased with the addition of MMP9. In responder patient cells, treatment with dexamethasone reduced expression of IL1B and MMP9, whereas IL1B expression could only be reduced in nonresponder cells by treatment with anakinra, the soluble IL1R antagonist (IL1RN; 147679). Pathak et al. (2011) proposed that IL1B blockade may be a viable therapy for patients with autoimmune inner ear disease or sensorineural hearing loss that fail to respond to corticosteroids.

Using a knockdown screen in MDA-MB-231 human breast cancer cells, Jacob et al. (2013) identified RAB40B (619550) as a small monomeric GTPase required for secretion of MMP2 and MMP9. Secretion of MMP2 and MMP9 was not dependent on endocytic transport, but instead relied on transport from the trans-Golgi network through VAMP4 (606909)- and RAB40B-containing secretory vesicles. RAB40B knockdown not only decreased MMP2 and MMP9 secretion, but also resulted in mistargeting of MMP2 and MMP9 to lysosomes, where they were degraded. Further analysis demonstrated that RAB40B regulated MMP2 and MMP9 trafficking during invadopodia formation and was required for invadopodia-dependent extracellular matrix degradation.


Molecular Genetics

Metaphyseal Anadysplasia 2

Lausch et al. (2009) investigated the molecular basis of metaphyseal anadysplasia in 5 families. In affected members of a nonconsanguineous Pakistani family, they identified homozygosity for a mutation in the MMP9 gene (120361.0001); see MANDP2 (613073). In 3 other families, they identified heterozygous mutations in the MMP13 gene (600108.0002 and 600108.0003); see MANDP1 (602111). Lausch et al. (2009) found that recessive MANDP (MANDP2) is caused by homozygous loss of function of MMP9, whereas dominant MANDP (MANDP1) is caused by missense mutations in the prodomain of MMP13; these mutations determine autoactivation of MMP13 and intracellular degradation of both MMP13 and MMP9, resulting in a double enzymatic deficiency. In the fifth family studied by Lausch et al. (2009), the proband (patient 11) was homozygous for a missense mutation in the MMP13 gene (H213N; 600108.0004). Bonafe et al. (2014) stated that although this Moroccan boy was initially diagnosed as having a recessive form of MANDP1, he could be retrospectively diagnosed with the Spahr type of metaphyseal dysplasia (MDST; 250400).

By targeted next-generation sequencing of a skeletal dysplasia gene panel in a Spanish boy with scoliosis, genu varum, and metaphyseal abnormalities, Bonilla-Fornes et al. (2021) identified a homozygous nonsense mutation in the MMP9 gene (W588X; 120361.0002). The parents were confirmed by Sanger sequencing to be heterozygous for the mutation.

Associations Pending Confirmation

Zhang et al. (1999) showed that a polymorphism (-1562C-T) in the promoter region of the MMP9 gene has a functional effect on transcription and is associated with the severity of the atherosclerosis in patients with coronary artery disease. Prompted by this, Zhang et al. (1999) cataloged sequence variants in the 2.2-kb promoter sequence and all 13 exons (totaling 3.3 kb) of the MMP9 gene. They identified a total of 10 variable sites, 4 in the promoter region, 5 in the coding region (3 of which altered the amino acid encoded), and 1 in the 3-prime untranslated sequence. Sequence inspection suggested that some of the variants would have a functional impact on either level of expression or enzymatic activity. Tight linkage disequilibrium was detected between variants across the entire length of the gene, and frequencies of different haplotypes were determined.

Minematsu et al. (2001) noted that it had recently been suggested that matrix metalloproteinases play roles in the pathogenesis of pulmonary emphysema. MMP9 and MMP12 (601046) account for most of the macrophage-derived elastase activity in smokers. Minematsu et al. (2001) studied the association between a functional polymorphism of MMP9, -1562C-T, and the development of pulmonary emphysema in 110 smokers and 94 nonsmokers in Japan. The T allele frequency was higher in 45 smokers with distinct emphysema on chest CT scans than in 65 smokers without it (0.244 vs 0.123; p = 0.02). The results suggested that the polymorphism of MMP9 acts as a genetic factor for the development of smoking-induced pulmonary emphysema.

By sequencing all 13 MMP9 exons and flanking regions in 290 Japanese pediatric atopic asthma patients and 638 healthy Japanese controls, Nakashima et al. (2006) identified 17 SNPs and selected 5 of these for association studies. Significant associations with risk of pediatric atopic asthma were found for a 2127G-T SNP in intron 4 and a nonsynonymous SNP, 5546G-A (arg668 to gln; R668Q), in exon 12 (p of 0.0032 and 0.0016, respectively). The haplotype containing 2127T and 5546A was also associated with atopia (p of 0.0053). Treatment of normal human bronchial epithelial cells showed that poly(I:C) was the only Toll-like receptor (TLR; see 601194) agonist that enhanced MMP9 expression. Reporter analysis showed increased activity with the MMP9 -1590C-T promoter SNP, which is in strong linkage disequilibrium with 2127G-T. Nakashima et al. (2006) concluded that MMP9 has an important role in asthma.

In a case-control association study involving 2 independent Japanese cohorts, Hirose et al. (2008) found a significant association between a missense SNP in the MMP9 gene (G279R; rs17576) and lumbar disc herniation (LDH; 603932). An intronic SNP in the THBS2 gene (rs9406328; 188061.0001) was also strongly associated with LDH in the Japanese population and showed a combinatorial effect with MMP9, with an odds ratio of 3.03 for the genotype that was homozygous for the susceptibility alleles of both SNPs.


Animal Model

By targeted disruption in embryonic stem cells, Vu et al. (1998) created homozygous mice with a null mutation in the MMP9/gelatinase B gene. These mice exhibited an abnormal pattern of skeletal growth plate vascularization and ossification. Although hypertrophic chondrocytes developed normally, apoptosis, vascularization, and ossification were delayed, resulting in progressive lengthening of the growth plate to about 8 times normal. After 3 weeks postnatal, aberrant apoptosis, vascularization, and ossification compensated to remodel the enlarged growth plate and ultimately produced an axial skeleton of normal appearance. Transplantation of wildtype bone marrow cells rescued vascularization and ossification in Mmp9-null growth plates, indicating that these processes are mediated by Mmp9-expressing cells of bone marrow origin, designated chondroclasts. Growth plates from Mmp9-null mice in culture showed a delayed release of an angiogenic activator, establishing a role for this proteinase in controlling angiogenesis.

Dubois et al. (1999) generated Mmp9-deficient mice by replacing the catalytic and zinc-binding domains with an antisense-oriented neomycin resistance gene. They determined that young Mmp9 -/- mice were resistant to the induction of experimental autoimmune encephalomyelitis (EAE). Adult Mmp9 -/- mice developed EAE, but unlike wildtype mice, they did not display necrotizing tail lesions with hyperplasia of osteocartilaginous tissue. Dubois et al. (1999) concluded that MMP9 is involved in immune system development and in the propensity to develop autoimmune disease.

Coussens et al. (2000) reported that transgenic mice lacking Mmp9 showed reduced keratinocyte hyperproliferation at all neoplastic stages and a decreased incidence of invasive tumors. However, those carcinomas that did arise in the absence of Mmp9 exhibited a greater loss of keratinocyte differentiation, indicative of a more aggressive and higher grade tumor. MMP9 is predominantly expressed in neutrophils, macrophages, and mast cells, rather than in oncogene-positive neoplastic cells. Chimeric mice expressing Mmp9 only in cells of hematopoietic origin, produced by bone marrow transplantation, reconstituted the MMP9-dependent contributions to squamous carcinogenesis. Thus, inflammatory cells can be coconspirators in carcinogenesis.

Gu et al. (2002) reported activation of Mmp9 by neuronal nitric oxide synthase (NOS1; 163731) in a mouse model of cerebral ischemia. Immunochemical analysis of the ischemic cortex following stroke in wildtype animals showed that activated Mmp9 colocalized with Nos1 within neurons. Activation of Mmp9 was abrogated after stroke in Nos1 null mice or in wildtype mice treated with an NOS inhibitor. Biochemical analysis and mass spectrometry revealed that MMP9 activation is initiated by NOS1 through S-nitrosylation of the Zn(2+)-coordinating cysteine within the active site of MMP9. Further oxidation causes irreversible modification of the residue to sulfinic or sulfonic acid. Gu et al. (2002) demonstrated that activated MMP9 leads to neuronal cell death. Treatment of cultured cerebrocortical neurons with NOS1-activated MMP9 increased apoptosis and detachment from the culture dish. Pretreatment with an MMP inhibitor blocked neuronal cell death.

MMP9, induced in bone marrow cells, releases soluble Kit ligand (KITLG; 184745), permitting the transfer of endothelial and hematopoietic stem cells (HSCs) from the quiescent to proliferative niche. Heissig et al. (2002) found that bone marrow ablation in wildtype Mmp9 mice induced Sdf1 (600835), which upregulated Mmp9 expression and caused shedding of Kitlg and recruitment of Kit (164920)-positive stem/progenitors. In Mmp9 -/- mice, release of Kitlg and HSC motility were impaired, resulting in failure of hematopoietic recovery and increased mortality, while exogenous Kitlg restored hematopoiesis and survival after bone marrow ablation. Release of Kitlg by Mmp9 enabled bone marrow repopulating cells to translocate to a permissive vascular niche favoring differentiation and reconstitution of the stem/progenitor cell pool.

By examining the effects of an Il13 (147683) transgene on wildtype mice and mice lacking Mmp9 or Mmp12, Lanone et al. (2002) determined that the IL13-mediated eosinophilic and lymphocytic inflammation and alveolar remodeling in the lung that occurs in asthma (600807), COPD (606963), and interstitial lung disease is dependent on both MMP9 and MMP12 mechanisms. The results indicated that MMP9 inhibits neutrophil accumulation, but, unlike MMP12, has no effect on eosinophil, macrophage, or lymphocyte accumulation. Furthermore, IL13-induced production of MMP2 (120360), MMP9, MMP13 (600108), and MMP14 was found to be dependent on MMP12.

In a culture of murine cerebral endothelial cells, Lee et al. (2003) found that amyloid beta peptide (APP; 104760) induced the synthesis, release, and activation of MMP9, resulting in increased extracellular matrix degradation. In the brains of transgenic mice expressing an APP mutation associated with increased amyloid deposition, similar to that found in cerebral amyloid angiopathy (CAA) (see 105150), MMP9 immunoreactivity was detected at 79% of the sites of microhemorrhage. Lee et al. (2003) concluded that vascular MMP9 expression, induced by amyloid beta deposition, may contribute to the development of spontaneous intracerebral hemorrhage in CAA.

Gursoy-Ozdemir et al. (2004) induced cortical spreading depression (CSD) in wildtype rats and mice and in Mmp9 null mice. In the wildtype animals, they found increased Mmp9 levels within 3 to 6 hours in the cortex ipsilateral to the CSD. Gelatinolytic activity and plasma protein leakage were detected at 30 minutes and 3 hours after CSD, respectively; both were suppressed by injection of a metalloprotease inhibitor. Protein leakage was not detected in Mmp9 null mice. Gursoy-Ozdemir et al. (2004) concluded that intense neuronal and glial depolarization initiates a cascade that disrupts the blood-brain barrier via an MMP9-dependent mechanism.

Using mesenteric resistance arteries from wildtype and Mmp9 -/- mice, Su et al. (2006) found that inhibition of Mmp2/Mmp9 significantly decreased myogenic tone in wildtype, but not Mmp9 -/- mice. Enos (NOS3; 163729) expression was also increased in Mmp9 -/- mice. Pharmacologic inhibition of Enos significantly decreased endothelium response to shear stress, which was more pronounced in Mmp9 -/- resistance arteries. Su et al. (2006) concluded that MMP9 has a selective effect on endothelium function.

Taylor et al. (2006) reported that a mouse strain (C57BL/6) with greater resistance to Mycobacterium tuberculosis infection expressed higher levels of active Mmp9 protein than a susceptible strain (CBA/J). They suggested that expression of active Mmp9 may have facilitated early dissemination of M. tuberculosis, which was associated with induction of Th1-type immunity and protection in C57BL/6 mice. Blocking of Mmp9 with a broad spectrum inhibitor reduced early dissemination. Mice lacking Mmp9 and infected with M. tuberculosis were less able to recruit macrophages to lungs and to initiate tissue remodeling that would facilitate development of well-formed granulomas.

In aneurysmal aortic tissue from Fbn1 (134797)-deficient mice, a model of Marfan syndrome (154700), Chung et al. (2007) found upregulation of Mmp2 and Mmp9, accompanied by severe elastic fiber fragmentation and degradation. Contractile force in response to depolarization or receptor stimulation was 50 to 80% lower in the aneurysmal thoracic aorta compared to controls, but the expression of alpha-smooth muscle actin (ACTC1; 102540) in the aorta of Marfan and wildtype mice was not significantly different. Chung et al. (2007) concluded that MMP2 and MMP9 are upregulated during thoracic aortic aneurysm formation in Marfan syndrome, and that the resulting elastic fiber degeneration with deterioration of aortic contraction and mechanical properties might explain the pathogenesis of thoracic aortic aneurysm.

In a mouse model of chronic neuropathic pain induced by spinal cord ligation, Kawasaki et al. (2008) found rapid and transient increased expression of Mmp9 in injured dorsal root ganglion primary sensory neurons. Upregulation of Mmp2 showed a delayed response in dorsal root ganglion satellite cells and spinal astrocytes. Local inhibition of Mmp9 inhibited the early phase of neuropathic pain and inhibition of Mmp2 suppressed the later phase of neuropathic pain. Intrathecal administration of either Mmp9 or Mmp2 produced pain symptoms. Mmp9-null mice did not show early-phase mechanical allodynia, but pain developed on day 10. Further studies indicated that pain was associated with Mmp9 and Mmp2 cleavage of IL1B (147720), as well as activation of microglia and astrocytes. The findings indicated a temporal mechanism for neuropathic pain.

Volkman et al. (2010) noted that mycobacteria direct early granuloma formation via their region of difference-1 (RD1) locus that encodes the Esat6 secretion system-1 (Esx1), which consists of at least 10 genes, including Esat6. Using zebrafish infected with Mycobacterium marinum as a model of tuberculous granuloma formation, Volkman et al. (2010) showed that the 6-kD Esat6 protein induced production of Mmp9 by epithelial cells neighboring infected macrophages as demonstrated by confocal microscopy. Mmp9 enhances the recruitment of macrophages that form an early granuloma, which instead of curtailing infection allows for the initial expansion of bacterial numbers. Mycobacterium marinum lacking the RD1 locus failed to induce Mmp9 and granulomas. Transient knockdown of Mmp9 expression in zebrafish reduced granuloma formation and bacterial burden. Injection of Esat6 into fish lacking macrophages also resulted in epithelial cell Mmp9 production in a Tnf 191160- and Myd88 602170-independent manner. Volkman et al. (2010) proposed that interception of MMP9 may be broadly useful in treating a variety of inflammatory conditions and tuberculosis. Agarwal and Bishai (2010) noted that Esat6 targeting could be an antivirulence strategy analogous to antitoxin therapy and that MMP9 inhibition, like corticosteroid treatment of tuberculous meningitis (see Price et al. (2001)) could augment antibiotic treatment.


ALLELIC VARIANTS ( 2 Selected Examples):

.0001 METAPHYSEAL ANADYSPLASIA 2, AUTOSOMAL RECESSIVE

MMP9, MET1LYS
  
RCV000018642...

In 2 sibs of a nonconsanguineous Pakistani family segregating metaphyseal anadysplasia (MANDP2; 613073), Lausch et al. (2009) identified homozygosity for a 21T-A transversion in exon 1 of the MMP9 gene, resulting in a met1-to-lys (M1K) substitution. As the next AUG providing a putative aberrant initiation site in the mRNA sequence is located 177 nucleotides downstream, the mutation is likely to ablate translation of a functional proMMP9 protein. The parents were heterozygous for the mutation and unaffected sibs were heterozygous or homozygous wildtype. The mutation was not present among 228 alleles of unaffected controls.


.0002 METAPHYSEAL ANADYSPLASIA 2, AUTOSOMAL RECESSIVE

MMP9, TRP588TER
  
RCV000778634...

By targeted next-generation sequencing of a skeletal dysplasia gene panel in a Spanish boy with metaphyseal anadysplasia-2 (MANDP2; 613073), Bonilla-Fornes et al. (2021) identified a homozygous c.1764G-A transition (c.1764G-A, NM_004994.2) in exon 11 of the MMP9 gene, predicted to cause a premature stop codon that may result in a truncated protein or nonsense-mediated mRNA decay. The variant was present in heterozygous state (14/165,172 alleles) in the gnomAD database at a minor allele frequency of 0.00084. Bonilla-Fornes et al. (2021) classified the variant as pathogenic according to ACMG guidelines.


REFERENCES

  1. Agarwal, N., Bishai, W. R. Microbiology: Subversion from the sidelines. Science 327: 417-418, 2010. [PubMed: 20093460, related citations] [Full Text]

  2. Ardi, V. C., Kupriyanova, T. A., Deryugina, E. I., Quigley, J. P. Human neutrophils uniquely release TIMP-free MMP-9 to provide a potent catalytic stimulator of angiogenesis. Proc. Nat. Acad. Sci. 104: 20262-20267, 2007. [PubMed: 18077379, images, related citations] [Full Text]

  3. Bonafe, L., Liang, J., Gorna, M. W., Zhang, Q., Ha-Vinh, R., Campos-Xavier, A. B., Unger, S., Beckmann, J. S., Le Bechec, A., Stevenson, B., Giedion, A., Liu, X., Superti-Furga, G., Wang, W., Spahr, A., Superti-Furga, A. MMP13 mutations are the cause of recessive metaphyseal dysplasia, Spahr type. Am. J. Med. Genet. 164A: 1175-1179, 2014. [PubMed: 24648384, related citations] [Full Text]

  4. Bonilla-Fornes, S., Galan-Ledesma, L., Mendea Perez, P., Modamio-Hoybjor, S., Carbonell-Perez, J. M., Parron-Pajares, M., Heath, K. E., Galan-Gomez, E. Early clinical and radiological improvement in a young boy with metaphyseal anadysplasia type 2. Europ. J. Med. Genet. 64: 104307, 2021. [PubMed: 34407464, related citations] [Full Text]

  5. Chung, A. W. Y., Au Yeung, K., Sandor, G. G. S., Judge, D. P., Dietz, H. C., van Breemen, C. Loss of elastic fiber integrity and reduction of vascular smooth muscle contraction resulting from the upregulated activities of matrix metalloproteinase-2 and -9 in the thoracic aortic aneurysm in Marfan syndrome. Circ. Res. 101: 512-522, 2007. [PubMed: 17641224, related citations] [Full Text]

  6. Collier, I. E., Bruns, G. A. P., Goldberg, G. I., Gerhard, D. S. On the structure and chromosome location of the 72- and 92-kDa human type IV collagenase genes. Genomics 9: 429-434, 1991. [PubMed: 1851724, related citations] [Full Text]

  7. Coussens, L. M., Tinkle, C. L., Hanahan, D., Werb, Z. MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis. Cell 103: 481-490, 2000. [PubMed: 11081634, images, related citations] [Full Text]

  8. Dubois, B., Masure, S., Hurtenbach, U., Paemen, L., Heremans, H., van den Oord, J., Sciot, R., Meinhardt, T., Hammerling, G., Opdenakker, G., Arnold, B. Resistance of young gelatinase B-deficient mice to experimental autoimmune encephalomyelitis and necrotizing tail lesions. J. Clin. Invest. 104: 1507-1515, 1999. [PubMed: 10587514, images, related citations] [Full Text]

  9. Gijbels, K., Masure, S., Carton, H., Opdenakker, G. Gelatinase in the cerebrospinal fluid of patients with multiple sclerosis and other inflammatory neurological disorders. J. Neuroimmun. 41: 29-34, 1992. [PubMed: 1334098, related citations] [Full Text]

  10. Gong, Y., Hart, E., Shchurin, A., Hoover-Plow, J. Inflammatory macrophage migration requires MMP-9 activation by plasminogen in mice. J. Clin. Invest. 118: 3012-3024, 2008. [PubMed: 18677407, images, related citations] [Full Text]

  11. Gu, Z., Kaul, M., Yan, B., Kridel, S. J., Cui, J., Strongin, A., Smith, J. W., Liddington, R. C., Lipton, S. A. S-nitrosylation of matrix metalloproteinases: signaling pathway to neuronal cell death. Science 297: 1186-1190, 2002. [PubMed: 12183632, related citations] [Full Text]

  12. Gursoy-Ozdemir, Y., Qiu, J., Matsuoka, N., Bolay, H., Bermpohl, D., Jin, H., Wang, X., Rosenberg, G. A., Lo, E. H., Moskowitz, M. A. Cortical spreading depression activates and upregulates MMP-9. J. Clin. Invest. 113: 1447-1455, 2004. [PubMed: 15146242, images, related citations] [Full Text]

  13. Heissig, B., Hattori, K., Dias, S., Friedrich, M., Ferris, B., Hackett, N. R., Crystal, R. G., Besmer, P., Lyden, D., Moore, M. A. S., Werb, Z., Rafii, S. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of Kit-ligand. Cell 109: 625-637, 2002. [PubMed: 12062105, images, related citations] [Full Text]

  14. Hirose, Y., Chiba, K., Karasugi, T., Nakajima, M., Kawaguchi, Y., Mikami, Y., Furuichi, T., Mio, F., Miyake, A., Miyamoto, T., Ozaki, K., Takahashi, A., Mizuta, H., Kubo, T., Kimura, T., Tanaka, T., Toyama, Y., Ikegawa, S. A functional polymorphism in THBS2 that affects alternative splicing and MMP binding is associated with lumbar-disc herniation. Am. J. Hum. Genet. 82: 1122-1129, 2008. [PubMed: 18455130, images, related citations] [Full Text]

  15. Huhtala, P., Tuuttila, A., Chow, L. T., Lohi, J., Keski-Oja, J., Tryggvason, K. Complete structure of the human gene for 92-kDa type IV collagenase: divergent regulation of expression for the 92- and 72-kilodalton enzyme genes in HT-1080 cells. J. Biol. Chem. 266: 16485-16490, 1991. [PubMed: 1653238, related citations]

  16. Jacob, A., Jing, J., Lee, J., Schedin, P., Gilbert, S. M., Peden, A. A., Junutula, J. R., Prekeris, R. Rab40b regulates trafficking of MMP2 and MMP9 during invadopodia formation and invasion of breast cancer cells. J. Cell Sci. 126: 4647-4658, 2013. [PubMed: 23902685, images, related citations] [Full Text]

  17. Kanbe, N., Tanaka, A., Kanbe, M., Itakura, A., Kurosawa, M., Matsuda, H. Human mast cells produce matrix metalloproteinase 9. Europ. J. Immun. 29: 2645-2649, 1999. [PubMed: 10458779, related citations] [Full Text]

  18. Kawasaki, Y., Xu, Z.-Z., Wang, X., Park, J. Y., Zhuang, Z.-Y., Tan, P.-H., Gao, Y.-J., Roy, K., Corfas, G., Lo, E. H., Ji, R.-R. Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain. Nature Med. 14: 331-336, 2008. [PubMed: 18264108, images, related citations] [Full Text]

  19. Kelly, E. A. B., Busse, W. W., Jarjour, N. N. Increased matrix metalloproteinase-9 in the airway after allergen challenge. Am. J. Resp. Crit. Care Med. 162: 1157-1161, 2000. [PubMed: 10988146, related citations] [Full Text]

  20. Lanone, S., Zheng, T., Zhu, Z., Liu, W., Lee, C. G., Ma, B., Chen, Q., Homer, R. J., Wang, J., Rabach, L. A., Rabach, M. E., Shipley, J. M., Shapiro, S. D., Senior, R. M., Elias, J. A. Overlapping and enzyme-specific contributions of matrix metalloproteinases-9 and -12 in IL-13-induced inflammation and remodeling. J. Clin. Invest. 110: 463-474, 2002. [PubMed: 12189240, images, related citations] [Full Text]

  21. Laterveer, L., Lindley, I. J. D., Heemskerk, D. P. M., Camps, J. A. J., Pauwels, E. K. J., Willemze, R., Fibbe, W. E. Rapid mobilization of hematopoietic progenitor cells in Rhesus monkeys by a single intravenous injection of interleukin-8. Blood 87: 781-788, 1996. [PubMed: 8555503, related citations]

  22. Lausch, E., Keppler, R., Hilbert, K., Cormier-Daire, V., Nikkel, S., Nishimura, G., Unger, S., Spranger, J., Superti-Furga, A., Zabel, B. Mutations in MMP9 and MMP13 determine the mode of inheritance and the clinical spectrum of metaphyseal anadysplasia. Am. J. Hum. Genet. 85: 168-178, 2009. Erratum: Am. J. Hum. Genet. 85: 420 only, 2009. [PubMed: 19615667, images, related citations] [Full Text]

  23. Lee, J.-M., Yin, K., Hsin, I., Chen, S., Fryer, J. D., Holtzman, D. M., Hsu, C. Y., Xu, J. Matrix metalloproteinase-9 and spontaneous hemorrhage in an animal model of cerebral amyloid angiopathy. Ann. Neurol. 54: 379-382, 2003. [PubMed: 12953271, related citations] [Full Text]

  24. Linn, R., DuPont, B. R., Knight, C. B., Plaetke, R., Leach, R. J. Reassignment of the 92-kDa type IV collagenase gene (CLG4B) to human chromosome 20. Cytogenet. Cell Genet. 72: 159-161, 1996. [PubMed: 8978762, related citations] [Full Text]

  25. Matsuyama, A., Sakai, N., Ishigami, M., Hiraoka, H., Kashine, S., Hirata, A., Nakamura, T., Yamashita, S., Matsuzawa, Y. Matrix metalloproteinases as novel disease markers in Takayasu arteritis. Circulation 108: 1469-1473, 2003. [PubMed: 12952836, related citations] [Full Text]

  26. Minematsu, N., Nakamura, H., Tateno, H., Nakajima, T., Yamaguchi, K. Genetic polymorphism in matrix metalloproteinase-9 and pulmonary emphysema. Biochem. Biophys. Res. Commun. 289: 116-119, 2001. [PubMed: 11708786, related citations] [Full Text]

  27. Nagase, H., Barrett, A. J., Woessner, J. F., Jr. Nomenclature and glossary of the matrix metalloproteinases. Matrix Suppl. 1: 421-424, 1992. [PubMed: 1480083, related citations]

  28. Nair, R. R., Solway, J., Boyd, D. D. Expression cloning identifies transgelin (SM22) as a novel repressor of 92-kDa type IV collagenase (MMP-9) expression. J. Biol. Chem. 281: 26424-26436, 2006. [PubMed: 16835221, related citations] [Full Text]

  29. Nakashima, K., Hirota, T., Obara, K., Shimizu, M., Doi, S., Fujita, K., Shirakawa, T., Enomoto, T., Yoshihara, S., Ebisawa, M., Matsumoto, K., Saito, H., Suzuki, Y., Nakamura, Y., Tamari, M. A functional polymorphism in MMP-9 is associated with childhood atopic asthma. Biochem. Biophys. Res. Commun. 344: 300-307, 2006. [PubMed: 16631427, related citations] [Full Text]

  30. Opdenakker, G., Fibbe, W. E., Van Damme, J. The molecular basis of leukocytosis. Immun. Today 19: 182-189, 1998. [PubMed: 9577095, related citations] [Full Text]

  31. Opdenakker, G., Masure, S., Grillet, B., Van Damme, J. Cytokine-mediated regulation of human leukocyte gelatinases and role in arthritis. Lymphokine Cytokine Res. 10: 317-324, 1991. [PubMed: 1932376, related citations]

  32. Osman, M., Tortorella, M., Londei, M., Quaratino, S. Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases define the migratory characteristics of human monocyte-derived dendritic cells. Immunology 105: 73-82, 2002. [PubMed: 11849317, images, related citations] [Full Text]

  33. Pathak, S., Goldofsky, E., Vivas, E. X., Bonagura, V. R., Vambutas, A. IL-1-beta is overexpressed and aberrantly regulated in corticosteroid nonresponders with autoimmune inner ear disease. J. Immun. 186: 1870-1879, 2011. [PubMed: 21199898, images, related citations] [Full Text]

  34. Price, N. M., Farrar, J., Chau, T. T. H., Mai, N. T. H., Hien, T. T., Friedland, J. S. Identification of a matrix-degrading phenotype in human tuberculosis in vitro and in vivo. J. Immun. 166: 4223-4230, 2001. [PubMed: 11238675, related citations] [Full Text]

  35. Pruijt, J. F. M., Fibbe, W. E., Laterveer, L., Pieters, R. A., Lindley, I. J. D., Paemen, L., Masure, S., Willemze, R., Opdenakker, G. Prevention of interleukin-8-induced mobilization of hematopoietic progenitor cells in rhesus monkeys by inhibitory antibodies against the metalloproteinase gelatinase B (MMP-9). Proc. Nat. Acad. Sci. 96: 10863-10868, 1999. [PubMed: 10485917, images, related citations] [Full Text]

  36. St Jean, P. L., Zhang, X. C., Hart, B. K., Lamlum, H., Webster, M. W., Steed, D. L., Henney, A. M., Ferrell, R. E. Characterization of a dinucleotide repeat in the 92 kDa type IV collagenase gene (CLG4B), localization of CLG4B to chromosome 20 and the role of CLG4B in aortic aneurysmal disease. Ann. Hum. Genet. 59: 17-24, 1995. [PubMed: 7762981, related citations] [Full Text]

  37. Su, J., Palen, D. I., Lucchesi, P. A., Matrougui, K. Mice lacking the gene encoding for MMP-9 and resistance artery reactivity. Biochem. Biophys. Res. Commun. 349: 1177-1181, 2006. [PubMed: 16979597, related citations] [Full Text]

  38. Sundstrom, J., Evans, J. C., Benjamin, E. J., Levy, D., Larson, M. G., Sawyer, D. B., Siwik, D. A., Colucci, W. S., Sutherland, P., Wilson, P. W. F., Vasan, R. S. Relations of plasma matrix metalloproteinase-9 to clinical cardiovascular risk factors and echocardiographic left ventricular measures: the Framingham Heart Study. Circulation 109: 2850-2856, 2004. [PubMed: 15173025, related citations] [Full Text]

  39. Taylor, J. L., Hattle, J. M., Dreitz, S. A., Troudt, J. M., Izzo, L. S., Basaraba, R. J., Orme, I. M., Matrisian, L. M., Izzo, A. A. Role for matrix metalloproteinase 9 in granuloma formation during pulmonary Mycobacterium tuberculosis infection. Infect. Immunity. 74: 6135-6144, 2006. [PubMed: 16982845, images, related citations] [Full Text]

  40. Turner, H. E., Nagy, Z., Esiri, M. M., Harris, A. L., Wass, J. A. H. Role of matrix metalloproteinase 9 in pituitary tumor behavior. J. Clin. Endocr. Metab. 85: 2931-2935, 2000. [PubMed: 10946906, related citations] [Full Text]

  41. Ueda, M., Yamashita, Y., Takehara, M., Terai, Y., Kumagai, K., Ueki, K., Kanda, K., Yamaguchi, H., Akise, D., Hung, Y.-C., Ueki, M. Survivin gene expression in endometriosis. J. Clin. Endocr. Metab. 87: 3452-3459, 2002. [PubMed: 12107265, related citations] [Full Text]

  42. Van den Steen, P. E., Proost, P., Wuyts, A., Van Damme, J., Opdenakker, G. Neutrophil gelatinase B potentiates interleukin-8 tenfold by aminoterminal processing, whereas it degrades CTAP-III, PF-4, and GRO-alpha and leaves RANTES and MCP-2 intact. Blood 96: 2673-2681, 2000. [PubMed: 11023497, related citations]

  43. Volkman, H. E., Pozos, T. C., Zheng, J., Davis, J. M., Rawls, J. F., Ramakrishnan, L. Tuberculous granuloma induction via interaction of a bacterial secreted protein with host epithelium. Science 327: 466-469, 2010. [PubMed: 20007864, images, related citations] [Full Text]

  44. Vu, T. H., Shipley, J. M., Bergers, G., Berger, J. E., Helms, J. A., Hanahan, D., Shapiro, S. D., Senior, R. M., Werb, Z. MMP-9/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes. Cell 93: 411-422, 1998. [PubMed: 9590175, images, related citations] [Full Text]

  45. Wang, X., Lee, S.-R., Arai, K., Lee, S.-R., Tsuji, K., Rebeck, G. W., Lo, E. H. Lipoprotein receptor-mediated induction of matrix metalloproteinase by tissue plasminogen activator. Nature Med. 9: 1313-1317, 2003. [PubMed: 12960961, related citations] [Full Text]

  46. Yan, C., Wang, H., Toh, Y., Boyd, D. D. Repression of 92-kDa type IV collagenase expression by MTA1 is mediated through direct interactions with the promoter via a mechanism, which is both dependent on and independent of histone deacetylation. J. Biol. Chem. 278: 2309-2316, 2003. [PubMed: 12431981, related citations] [Full Text]

  47. Yu, Q., Stamenkovic, I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev. 14: 163-176, 2000. [PubMed: 10652271, images, related citations]

  48. Zhang, B., Henney, A., Eriksson, P., Hamsten, A., Watkins, H., Ye, S. Genetic variation at the matrix metalloproteinase-9 locus on chromosome 20q12.2-13.1. Hum. Genet. 105: 418-423, 1999. [PubMed: 10598806, related citations] [Full Text]

  49. Zhang, B., Ye, S., Herrmann, S.-M., Eriksson, P., de Maat, M., Evans, A., Arveiler, D., Luc, G., Cambien, F., Hamsten, A., Watkins, H., Henney, A. M. Functional polymorphism in the regulatory region of gelatinase B gene in relation to severity of coronary atherosclerosis. Circulation 99: 1788-1794, 1999. [PubMed: 10199873, related citations] [Full Text]


Kelly A. Przylepa - updated : 04/26/2022
Bao Lige - updated : 09/30/2021
Marla J. F. O'Neill - updated : 3/17/2015
Paul J. Converse - updated : 3/21/2012
Marla J. F. O'Neill - updated : 5/13/2010
Paul J. Converse - updated : 3/3/2010
Paul J. Converse - updated : 2/3/2010
Nara Sobreira - updated : 10/6/2009
Paul J. Converse - updated : 11/6/2008
Marla J. F. O'Neill - updated : 6/10/2008
Cassandra L. Kniffin - updated : 4/28/2008
Paul J. Converse - updated : 4/16/2008
Paul J. Converse - updated : 2/13/2006
Marla J. F. O'Neill - updated : 1/25/2006
Marla J. F. O'Neill - updated : 9/8/2004
Marla J. F. O'Neill - updated : 6/17/2004
Cassandra L. Kniffin - updated : 12/23/2003
Ada Hamosh - updated : 9/23/2003
Patricia A. Hartz - updated : 5/19/2003
John A. Phillips, III - updated : 12/6/2002
Stylianos E. Antonarakis - updated : 9/24/2002
Patricia A. Hartz - updated : 8/23/2002
Paul J. Converse - updated : 4/17/2002
Paul J. Converse - updated : 3/27/2002
Paul J. Converse - updated : 3/25/2002
Victor A. McKusick - updated : 1/14/2002
John A. Phillips, III - updated : 5/10/2001
Paul J. Converse - updated : 4/25/2001
Stylianos E. Antonarakis - updated : 11/21/2000
Paul J. Converse - updated : 7/28/2000
Victor A. McKusick - updated : 12/6/1999
Victor A. McKusick - updated : 10/29/1999
Stylianos E. Antonarakis - updated : 6/1/1998
Creation Date:
Victor A. McKusick : 3/6/1991
alopez : 10/03/2023
joanna : 10/03/2023
carol : 04/28/2022
carol : 04/26/2022
mgross : 09/30/2021
carol : 06/27/2019
alopez : 03/19/2015
mcolton : 3/17/2015
alopez : 12/11/2014
mgross : 4/3/2012
terry : 3/21/2012
wwang : 5/13/2010
mgross : 3/5/2010
mgross : 3/5/2010
terry : 3/3/2010
wwang : 2/3/2010
carol : 10/9/2009
terry : 10/6/2009
mgross : 11/12/2008
terry : 11/6/2008
carol : 6/11/2008
terry : 6/10/2008
wwang : 5/16/2008
ckniffin : 4/28/2008
mgross : 4/16/2008
mgross : 4/16/2008
mgross : 2/13/2006
wwang : 2/1/2006
terry : 1/25/2006
carol : 12/5/2005
terry : 3/14/2005
carol : 9/8/2004
carol : 6/21/2004
terry : 6/17/2004
tkritzer : 12/30/2003
ckniffin : 12/23/2003
alopez : 10/16/2003
alopez : 9/23/2003
alopez : 9/23/2003
mgross : 5/19/2003
alopez : 12/6/2002
mgross : 9/24/2002
mgross : 8/23/2002
mgross : 4/17/2002
mgross : 3/27/2002
mgross : 3/26/2002
terry : 3/25/2002
carol : 1/20/2002
mcapotos : 1/14/2002
mgross : 5/11/2001
terry : 5/10/2001
mgross : 4/25/2001
mgross : 11/21/2000
mgross : 7/28/2000
yemi : 2/18/2000
mgross : 12/8/1999
terry : 12/6/1999
terry : 11/30/1999
mgross : 11/17/1999
terry : 10/29/1999
carol : 6/2/1998
terry : 6/1/1998
psherman : 5/15/1998
mark : 9/4/1997
terry : 6/13/1996
terry : 6/7/1996
terry : 4/19/1995
carol : 4/7/1994
supermim : 3/16/1992
carol : 3/6/1991

* 120361

MATRIX METALLOPROTEINASE 9; MMP9


Alternative titles; symbols

COLLAGENASE TYPE IV-B; CLG4B
COLLAGENASE TYPE IV, 92-KD
COLLAGENASE TYPE V
GELATINASE, 92-KD
GELATINASE B; GELB


HGNC Approved Gene Symbol: MMP9

Cytogenetic location: 20q13.12     Genomic coordinates (GRCh38): 20:46,008,908-46,016,561 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
20q13.12 Metaphyseal anadysplasia 2 613073 Autosomal recessive 3

TEXT

Description

The 72- and 92-kD type IV collagenases are members of a group of secreted zinc metalloproteases which, in mammals, degrade the collagens of the extracellular matrix. Other members of this group include interstitial collagenase (MMP1; 120353) and stromelysin (MMP3; 185250). The 72-kD type IV collagenase (MMP2, or CLG4A; 120360) is secreted from normal skin fibroblasts, whereas the 92-kD collagenase (CLG4B) is produced by normal alveolar macrophages and granulocytes. The 92-kD type IV collagenase is also known as 92-kD gelatinase, type V collagenase, or matrix metalloproteinase-9 (MMP9); see the glossary of matrix metalloproteinases provided by Nagase et al. (1992).


Gene Structure

Both CLG4A and CLG4B have 13 exons and similar intron locations (Huhtala et al., 1991). The 13 exons of both CLG4A and CLG4B are 3 more than have been found in other members of this gene family. The extra exons encode the amino acids of the fibronectin-like domain, which has been found only in the 72- and 92-kD type IV collagenases.


Mapping

By hybridization to somatic cell hybrid DNAs, Collier et al. (1991) demonstrated that both CLG4A and CLG4B are situated on chromosome 16. However, St Jean et al. (1995) assigned CLG4B to chromosome 20. They did linkage mapping of the CLG4B locus in 10 CEPH reference pedigrees using a polymorphic dinucleotide repeat in the 5-prime flanking region of the gene. St Jean et al. (1995) observed lod scores of between 10.45 and 20.29 with markers spanning chromosome region 20q11.2-q13.1. Further support for assignment of CLG4B to chromosome 20 was provided by analysis of human/rodent somatic cell hybrids. Due to their similar gene structures, the CLG4B cDNA clone used in the mapping to chromosome 16 may have hybridized to CLG4A rather than to CLG4B on chromosome 20.

Linn et al. (1996) reassigned MMP9 (referred to as CLG4B by them) to chromosome 20 based on 3 different lines of evidence: screening of a somatic cell hybrid mapping panel, fluorescence in situ hybridization, and linkage analysis using a newly identified polymorphism. They also mapped mouse Clg4b to mouse chromosome 2, which has no known homology to human chromosome 16 but large regions of homology with human chromosome 20.


Gene Function

Laterveer et al. (1996) demonstrated that interleukin-8 (IL8; 146930) induces rapid mobilization of hematopoietic progenitor cells (HPCs) from the bone marrow of rhesus monkeys. Because activation of neutrophils by IL8 induces the release of MMP9, which is involved in the degradation of extracellular matrix molecules, Opdenakker et al. (1998) and Pruijt et al. (1999) hypothesized that MMP9 release might induce stem cell mobilization by cleaving matrix molecules to which stem cells are attached. Pruijt et al. (1999) showed that the mobilization of HPCs could be prevented by pretreatment with an inhibitory anti-gelatinase B antibody, indicating that MMP9 is involved as a mediator of the IL8-induced mobilization of HPCs. Van den Steen et al. (2000) showed that MMP9-mediated N-terminal cleavage of IL8 potentiates IL8 activation of neutrophils, as measured by increased intracellular calcium, MMP9 secretion, and neutrophil chemotaxis.

Yu and Stamenkovic (2000) identified a functional relationship between the hyaluronan receptor CD44 (107269), MMP9, and transforming growth factor-beta (TGFB; see 190180) in the control of tumor-associated tissue remodeling. They showed that several isoforms of CD44 expressed on murine mammary carcinoma cells provide cell surface docking receptors for proteolytically active MMP9. Localization of MMP9 to the cell surface is required to promote tumor invasion and angiogenesis. Cell surface expression of MMP9 stimulated the formation of capillary tubes by bovine microvascular endothelial cells. Yu and Stamenkovic (2000) demonstrated that MMP9 and MMP2 proteolytically cleave latent TGFB2 (190220), a mechanism required to activate TGFB. The authors suggested that the activation of TGFB may be part of the mechanism by which MMP9 activity induces or promotes angiogenesis.

Using substrate conversion assays, Opdenakker et al. (1991) and Gijbels et al. (1992) detected increased levels of MMP9 in arthritis patient synovial fluid and in multiple sclerosis patient cerebrospinal fluid, respectively. Price et al. (2001) detected a significantly higher concentration of MMP9 per leukocyte in cerebrospinal fluid from adult tuberculous meningitis patients than in patients with bacterial or viral meningitis. In vitro studies indicated that viable bacilli were not required to stimulate MMP9 production. In contrast to the changes in MMP9 expression, MMP2 and tissue inhibitor of metalloproteinase-1 (TIMP1; 305370) were constitutively expressed, and the latter did not oppose the MMP9 activity. Elevated MMP9 activity was related to unconsciousness, confusion, focal neurologic damage, and death in the tuberculous meningitis patients.

Using RT-PCR, gelatin zymography, and Western blot analysis, Kanbe et al. (1999) showed that cultured human mast cells expressed MMP9 mRNA following activation, and that culture supernatants produced a 92-kD MMP9 protein with gelatinolytic activity. Immunohistochemical analysis detected MMP9 in mast cells in human skin, lung, and synovial tissue. Kanbe et al. (1999) concluded that mast cells produce MMP9, which might contribute to extracellular matrix degradation and absorption in the process of allergic and nonallergic responses.

Using a monoclonal antibody on a series of well-characterized paraffin-embedded sections of pituitary tumors, Turner et al. (2000) investigated whether expression of MMP9 plays a role in allowing angiogenesis and invasion by different pituitary tumor types. They found that invasive macroprolactinomas were significantly more likely to express MMP9 than noninvasive macroprolactinomas. Invasive macroprolactinomas showed higher-density MMP9 staining than noninvasive tumors and normal pituitary gland, or between different sized prolactinomas. MMP9 expression was related to aggressive tumor behavior. The authors concluded that MMP9 expression is present in some invasive and recurrent pituitary adenomas and in the majority of pituitary carcinoma. While the mechanisms whereby MMP9 expression influences tumor recurrence and invasiveness, and its association with angiogenesis, remained to be elucidated, these observations suggested that a future potential therapeutic strategy for some pituitary tumors may be administration of a synthetic MMP9 inhibitor.

Concentrations of MMP9 are increased in the bronchoalveolar lavage fluid (BAL), sputum, bronchi, and serum of asthmatic subjects compared with normal individuals. Using segmental bronchoprovocation (SBP) and ELISA analysis of BAL from allergic subjects, Kelly et al. (2000) detected increased MMP9 48 hours after SBP in antigen-challenged patients compared with saline-challenged patients. TIMP1 inhibitor was also increased in all subjects, but the ratio of MMP9 to TIMP1 was significantly higher in the antigen-challenged group. No differences were found in serum. Immunocytochemical analysis demonstrated MMP9 expression primarily in neutrophils. Kelly et al. (2000) concluded that antigen may contribute not only to inflammation but also to eventual airway remodeling in asthma.

Osman et al. (2002) showed that mature dendritic cells (DCs) produce more MMP9 than do immature DCs, facilitating their hydroxaminic acid-inhibitable migration through gel in vitro and, presumably, through the extracellular matrix to monitor the antigenic environment in vivo. RT-PCR analysis indicated that the enhanced expression of MMP9 is correlated with a downregulation of TIMP1 and, particularly, TIMP2 (188825), while expression of TIMP3 (188826) is upregulated. The authors concluded that the balance of MMP and TIMP determines the net migratory capacity of DCs. They proposed that TIMP3 may be a marker for mature DCs.

Ueda et al. (2002) investigated survivin (603352) gene and protein expression in a tumor-like benign disease, endometriosis, and correlated them with apoptosis and invasive phenotype of endometriotic tissues. Gene expression levels of survivin, MMP2, MMP9, and MMP14 (600754) in 63 pigmented or nonpigmented endometriotic tissues surgically obtained from 35 women with endometriosis were compared with those in normal eutopic endometrium obtained from 12 women without endometriosis. Survivin, MMP2, MMP9, and MMP14 mRNA expression levels in clinically aggressive pigmented lesions were significantly higher than those in normal eutopic endometrium, and survivin gene expression in pigmented lesions was also higher than that in nonpigmented lesions (P less than 0.05). There was a close correlation between survivin and MMP2, MMP9, and MMP14 gene expression levels in 63 endometriotic tissues examined (P less than 0.01). The authors concluded that upregulation of survivin and MMPs may cooperatively contribute to survival and invasion of endometriosis.

Following enforced expression in a fibrosarcoma cell line, Yan et al. (2003) found that MTA1 (603526) repressed MMP9 expression. MTA1 directly bound the MMP9 promoter and repressed expression via both histone-dependent and -independent mechanisms.

Wang et al. (2003) demonstrated that tissue plasminogen activator (TPA; 173370) upregulates MMP9 in cell culture and in vivo. MMP9 levels were lower in TPA knockout compared with wildtype mice after focal cerebral ischemia. In human cerebral microvascular endothelial cells, MMP9 was upregulated when recombinant TPA was added. RNA interference suggested that this response was mediated by the LDL receptor-related protein (LRP1; 107770), which avidly binds TPA and possesses signaling properties.

Matsuyama et al. (2003) measured circulating levels of MMP2, MMP3, and MMP9 in 25 patients with Takayasu arteritis (207600) and 20 age- and sex-matched healthy controls. Levels of all 3 metalloproteinases were higher in patients with active disease than in controls (p less than 0.0001 for each), and MMP2 levels remained elevated even in remission. In contrast, an improvement in clinical signs and symptoms was associated with a marked reduction in circulating MMP3 and MMP9 levels in all patients (p less than 0.05). Matsuyama et al. (2003) concluded that MMP2 could be helpful in diagnosing Takayasu arteritis and that MMP3 and MMP9 could be used as activity markers for the disease.

In a study of 699 Framingham Study participants who had no history of heart failure or myocardial infarction and who underwent routine echocardiography, Sundstrom et al. (2004) found that detectable plasma MMP9 levels were associated with increased left ventricular dimensions and increased wall thickness in men. Sundstrom et al. (2004) suggested that plasma MMP9 level may be a marker for cardiac extracellular matrix degradation, a process involved in left ventricular remodeling.

Using an expression cloning strategy with HT1080 human fibrosarcoma cells, Nair et al. (2006) identified SM22 (TAGLN; 600818) as a regulator of MMP9 expression. Stable expression of SM22 in HT1080 cells repressed MMP9 expression, whereas suppression of SM22 via small interfering RNA in human lung fibroblasts enhanced MMP9 expression and enzymatic activity. Mmp9 expression was weak in wildtype mouse uterine tissue, which constitutively expresses Sm22, but it was strong in uterine tissue from Sm22 -/- mice. Mutation analysis indicated that the N-terminal calponin homology domain of SM22, but not the actin-binding domain, mediated MMP9 repression, probably through interference with ERK1 (MAPK3; 601795) and ERK2 (MAPK1; 176948) signaling. Nair et al. (2006) concluded that SM22, which often exhibits diminished expression in cancer, regulates MMP9 expression.

Using a modified angiogenic model, Ardi et al. (2007) demonstrated that intact human neutrophils, their granule contents, and, specifically, neutrophil MMP9 had potent proangiogenic activity in the absence of TIMP1.

Gong et al. (2008) found that Plg (173350) -/- mice displayed diminished macrophage trans-extracellular matrix (ECM) migration and decreased Mmp9 activation following induction of peritonitis. Injection of active Mmp9 rescued macrophage migration in Plg -/- mice. Macrophage migration and aneurysm formation were also reduced in Plg -/- mice induced to undergo abdominal aortic aneurysm (AAA). Administration of active Mmp9 to Plg -/- mice promoted macrophage infiltration and development of AAA. Gong et al. (2008) concluded that PLG regulates macrophage migration in inflammation via activation of MMP9, which in turn regulates the ability of macrophages to migrate across ECM.

Lausch et al. (2009) suggested that there is a functional link between MMP13 (600108) and MMP9 in the endochondral ossification, as impaired MMP9 protein function, caused by direct inactivation (in recessive disease due to MMP9 loss of function), impaired activation (in recessive disease due to MMP13 loss of function), or transcatalytic degradation (in dominant disease caused by MMP13 gain of function) appears to be a common downstream step in the pathogenesis of metaphyseal anadysplasia (MANDP1, 602111; MANDP2, 613073).

Pathak et al. (2011) studied plasma and peripheral blood cell expression of IL1B (147720), MMP9, soluble IL1R2 (147811), and IL17 (see 603149) in 47 patients with either autoimmune inner ear disease or sensorineural hearing loss of likely immunologic origin who were treated with corticosteroids. They found that 18 corticosteroid nonresponder patients expressed significantly higher levels of IL1B and MMP9, but not IL17 or soluble IL1R2, compared with clinically responsive patients. RT-PCR analysis showed that treating control blood cells with IL1B induced expression of MMP9. Treatment with the MMP9 catalytic domain plus dexamethasone, but not MMP9 alone, reciprocally induced IL1B expression. Treatment of cells with dexamethasone alone increased IL1R2 expression in cells and plasma, and IL1R2 expression was further increased with the addition of MMP9. In responder patient cells, treatment with dexamethasone reduced expression of IL1B and MMP9, whereas IL1B expression could only be reduced in nonresponder cells by treatment with anakinra, the soluble IL1R antagonist (IL1RN; 147679). Pathak et al. (2011) proposed that IL1B blockade may be a viable therapy for patients with autoimmune inner ear disease or sensorineural hearing loss that fail to respond to corticosteroids.

Using a knockdown screen in MDA-MB-231 human breast cancer cells, Jacob et al. (2013) identified RAB40B (619550) as a small monomeric GTPase required for secretion of MMP2 and MMP9. Secretion of MMP2 and MMP9 was not dependent on endocytic transport, but instead relied on transport from the trans-Golgi network through VAMP4 (606909)- and RAB40B-containing secretory vesicles. RAB40B knockdown not only decreased MMP2 and MMP9 secretion, but also resulted in mistargeting of MMP2 and MMP9 to lysosomes, where they were degraded. Further analysis demonstrated that RAB40B regulated MMP2 and MMP9 trafficking during invadopodia formation and was required for invadopodia-dependent extracellular matrix degradation.


Molecular Genetics

Metaphyseal Anadysplasia 2

Lausch et al. (2009) investigated the molecular basis of metaphyseal anadysplasia in 5 families. In affected members of a nonconsanguineous Pakistani family, they identified homozygosity for a mutation in the MMP9 gene (120361.0001); see MANDP2 (613073). In 3 other families, they identified heterozygous mutations in the MMP13 gene (600108.0002 and 600108.0003); see MANDP1 (602111). Lausch et al. (2009) found that recessive MANDP (MANDP2) is caused by homozygous loss of function of MMP9, whereas dominant MANDP (MANDP1) is caused by missense mutations in the prodomain of MMP13; these mutations determine autoactivation of MMP13 and intracellular degradation of both MMP13 and MMP9, resulting in a double enzymatic deficiency. In the fifth family studied by Lausch et al. (2009), the proband (patient 11) was homozygous for a missense mutation in the MMP13 gene (H213N; 600108.0004). Bonafe et al. (2014) stated that although this Moroccan boy was initially diagnosed as having a recessive form of MANDP1, he could be retrospectively diagnosed with the Spahr type of metaphyseal dysplasia (MDST; 250400).

By targeted next-generation sequencing of a skeletal dysplasia gene panel in a Spanish boy with scoliosis, genu varum, and metaphyseal abnormalities, Bonilla-Fornes et al. (2021) identified a homozygous nonsense mutation in the MMP9 gene (W588X; 120361.0002). The parents were confirmed by Sanger sequencing to be heterozygous for the mutation.

Associations Pending Confirmation

Zhang et al. (1999) showed that a polymorphism (-1562C-T) in the promoter region of the MMP9 gene has a functional effect on transcription and is associated with the severity of the atherosclerosis in patients with coronary artery disease. Prompted by this, Zhang et al. (1999) cataloged sequence variants in the 2.2-kb promoter sequence and all 13 exons (totaling 3.3 kb) of the MMP9 gene. They identified a total of 10 variable sites, 4 in the promoter region, 5 in the coding region (3 of which altered the amino acid encoded), and 1 in the 3-prime untranslated sequence. Sequence inspection suggested that some of the variants would have a functional impact on either level of expression or enzymatic activity. Tight linkage disequilibrium was detected between variants across the entire length of the gene, and frequencies of different haplotypes were determined.

Minematsu et al. (2001) noted that it had recently been suggested that matrix metalloproteinases play roles in the pathogenesis of pulmonary emphysema. MMP9 and MMP12 (601046) account for most of the macrophage-derived elastase activity in smokers. Minematsu et al. (2001) studied the association between a functional polymorphism of MMP9, -1562C-T, and the development of pulmonary emphysema in 110 smokers and 94 nonsmokers in Japan. The T allele frequency was higher in 45 smokers with distinct emphysema on chest CT scans than in 65 smokers without it (0.244 vs 0.123; p = 0.02). The results suggested that the polymorphism of MMP9 acts as a genetic factor for the development of smoking-induced pulmonary emphysema.

By sequencing all 13 MMP9 exons and flanking regions in 290 Japanese pediatric atopic asthma patients and 638 healthy Japanese controls, Nakashima et al. (2006) identified 17 SNPs and selected 5 of these for association studies. Significant associations with risk of pediatric atopic asthma were found for a 2127G-T SNP in intron 4 and a nonsynonymous SNP, 5546G-A (arg668 to gln; R668Q), in exon 12 (p of 0.0032 and 0.0016, respectively). The haplotype containing 2127T and 5546A was also associated with atopia (p of 0.0053). Treatment of normal human bronchial epithelial cells showed that poly(I:C) was the only Toll-like receptor (TLR; see 601194) agonist that enhanced MMP9 expression. Reporter analysis showed increased activity with the MMP9 -1590C-T promoter SNP, which is in strong linkage disequilibrium with 2127G-T. Nakashima et al. (2006) concluded that MMP9 has an important role in asthma.

In a case-control association study involving 2 independent Japanese cohorts, Hirose et al. (2008) found a significant association between a missense SNP in the MMP9 gene (G279R; rs17576) and lumbar disc herniation (LDH; 603932). An intronic SNP in the THBS2 gene (rs9406328; 188061.0001) was also strongly associated with LDH in the Japanese population and showed a combinatorial effect with MMP9, with an odds ratio of 3.03 for the genotype that was homozygous for the susceptibility alleles of both SNPs.


Animal Model

By targeted disruption in embryonic stem cells, Vu et al. (1998) created homozygous mice with a null mutation in the MMP9/gelatinase B gene. These mice exhibited an abnormal pattern of skeletal growth plate vascularization and ossification. Although hypertrophic chondrocytes developed normally, apoptosis, vascularization, and ossification were delayed, resulting in progressive lengthening of the growth plate to about 8 times normal. After 3 weeks postnatal, aberrant apoptosis, vascularization, and ossification compensated to remodel the enlarged growth plate and ultimately produced an axial skeleton of normal appearance. Transplantation of wildtype bone marrow cells rescued vascularization and ossification in Mmp9-null growth plates, indicating that these processes are mediated by Mmp9-expressing cells of bone marrow origin, designated chondroclasts. Growth plates from Mmp9-null mice in culture showed a delayed release of an angiogenic activator, establishing a role for this proteinase in controlling angiogenesis.

Dubois et al. (1999) generated Mmp9-deficient mice by replacing the catalytic and zinc-binding domains with an antisense-oriented neomycin resistance gene. They determined that young Mmp9 -/- mice were resistant to the induction of experimental autoimmune encephalomyelitis (EAE). Adult Mmp9 -/- mice developed EAE, but unlike wildtype mice, they did not display necrotizing tail lesions with hyperplasia of osteocartilaginous tissue. Dubois et al. (1999) concluded that MMP9 is involved in immune system development and in the propensity to develop autoimmune disease.

Coussens et al. (2000) reported that transgenic mice lacking Mmp9 showed reduced keratinocyte hyperproliferation at all neoplastic stages and a decreased incidence of invasive tumors. However, those carcinomas that did arise in the absence of Mmp9 exhibited a greater loss of keratinocyte differentiation, indicative of a more aggressive and higher grade tumor. MMP9 is predominantly expressed in neutrophils, macrophages, and mast cells, rather than in oncogene-positive neoplastic cells. Chimeric mice expressing Mmp9 only in cells of hematopoietic origin, produced by bone marrow transplantation, reconstituted the MMP9-dependent contributions to squamous carcinogenesis. Thus, inflammatory cells can be coconspirators in carcinogenesis.

Gu et al. (2002) reported activation of Mmp9 by neuronal nitric oxide synthase (NOS1; 163731) in a mouse model of cerebral ischemia. Immunochemical analysis of the ischemic cortex following stroke in wildtype animals showed that activated Mmp9 colocalized with Nos1 within neurons. Activation of Mmp9 was abrogated after stroke in Nos1 null mice or in wildtype mice treated with an NOS inhibitor. Biochemical analysis and mass spectrometry revealed that MMP9 activation is initiated by NOS1 through S-nitrosylation of the Zn(2+)-coordinating cysteine within the active site of MMP9. Further oxidation causes irreversible modification of the residue to sulfinic or sulfonic acid. Gu et al. (2002) demonstrated that activated MMP9 leads to neuronal cell death. Treatment of cultured cerebrocortical neurons with NOS1-activated MMP9 increased apoptosis and detachment from the culture dish. Pretreatment with an MMP inhibitor blocked neuronal cell death.

MMP9, induced in bone marrow cells, releases soluble Kit ligand (KITLG; 184745), permitting the transfer of endothelial and hematopoietic stem cells (HSCs) from the quiescent to proliferative niche. Heissig et al. (2002) found that bone marrow ablation in wildtype Mmp9 mice induced Sdf1 (600835), which upregulated Mmp9 expression and caused shedding of Kitlg and recruitment of Kit (164920)-positive stem/progenitors. In Mmp9 -/- mice, release of Kitlg and HSC motility were impaired, resulting in failure of hematopoietic recovery and increased mortality, while exogenous Kitlg restored hematopoiesis and survival after bone marrow ablation. Release of Kitlg by Mmp9 enabled bone marrow repopulating cells to translocate to a permissive vascular niche favoring differentiation and reconstitution of the stem/progenitor cell pool.

By examining the effects of an Il13 (147683) transgene on wildtype mice and mice lacking Mmp9 or Mmp12, Lanone et al. (2002) determined that the IL13-mediated eosinophilic and lymphocytic inflammation and alveolar remodeling in the lung that occurs in asthma (600807), COPD (606963), and interstitial lung disease is dependent on both MMP9 and MMP12 mechanisms. The results indicated that MMP9 inhibits neutrophil accumulation, but, unlike MMP12, has no effect on eosinophil, macrophage, or lymphocyte accumulation. Furthermore, IL13-induced production of MMP2 (120360), MMP9, MMP13 (600108), and MMP14 was found to be dependent on MMP12.

In a culture of murine cerebral endothelial cells, Lee et al. (2003) found that amyloid beta peptide (APP; 104760) induced the synthesis, release, and activation of MMP9, resulting in increased extracellular matrix degradation. In the brains of transgenic mice expressing an APP mutation associated with increased amyloid deposition, similar to that found in cerebral amyloid angiopathy (CAA) (see 105150), MMP9 immunoreactivity was detected at 79% of the sites of microhemorrhage. Lee et al. (2003) concluded that vascular MMP9 expression, induced by amyloid beta deposition, may contribute to the development of spontaneous intracerebral hemorrhage in CAA.

Gursoy-Ozdemir et al. (2004) induced cortical spreading depression (CSD) in wildtype rats and mice and in Mmp9 null mice. In the wildtype animals, they found increased Mmp9 levels within 3 to 6 hours in the cortex ipsilateral to the CSD. Gelatinolytic activity and plasma protein leakage were detected at 30 minutes and 3 hours after CSD, respectively; both were suppressed by injection of a metalloprotease inhibitor. Protein leakage was not detected in Mmp9 null mice. Gursoy-Ozdemir et al. (2004) concluded that intense neuronal and glial depolarization initiates a cascade that disrupts the blood-brain barrier via an MMP9-dependent mechanism.

Using mesenteric resistance arteries from wildtype and Mmp9 -/- mice, Su et al. (2006) found that inhibition of Mmp2/Mmp9 significantly decreased myogenic tone in wildtype, but not Mmp9 -/- mice. Enos (NOS3; 163729) expression was also increased in Mmp9 -/- mice. Pharmacologic inhibition of Enos significantly decreased endothelium response to shear stress, which was more pronounced in Mmp9 -/- resistance arteries. Su et al. (2006) concluded that MMP9 has a selective effect on endothelium function.

Taylor et al. (2006) reported that a mouse strain (C57BL/6) with greater resistance to Mycobacterium tuberculosis infection expressed higher levels of active Mmp9 protein than a susceptible strain (CBA/J). They suggested that expression of active Mmp9 may have facilitated early dissemination of M. tuberculosis, which was associated with induction of Th1-type immunity and protection in C57BL/6 mice. Blocking of Mmp9 with a broad spectrum inhibitor reduced early dissemination. Mice lacking Mmp9 and infected with M. tuberculosis were less able to recruit macrophages to lungs and to initiate tissue remodeling that would facilitate development of well-formed granulomas.

In aneurysmal aortic tissue from Fbn1 (134797)-deficient mice, a model of Marfan syndrome (154700), Chung et al. (2007) found upregulation of Mmp2 and Mmp9, accompanied by severe elastic fiber fragmentation and degradation. Contractile force in response to depolarization or receptor stimulation was 50 to 80% lower in the aneurysmal thoracic aorta compared to controls, but the expression of alpha-smooth muscle actin (ACTC1; 102540) in the aorta of Marfan and wildtype mice was not significantly different. Chung et al. (2007) concluded that MMP2 and MMP9 are upregulated during thoracic aortic aneurysm formation in Marfan syndrome, and that the resulting elastic fiber degeneration with deterioration of aortic contraction and mechanical properties might explain the pathogenesis of thoracic aortic aneurysm.

In a mouse model of chronic neuropathic pain induced by spinal cord ligation, Kawasaki et al. (2008) found rapid and transient increased expression of Mmp9 in injured dorsal root ganglion primary sensory neurons. Upregulation of Mmp2 showed a delayed response in dorsal root ganglion satellite cells and spinal astrocytes. Local inhibition of Mmp9 inhibited the early phase of neuropathic pain and inhibition of Mmp2 suppressed the later phase of neuropathic pain. Intrathecal administration of either Mmp9 or Mmp2 produced pain symptoms. Mmp9-null mice did not show early-phase mechanical allodynia, but pain developed on day 10. Further studies indicated that pain was associated with Mmp9 and Mmp2 cleavage of IL1B (147720), as well as activation of microglia and astrocytes. The findings indicated a temporal mechanism for neuropathic pain.

Volkman et al. (2010) noted that mycobacteria direct early granuloma formation via their region of difference-1 (RD1) locus that encodes the Esat6 secretion system-1 (Esx1), which consists of at least 10 genes, including Esat6. Using zebrafish infected with Mycobacterium marinum as a model of tuberculous granuloma formation, Volkman et al. (2010) showed that the 6-kD Esat6 protein induced production of Mmp9 by epithelial cells neighboring infected macrophages as demonstrated by confocal microscopy. Mmp9 enhances the recruitment of macrophages that form an early granuloma, which instead of curtailing infection allows for the initial expansion of bacterial numbers. Mycobacterium marinum lacking the RD1 locus failed to induce Mmp9 and granulomas. Transient knockdown of Mmp9 expression in zebrafish reduced granuloma formation and bacterial burden. Injection of Esat6 into fish lacking macrophages also resulted in epithelial cell Mmp9 production in a Tnf 191160- and Myd88 602170-independent manner. Volkman et al. (2010) proposed that interception of MMP9 may be broadly useful in treating a variety of inflammatory conditions and tuberculosis. Agarwal and Bishai (2010) noted that Esat6 targeting could be an antivirulence strategy analogous to antitoxin therapy and that MMP9 inhibition, like corticosteroid treatment of tuberculous meningitis (see Price et al. (2001)) could augment antibiotic treatment.


ALLELIC VARIANTS 2 Selected Examples):

.0001   METAPHYSEAL ANADYSPLASIA 2, AUTOSOMAL RECESSIVE

MMP9, MET1LYS
SNP: rs121434556, gnomAD: rs121434556, ClinVar: RCV000018642, RCV001851918

In 2 sibs of a nonconsanguineous Pakistani family segregating metaphyseal anadysplasia (MANDP2; 613073), Lausch et al. (2009) identified homozygosity for a 21T-A transversion in exon 1 of the MMP9 gene, resulting in a met1-to-lys (M1K) substitution. As the next AUG providing a putative aberrant initiation site in the mRNA sequence is located 177 nucleotides downstream, the mutation is likely to ablate translation of a functional proMMP9 protein. The parents were heterozygous for the mutation and unaffected sibs were heterozygous or homozygous wildtype. The mutation was not present among 228 alleles of unaffected controls.


.0002   METAPHYSEAL ANADYSPLASIA 2, AUTOSOMAL RECESSIVE

MMP9, TRP588TER
SNP: rs200746714, gnomAD: rs200746714, ClinVar: RCV000778634, RCV001869136

By targeted next-generation sequencing of a skeletal dysplasia gene panel in a Spanish boy with metaphyseal anadysplasia-2 (MANDP2; 613073), Bonilla-Fornes et al. (2021) identified a homozygous c.1764G-A transition (c.1764G-A, NM_004994.2) in exon 11 of the MMP9 gene, predicted to cause a premature stop codon that may result in a truncated protein or nonsense-mediated mRNA decay. The variant was present in heterozygous state (14/165,172 alleles) in the gnomAD database at a minor allele frequency of 0.00084. Bonilla-Fornes et al. (2021) classified the variant as pathogenic according to ACMG guidelines.


REFERENCES

  1. Agarwal, N., Bishai, W. R. Microbiology: Subversion from the sidelines. Science 327: 417-418, 2010. [PubMed: 20093460] [Full Text: https://doi.org/10.1126/science.1185569]

  2. Ardi, V. C., Kupriyanova, T. A., Deryugina, E. I., Quigley, J. P. Human neutrophils uniquely release TIMP-free MMP-9 to provide a potent catalytic stimulator of angiogenesis. Proc. Nat. Acad. Sci. 104: 20262-20267, 2007. [PubMed: 18077379] [Full Text: https://doi.org/10.1073/pnas.0706438104]

  3. Bonafe, L., Liang, J., Gorna, M. W., Zhang, Q., Ha-Vinh, R., Campos-Xavier, A. B., Unger, S., Beckmann, J. S., Le Bechec, A., Stevenson, B., Giedion, A., Liu, X., Superti-Furga, G., Wang, W., Spahr, A., Superti-Furga, A. MMP13 mutations are the cause of recessive metaphyseal dysplasia, Spahr type. Am. J. Med. Genet. 164A: 1175-1179, 2014. [PubMed: 24648384] [Full Text: https://doi.org/10.1002/ajmg.a.36431]

  4. Bonilla-Fornes, S., Galan-Ledesma, L., Mendea Perez, P., Modamio-Hoybjor, S., Carbonell-Perez, J. M., Parron-Pajares, M., Heath, K. E., Galan-Gomez, E. Early clinical and radiological improvement in a young boy with metaphyseal anadysplasia type 2. Europ. J. Med. Genet. 64: 104307, 2021. [PubMed: 34407464] [Full Text: https://doi.org/10.1016/j.ejmg.2021.104307]

  5. Chung, A. W. Y., Au Yeung, K., Sandor, G. G. S., Judge, D. P., Dietz, H. C., van Breemen, C. Loss of elastic fiber integrity and reduction of vascular smooth muscle contraction resulting from the upregulated activities of matrix metalloproteinase-2 and -9 in the thoracic aortic aneurysm in Marfan syndrome. Circ. Res. 101: 512-522, 2007. [PubMed: 17641224] [Full Text: https://doi.org/10.1161/CIRCRESAHA.107.157776]

  6. Collier, I. E., Bruns, G. A. P., Goldberg, G. I., Gerhard, D. S. On the structure and chromosome location of the 72- and 92-kDa human type IV collagenase genes. Genomics 9: 429-434, 1991. [PubMed: 1851724] [Full Text: https://doi.org/10.1016/0888-7543(91)90408-7]

  7. Coussens, L. M., Tinkle, C. L., Hanahan, D., Werb, Z. MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis. Cell 103: 481-490, 2000. [PubMed: 11081634] [Full Text: https://doi.org/10.1016/s0092-8674(00)00139-2]

  8. Dubois, B., Masure, S., Hurtenbach, U., Paemen, L., Heremans, H., van den Oord, J., Sciot, R., Meinhardt, T., Hammerling, G., Opdenakker, G., Arnold, B. Resistance of young gelatinase B-deficient mice to experimental autoimmune encephalomyelitis and necrotizing tail lesions. J. Clin. Invest. 104: 1507-1515, 1999. [PubMed: 10587514] [Full Text: https://doi.org/10.1172/JCI6886]

  9. Gijbels, K., Masure, S., Carton, H., Opdenakker, G. Gelatinase in the cerebrospinal fluid of patients with multiple sclerosis and other inflammatory neurological disorders. J. Neuroimmun. 41: 29-34, 1992. [PubMed: 1334098] [Full Text: https://doi.org/10.1016/0165-5728(92)90192-n]

  10. Gong, Y., Hart, E., Shchurin, A., Hoover-Plow, J. Inflammatory macrophage migration requires MMP-9 activation by plasminogen in mice. J. Clin. Invest. 118: 3012-3024, 2008. [PubMed: 18677407] [Full Text: https://doi.org/10.1172/JCI32750]

  11. Gu, Z., Kaul, M., Yan, B., Kridel, S. J., Cui, J., Strongin, A., Smith, J. W., Liddington, R. C., Lipton, S. A. S-nitrosylation of matrix metalloproteinases: signaling pathway to neuronal cell death. Science 297: 1186-1190, 2002. [PubMed: 12183632] [Full Text: https://doi.org/10.1126/science.1073634]

  12. Gursoy-Ozdemir, Y., Qiu, J., Matsuoka, N., Bolay, H., Bermpohl, D., Jin, H., Wang, X., Rosenberg, G. A., Lo, E. H., Moskowitz, M. A. Cortical spreading depression activates and upregulates MMP-9. J. Clin. Invest. 113: 1447-1455, 2004. [PubMed: 15146242] [Full Text: https://doi.org/10.1172/JCI21227]

  13. Heissig, B., Hattori, K., Dias, S., Friedrich, M., Ferris, B., Hackett, N. R., Crystal, R. G., Besmer, P., Lyden, D., Moore, M. A. S., Werb, Z., Rafii, S. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of Kit-ligand. Cell 109: 625-637, 2002. [PubMed: 12062105] [Full Text: https://doi.org/10.1016/s0092-8674(02)00754-7]

  14. Hirose, Y., Chiba, K., Karasugi, T., Nakajima, M., Kawaguchi, Y., Mikami, Y., Furuichi, T., Mio, F., Miyake, A., Miyamoto, T., Ozaki, K., Takahashi, A., Mizuta, H., Kubo, T., Kimura, T., Tanaka, T., Toyama, Y., Ikegawa, S. A functional polymorphism in THBS2 that affects alternative splicing and MMP binding is associated with lumbar-disc herniation. Am. J. Hum. Genet. 82: 1122-1129, 2008. [PubMed: 18455130] [Full Text: https://doi.org/10.1016/j.ajhg.2008.03.013]

  15. Huhtala, P., Tuuttila, A., Chow, L. T., Lohi, J., Keski-Oja, J., Tryggvason, K. Complete structure of the human gene for 92-kDa type IV collagenase: divergent regulation of expression for the 92- and 72-kilodalton enzyme genes in HT-1080 cells. J. Biol. Chem. 266: 16485-16490, 1991. [PubMed: 1653238]

  16. Jacob, A., Jing, J., Lee, J., Schedin, P., Gilbert, S. M., Peden, A. A., Junutula, J. R., Prekeris, R. Rab40b regulates trafficking of MMP2 and MMP9 during invadopodia formation and invasion of breast cancer cells. J. Cell Sci. 126: 4647-4658, 2013. [PubMed: 23902685] [Full Text: https://doi.org/10.1242/jcs.126573]

  17. Kanbe, N., Tanaka, A., Kanbe, M., Itakura, A., Kurosawa, M., Matsuda, H. Human mast cells produce matrix metalloproteinase 9. Europ. J. Immun. 29: 2645-2649, 1999. [PubMed: 10458779] [Full Text: https://doi.org/10.1002/(SICI)1521-4141(199908)29:08<2645::AID-IMMU2645>3.0.CO;2-1]

  18. Kawasaki, Y., Xu, Z.-Z., Wang, X., Park, J. Y., Zhuang, Z.-Y., Tan, P.-H., Gao, Y.-J., Roy, K., Corfas, G., Lo, E. H., Ji, R.-R. Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain. Nature Med. 14: 331-336, 2008. [PubMed: 18264108] [Full Text: https://doi.org/10.1038/nm1723]

  19. Kelly, E. A. B., Busse, W. W., Jarjour, N. N. Increased matrix metalloproteinase-9 in the airway after allergen challenge. Am. J. Resp. Crit. Care Med. 162: 1157-1161, 2000. [PubMed: 10988146] [Full Text: https://doi.org/10.1164/ajrccm.162.3.9908016]

  20. Lanone, S., Zheng, T., Zhu, Z., Liu, W., Lee, C. G., Ma, B., Chen, Q., Homer, R. J., Wang, J., Rabach, L. A., Rabach, M. E., Shipley, J. M., Shapiro, S. D., Senior, R. M., Elias, J. A. Overlapping and enzyme-specific contributions of matrix metalloproteinases-9 and -12 in IL-13-induced inflammation and remodeling. J. Clin. Invest. 110: 463-474, 2002. [PubMed: 12189240] [Full Text: https://doi.org/10.1172/JCI14136]

  21. Laterveer, L., Lindley, I. J. D., Heemskerk, D. P. M., Camps, J. A. J., Pauwels, E. K. J., Willemze, R., Fibbe, W. E. Rapid mobilization of hematopoietic progenitor cells in Rhesus monkeys by a single intravenous injection of interleukin-8. Blood 87: 781-788, 1996. [PubMed: 8555503]

  22. Lausch, E., Keppler, R., Hilbert, K., Cormier-Daire, V., Nikkel, S., Nishimura, G., Unger, S., Spranger, J., Superti-Furga, A., Zabel, B. Mutations in MMP9 and MMP13 determine the mode of inheritance and the clinical spectrum of metaphyseal anadysplasia. Am. J. Hum. Genet. 85: 168-178, 2009. Erratum: Am. J. Hum. Genet. 85: 420 only, 2009. [PubMed: 19615667] [Full Text: https://doi.org/10.1016/j.ajhg.2009.06.014]

  23. Lee, J.-M., Yin, K., Hsin, I., Chen, S., Fryer, J. D., Holtzman, D. M., Hsu, C. Y., Xu, J. Matrix metalloproteinase-9 and spontaneous hemorrhage in an animal model of cerebral amyloid angiopathy. Ann. Neurol. 54: 379-382, 2003. [PubMed: 12953271] [Full Text: https://doi.org/10.1002/ana.10671]

  24. Linn, R., DuPont, B. R., Knight, C. B., Plaetke, R., Leach, R. J. Reassignment of the 92-kDa type IV collagenase gene (CLG4B) to human chromosome 20. Cytogenet. Cell Genet. 72: 159-161, 1996. [PubMed: 8978762] [Full Text: https://doi.org/10.1159/000134175]

  25. Matsuyama, A., Sakai, N., Ishigami, M., Hiraoka, H., Kashine, S., Hirata, A., Nakamura, T., Yamashita, S., Matsuzawa, Y. Matrix metalloproteinases as novel disease markers in Takayasu arteritis. Circulation 108: 1469-1473, 2003. [PubMed: 12952836] [Full Text: https://doi.org/10.1161/01.CIR.0000090689.69973.B1]

  26. Minematsu, N., Nakamura, H., Tateno, H., Nakajima, T., Yamaguchi, K. Genetic polymorphism in matrix metalloproteinase-9 and pulmonary emphysema. Biochem. Biophys. Res. Commun. 289: 116-119, 2001. [PubMed: 11708786] [Full Text: https://doi.org/10.1006/bbrc.2001.5936]

  27. Nagase, H., Barrett, A. J., Woessner, J. F., Jr. Nomenclature and glossary of the matrix metalloproteinases. Matrix Suppl. 1: 421-424, 1992. [PubMed: 1480083]

  28. Nair, R. R., Solway, J., Boyd, D. D. Expression cloning identifies transgelin (SM22) as a novel repressor of 92-kDa type IV collagenase (MMP-9) expression. J. Biol. Chem. 281: 26424-26436, 2006. [PubMed: 16835221] [Full Text: https://doi.org/10.1074/jbc.M602703200]

  29. Nakashima, K., Hirota, T., Obara, K., Shimizu, M., Doi, S., Fujita, K., Shirakawa, T., Enomoto, T., Yoshihara, S., Ebisawa, M., Matsumoto, K., Saito, H., Suzuki, Y., Nakamura, Y., Tamari, M. A functional polymorphism in MMP-9 is associated with childhood atopic asthma. Biochem. Biophys. Res. Commun. 344: 300-307, 2006. [PubMed: 16631427] [Full Text: https://doi.org/10.1016/j.bbrc.2006.03.102]

  30. Opdenakker, G., Fibbe, W. E., Van Damme, J. The molecular basis of leukocytosis. Immun. Today 19: 182-189, 1998. [PubMed: 9577095] [Full Text: https://doi.org/10.1016/s0167-5699(97)01243-7]

  31. Opdenakker, G., Masure, S., Grillet, B., Van Damme, J. Cytokine-mediated regulation of human leukocyte gelatinases and role in arthritis. Lymphokine Cytokine Res. 10: 317-324, 1991. [PubMed: 1932376]

  32. Osman, M., Tortorella, M., Londei, M., Quaratino, S. Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases define the migratory characteristics of human monocyte-derived dendritic cells. Immunology 105: 73-82, 2002. [PubMed: 11849317] [Full Text: https://doi.org/10.1046/j.0019-2805.2001.01349.x]

  33. Pathak, S., Goldofsky, E., Vivas, E. X., Bonagura, V. R., Vambutas, A. IL-1-beta is overexpressed and aberrantly regulated in corticosteroid nonresponders with autoimmune inner ear disease. J. Immun. 186: 1870-1879, 2011. [PubMed: 21199898] [Full Text: https://doi.org/10.4049/jimmunol.1002275]

  34. Price, N. M., Farrar, J., Chau, T. T. H., Mai, N. T. H., Hien, T. T., Friedland, J. S. Identification of a matrix-degrading phenotype in human tuberculosis in vitro and in vivo. J. Immun. 166: 4223-4230, 2001. [PubMed: 11238675] [Full Text: https://doi.org/10.4049/jimmunol.166.6.4223]

  35. Pruijt, J. F. M., Fibbe, W. E., Laterveer, L., Pieters, R. A., Lindley, I. J. D., Paemen, L., Masure, S., Willemze, R., Opdenakker, G. Prevention of interleukin-8-induced mobilization of hematopoietic progenitor cells in rhesus monkeys by inhibitory antibodies against the metalloproteinase gelatinase B (MMP-9). Proc. Nat. Acad. Sci. 96: 10863-10868, 1999. [PubMed: 10485917] [Full Text: https://doi.org/10.1073/pnas.96.19.10863]

  36. St Jean, P. L., Zhang, X. C., Hart, B. K., Lamlum, H., Webster, M. W., Steed, D. L., Henney, A. M., Ferrell, R. E. Characterization of a dinucleotide repeat in the 92 kDa type IV collagenase gene (CLG4B), localization of CLG4B to chromosome 20 and the role of CLG4B in aortic aneurysmal disease. Ann. Hum. Genet. 59: 17-24, 1995. [PubMed: 7762981] [Full Text: https://doi.org/10.1111/j.1469-1809.1995.tb01602.x]

  37. Su, J., Palen, D. I., Lucchesi, P. A., Matrougui, K. Mice lacking the gene encoding for MMP-9 and resistance artery reactivity. Biochem. Biophys. Res. Commun. 349: 1177-1181, 2006. [PubMed: 16979597] [Full Text: https://doi.org/10.1016/j.bbrc.2006.08.189]

  38. Sundstrom, J., Evans, J. C., Benjamin, E. J., Levy, D., Larson, M. G., Sawyer, D. B., Siwik, D. A., Colucci, W. S., Sutherland, P., Wilson, P. W. F., Vasan, R. S. Relations of plasma matrix metalloproteinase-9 to clinical cardiovascular risk factors and echocardiographic left ventricular measures: the Framingham Heart Study. Circulation 109: 2850-2856, 2004. [PubMed: 15173025] [Full Text: https://doi.org/10.1161/01.CIR.0000129318.79570.84]

  39. Taylor, J. L., Hattle, J. M., Dreitz, S. A., Troudt, J. M., Izzo, L. S., Basaraba, R. J., Orme, I. M., Matrisian, L. M., Izzo, A. A. Role for matrix metalloproteinase 9 in granuloma formation during pulmonary Mycobacterium tuberculosis infection. Infect. Immunity. 74: 6135-6144, 2006. [PubMed: 16982845] [Full Text: https://doi.org/10.1128/IAI.02048-05]

  40. Turner, H. E., Nagy, Z., Esiri, M. M., Harris, A. L., Wass, J. A. H. Role of matrix metalloproteinase 9 in pituitary tumor behavior. J. Clin. Endocr. Metab. 85: 2931-2935, 2000. [PubMed: 10946906] [Full Text: https://doi.org/10.1210/jcem.85.8.6754]

  41. Ueda, M., Yamashita, Y., Takehara, M., Terai, Y., Kumagai, K., Ueki, K., Kanda, K., Yamaguchi, H., Akise, D., Hung, Y.-C., Ueki, M. Survivin gene expression in endometriosis. J. Clin. Endocr. Metab. 87: 3452-3459, 2002. [PubMed: 12107265] [Full Text: https://doi.org/10.1210/jcem.87.7.8682]

  42. Van den Steen, P. E., Proost, P., Wuyts, A., Van Damme, J., Opdenakker, G. Neutrophil gelatinase B potentiates interleukin-8 tenfold by aminoterminal processing, whereas it degrades CTAP-III, PF-4, and GRO-alpha and leaves RANTES and MCP-2 intact. Blood 96: 2673-2681, 2000. [PubMed: 11023497]

  43. Volkman, H. E., Pozos, T. C., Zheng, J., Davis, J. M., Rawls, J. F., Ramakrishnan, L. Tuberculous granuloma induction via interaction of a bacterial secreted protein with host epithelium. Science 327: 466-469, 2010. [PubMed: 20007864] [Full Text: https://doi.org/10.1126/science.1179663]

  44. Vu, T. H., Shipley, J. M., Bergers, G., Berger, J. E., Helms, J. A., Hanahan, D., Shapiro, S. D., Senior, R. M., Werb, Z. MMP-9/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes. Cell 93: 411-422, 1998. [PubMed: 9590175] [Full Text: https://doi.org/10.1016/s0092-8674(00)81169-1]

  45. Wang, X., Lee, S.-R., Arai, K., Lee, S.-R., Tsuji, K., Rebeck, G. W., Lo, E. H. Lipoprotein receptor-mediated induction of matrix metalloproteinase by tissue plasminogen activator. Nature Med. 9: 1313-1317, 2003. [PubMed: 12960961] [Full Text: https://doi.org/10.1038/nm926]

  46. Yan, C., Wang, H., Toh, Y., Boyd, D. D. Repression of 92-kDa type IV collagenase expression by MTA1 is mediated through direct interactions with the promoter via a mechanism, which is both dependent on and independent of histone deacetylation. J. Biol. Chem. 278: 2309-2316, 2003. [PubMed: 12431981] [Full Text: https://doi.org/10.1074/jbc.M210369200]

  47. Yu, Q., Stamenkovic, I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev. 14: 163-176, 2000. [PubMed: 10652271]

  48. Zhang, B., Henney, A., Eriksson, P., Hamsten, A., Watkins, H., Ye, S. Genetic variation at the matrix metalloproteinase-9 locus on chromosome 20q12.2-13.1. Hum. Genet. 105: 418-423, 1999. [PubMed: 10598806] [Full Text: https://doi.org/10.1007/s004390051124]

  49. Zhang, B., Ye, S., Herrmann, S.-M., Eriksson, P., de Maat, M., Evans, A., Arveiler, D., Luc, G., Cambien, F., Hamsten, A., Watkins, H., Henney, A. M. Functional polymorphism in the regulatory region of gelatinase B gene in relation to severity of coronary atherosclerosis. Circulation 99: 1788-1794, 1999. [PubMed: 10199873] [Full Text: https://doi.org/10.1161/01.cir.99.14.1788]


Contributors:
Kelly A. Przylepa - updated : 04/26/2022
Bao Lige - updated : 09/30/2021
Marla J. F. O'Neill - updated : 3/17/2015
Paul J. Converse - updated : 3/21/2012
Marla J. F. O'Neill - updated : 5/13/2010
Paul J. Converse - updated : 3/3/2010
Paul J. Converse - updated : 2/3/2010
Nara Sobreira - updated : 10/6/2009
Paul J. Converse - updated : 11/6/2008
Marla J. F. O'Neill - updated : 6/10/2008
Cassandra L. Kniffin - updated : 4/28/2008
Paul J. Converse - updated : 4/16/2008
Paul J. Converse - updated : 2/13/2006
Marla J. F. O'Neill - updated : 1/25/2006
Marla J. F. O'Neill - updated : 9/8/2004
Marla J. F. O'Neill - updated : 6/17/2004
Cassandra L. Kniffin - updated : 12/23/2003
Ada Hamosh - updated : 9/23/2003
Patricia A. Hartz - updated : 5/19/2003
John A. Phillips, III - updated : 12/6/2002
Stylianos E. Antonarakis - updated : 9/24/2002
Patricia A. Hartz - updated : 8/23/2002
Paul J. Converse - updated : 4/17/2002
Paul J. Converse - updated : 3/27/2002
Paul J. Converse - updated : 3/25/2002
Victor A. McKusick - updated : 1/14/2002
John A. Phillips, III - updated : 5/10/2001
Paul J. Converse - updated : 4/25/2001
Stylianos E. Antonarakis - updated : 11/21/2000
Paul J. Converse - updated : 7/28/2000
Victor A. McKusick - updated : 12/6/1999
Victor A. McKusick - updated : 10/29/1999
Stylianos E. Antonarakis - updated : 6/1/1998

Creation Date:
Victor A. McKusick : 3/6/1991

Edit History:
alopez : 10/03/2023
joanna : 10/03/2023
carol : 04/28/2022
carol : 04/26/2022
mgross : 09/30/2021
carol : 06/27/2019
alopez : 03/19/2015
mcolton : 3/17/2015
alopez : 12/11/2014
mgross : 4/3/2012
terry : 3/21/2012
wwang : 5/13/2010
mgross : 3/5/2010
mgross : 3/5/2010
terry : 3/3/2010
wwang : 2/3/2010
carol : 10/9/2009
terry : 10/6/2009
mgross : 11/12/2008
terry : 11/6/2008
carol : 6/11/2008
terry : 6/10/2008
wwang : 5/16/2008
ckniffin : 4/28/2008
mgross : 4/16/2008
mgross : 4/16/2008
mgross : 2/13/2006
wwang : 2/1/2006
terry : 1/25/2006
carol : 12/5/2005
terry : 3/14/2005
carol : 9/8/2004
carol : 6/21/2004
terry : 6/17/2004
tkritzer : 12/30/2003
ckniffin : 12/23/2003
alopez : 10/16/2003
alopez : 9/23/2003
alopez : 9/23/2003
mgross : 5/19/2003
alopez : 12/6/2002
mgross : 9/24/2002
mgross : 8/23/2002
mgross : 4/17/2002
mgross : 3/27/2002
mgross : 3/26/2002
terry : 3/25/2002
carol : 1/20/2002
mcapotos : 1/14/2002
mgross : 5/11/2001
terry : 5/10/2001
mgross : 4/25/2001
mgross : 11/21/2000
mgross : 7/28/2000
yemi : 2/18/2000
mgross : 12/8/1999
terry : 12/6/1999
terry : 11/30/1999
mgross : 11/17/1999
terry : 10/29/1999
carol : 6/2/1998
terry : 6/1/1998
psherman : 5/15/1998
mark : 9/4/1997
terry : 6/13/1996
terry : 6/7/1996
terry : 4/19/1995
carol : 4/7/1994
supermim : 3/16/1992
carol : 3/6/1991