RBCC Red Blood Cell Collection

MMP9 (CLG4B) [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Matrix metalloproteinase-9; MMP-9; 3.4.24.35 (92 kDa gelatinase; 92 kDa type IV collagenase; Gelatinase B; GELB; 67 kDa matrix metalloproteinase-9; 82 kDa matrix metalloproteinase-9; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P14780
ID MMP9_HUMAN Reviewed; 707 AA.
AC P14780; B2R7V9; Q3LR70; Q8N725; Q9H4Z1; Q9UCJ9; Q9UCL1; Q9UDK2;
read moreDT 01-APR-1990, integrated into UniProtKB/Swiss-Prot.
DT 24-NOV-2009, sequence version 3.
DT 22-JAN-2014, entry version 182.
DE RecName: Full=Matrix metalloproteinase-9;
DE Short=MMP-9;
DE EC=3.4.24.35;
DE AltName: Full=92 kDa gelatinase;
DE AltName: Full=92 kDa type IV collagenase;
DE AltName: Full=Gelatinase B;
DE Short=GELB;
DE Contains:
DE RecName: Full=67 kDa matrix metalloproteinase-9;
DE Contains:
DE RecName: Full=82 kDa matrix metalloproteinase-9;
DE Flags: Precursor;
GN Name=MMP9; Synonyms=CLG4B;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 20-37, AND VARIANTS
RP ARG-279 AND PRO-574.
RX PubMed=2551898;
RA Wilhelm S.M., Collier I.E., Marmer B.L., Eisen A.Z., Grant G.A.,
RA Goldberg G.I.;
RT "SV40-transformed human lung fibroblasts secrete a 92-kDa type IV
RT collagenase which is identical to that secreted by normal human
RT macrophages.";
RL J. Biol. Chem. 264:17213-17221(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=1653238;
RA Huhtala P., Tuuttila A., Chow L.T., Lohi J., Keski-Oja J.,
RA Tryggvason K.;
RT "Complete structure of the human gene for 92-kDa type IV collagenase.
RT Divergent regulation of expression for the 92- and 72-kilodalton
RT enzyme genes in HT-1080 cells.";
RL J. Biol. Chem. 266:16485-16490(1991).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT PRO-574.
RC TISSUE=Umbilical cord blood;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS VAL-20; LYS-127;
RP ARG-279; PRO-574 AND GLN-668.
RG SeattleSNPs variation discovery resource;
RL Submitted (AUG-2002) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS VAL-20; HIS-239;
RP VAL-571; PRO-574 AND GLN-668.
RG NIEHS SNPs program;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=11780052; DOI=10.1038/414865a;
RA Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R.,
RA Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L.,
RA Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M.,
RA Beasley O.P., Bird C.P., Blakey S.E., Bridgeman A.M., Brown A.J.,
RA Buck D., Burrill W.D., Butler A.P., Carder C., Carter N.P.,
RA Chapman J.C., Clamp M., Clark G., Clark L.N., Clark S.Y., Clee C.M.,
RA Clegg S., Cobley V.E., Collier R.E., Connor R.E., Corby N.R.,
RA Coulson A., Coville G.J., Deadman R., Dhami P.D., Dunn M.,
RA Ellington A.G., Frankland J.A., Fraser A., French L., Garner P.,
RA Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E.,
RA Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J.,
RA Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D.,
RA Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S.,
RA Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D.,
RA Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A.,
RA Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T.,
RA Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I.,
RA Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H.,
RA Rice C.M., Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S.,
RA Skuce C.D., Smith M.L., Soderlund C., Steward C.A., Sulston J.E.,
RA Swann R.M., Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A.,
RA Tracey A., Tromans A.C., Vaudin M., Wall M., Wallis J.M.,
RA Whitehead S.L., Whittaker P., Willey D.L., Williams L., Williams S.A.,
RA Wilming L., Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S.,
RA Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 20.";
RL Nature 414:865-871(2001).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS ARG-279 AND
RP PRO-574.
RC TISSUE=B-cell;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-11.
RX PubMed=8426746;
RA Sato H., Seiki M.;
RT "Regulatory mechanism of 92 kDa type IV collagenase gene expression
RT which is associated with invasiveness of tumor cells.";
RL Oncogene 8:395-405(1993).
RN [9]
RP PROTEIN SEQUENCE OF 20-39, AND GLYCOSYLATION.
RC TISSUE=Neutrophil;
RX PubMed=1464361;
RA Kjeldsen L., Bjerrum O.W., Hovgaard D., Johnsen A.H., Sehested M.,
RA Borregaard N.;
RT "Human neutrophil gelatinase: a marker for circulating blood
RT neutrophils. Purification and quantitation by enzyme linked
RT immunosorbent assay.";
RL Eur. J. Haematol. 49:180-191(1992).
RN [10]
RP PROTEIN SEQUENCE OF 20-37.
RX PubMed=1653055; DOI=10.1016/1043-4666(91)90021-5;
RA van Ranst M., Norga K., Masure S., Proost P., Vandekerckhove F.,
RA Auwerx J., van Damme J., Opdenakker G.;
RT "The cytokine-protease connection: identification of a 96-kD THP-1
RT gelatinase and regulation by interleukin-1 and cytokine inducers.";
RL Cytokine 3:231-239(1991).
RN [11]
RP PROTEIN SEQUENCE OF 20-34; 60-71 AND 107-118, INDUCTION, AND
RP PROTEOLYTIC PROCESSING BY MMP3.
RX PubMed=1371271;
RA Ogata Y., Enghild J.J., Nagase H.;
RT "Matrix metalloproteinase 3 (stromelysin) activates the precursor for
RT the human matrix metalloproteinase 9.";
RL J. Biol. Chem. 267:3581-3584(1992).
RN [12]
RP PROTEIN SEQUENCE OF 20-32 AND 94-111, PROTEOLYTIC PROCESSING, AND
RP INDUCTION.
RC TISSUE=Fibrosarcoma;
RX PubMed=1400481;
RA Okada Y., Gonoji Y., Naka K., Tomita K., Nakanishi I., Iwata K.,
RA Yamashita K., Hayakawa T.;
RT "Matrix metalloproteinase 9 (92-kDa gelatinase/type IV collagenase)
RT from HT 1080 human fibrosarcoma cells. Purification and activation of
RT the precursor and enzymic properties.";
RL J. Biol. Chem. 267:21712-21719(1992).
RN [13]
RP PROTEIN SEQUENCE OF 20-27; 60-67; 94-101 AND 107-113.
RX PubMed=7669817; DOI=10.1016/0167-4838(95)00086-A;
RA Sang Q.X., Birkedal-Hansen H., Van Wart H.E.;
RT "Proteolytic and non-proteolytic activation of human neutrophil
RT progelatinase B.";
RL Biochim. Biophys. Acta 1251:99-108(1995).
RN [14]
RP PROTEIN SEQUENCE OF 28-60.
RC TISSUE=Neutrophil;
RX PubMed=1645657; DOI=10.1111/j.1432-1033.1991.tb16027.x;
RA Masure S., Proost P., van Damme J., Opdenakker G.;
RT "Purification and identification of 91-kDa neutrophil gelatinase.
RT Release by the activating peptide interleukin-8.";
RL Eur. J. Biochem. 198:391-398(1991).
RN [15]
RP PROTEIN SEQUENCE OF 28-37.
RX PubMed=1932376;
RA Opdenakker G., Masure S., Grillet B., Van Damme J.;
RT "Cytokine-mediated regulation of human leukocyte gelatinases and role
RT in arthritis.";
RL Lymphokine Cytokine Res. 10:317-324(1991).
RN [16]
RP PROTEIN SEQUENCE OF 93-115, FUNCTION, AND CATALYTIC ACTIVITY.
RC TISSUE=Blood;
RX PubMed=1480034;
RA Tschesche H., Knaeuper V., Kraemer S., Michaelis J., Oberhoff R.,
RA Reinke H.;
RT "Latent collagenase and gelatinase from human neutrophils and their
RT activation.";
RL Matrix Suppl. 1:245-255(1992).
RN [17]
RP CHARACTERIZATION.
RA Kang K., Lee D.-H.;
RT "Purification and characterization of human 92-kDa type IV collagenase
RT (gelatinase B).";
RL Exp. Mol. Med. 28:161-165(1996).
RN [18]
RP SUBUNIT.
RX PubMed=10644727; DOI=10.1074/jbc.275.4.2661;
RA Olson M.W., Bernardo M.M., Pietila M., Gervasi D.C., Toth M.,
RA Kotra L.P., Massova I., Mobashery S., Fridman R.;
RT "Characterization of the monomeric and dimeric forms of latent and
RT active matrix metalloproteinase-9. Differential rates for activation
RT by stromelysin 1.";
RL J. Biol. Chem. 275:2661-2668(2000).
RN [19]
RP ENZYME REGULATION.
RX PubMed=11179305; DOI=10.1128/IAI.69.3.1402-1408.2001;
RA Gusman H., Travis J., Helmerhorst E.J., Potempa J., Troxler R.F.,
RA Oppenheim F.G.;
RT "Salivary histatin 5 is an inhibitor of both host and bacterial
RT enzymes implicated in periodontal disease.";
RL Infect. Immun. 69:1402-1408(2001).
RN [20]
RP PROTEOLYTIC PROCESSING OF KISS1.
RX PubMed=12879005; DOI=10.1038/sj.onc.1206542;
RA Takino T., Koshikawa N., Miyamori H., Tanaka M., Sasaki T., Okada Y.,
RA Seiki M., Sato H.;
RT "Cleavage of metastasis suppressor gene product KiSS-1
RT protein/metastin by matrix metalloproteinases.";
RL Oncogene 22:4617-4626(2003).
RN [21]
RP INTERACTION WITH ECM1, AND ENZYME REGULATION.
RX PubMed=16512877; DOI=10.1111/j.0906-6705.2006.00409.x;
RA Fujimoto N., Terlizzi J., Aho S., Brittingham R., Fertala A.,
RA Oyama N., McGrath J.A., Uitto J.;
RT "Extracellular matrix protein 1 inhibits the activity of matrix
RT metalloproteinase 9 through high-affinity protein/protein
RT interactions.";
RL Exp. Dermatol. 15:300-307(2006).
RN [22]
RP INVOLVEMENT IN SUSCEPTIBILITY TO IDD.
RX PubMed=18455130; DOI=10.1016/j.ajhg.2008.03.013;
RA Hirose Y., Chiba K., Karasugi T., Nakajima M., Kawaguchi Y.,
RA Mikami Y., Furuichi T., Mio F., Miyake A., Miyamoto T., Ozaki K.,
RA Takahashi A., Mizuta H., Kubo T., Kimura T., Tanaka T., Toyama Y.,
RA Ikegawa S.;
RT "A functional polymorphism in THBS2 that affects alternative splicing
RT and MMP binding is associated with lumbar-disc herniation.";
RL Am. J. Hum. Genet. 82:1122-1129(2008).
RN [23]
RP INVOLVEMENT IN METAPHYSEAL ANADYSPLASIA TYPE 2.
RX PubMed=19615667; DOI=10.1016/j.ajhg.2009.06.014;
RA Lausch E., Keppler R., Hilbert K., Cormier-Daire V., Nikkel S.,
RA Nishimura G., Unger S., Spranger J., Superti-Furga A., Zabel B.;
RT "Mutations in MMP9 and MMP13 determine the mode of inheritance and the
RT clinical spectrum of metaphyseal anadysplasia.";
RL Am. J. Hum. Genet. 85:168-178(2009).
RN [24]
RP INDUCTION.
RX PubMed=19893577; DOI=10.1038/embor.2009.233;
RA Kawasaki Y., Tsuji S., Muroya K., Furukawa S., Shibata Y., Okuno M.,
RA Ohwada S., Akiyama T.;
RT "The adenomatous polyposis coli-associated exchange factors Asef and
RT Asef2 are required for adenoma formation in Apc(Min/+)mice.";
RL EMBO Rep. 10:1355-1362(2009).
RN [25]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 20-444 IN COMPLEX WITH ZINC
RP AND MAGNESIUM IONS.
RX PubMed=12077439; DOI=10.1107/S0907444902007849;
RA Elkins P.A., Ho Y.S., Smith W.W., Janson C.A., D'Alessio K.J.,
RA McQueney M.S., Cummings M.D., Romanic A.M.;
RT "Structure of the C-terminally truncated human ProMMP9, a gelatin-
RT binding matrix metalloproteinase.";
RL Acta Crystallogr. D 58:1182-1192(2002).
RN [26]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 107-215 IN COMPLEX WITH
RP INHIBITOR; ZINC AND CALCIUM IONS, AND MUTAGENESIS OF GLU-402.
RX PubMed=12051944; DOI=10.1016/S0022-2836(02)00262-0;
RA Rowsell S., Hawtin P., Minshull C.A., Jepson H., Brockbank S.M.V.,
RA Barratt D.G., Slater A.M., McPheat W.L., Waterson D., Henney A.M.,
RA Pauptit R.A.;
RT "Crystal structure of human MMP9 in complex with a reverse hydroxamate
RT inhibitor.";
RL J. Mol. Biol. 319:173-181(2002).
RN [27]
RP X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) OF 513-707, AND SUBUNIT.
RX PubMed=12126625; DOI=10.1016/S0022-2836(02)00558-2;
RA Cha H., Kopetzki E., Huber R., Lanzendoerfer M., Brandstetter H.;
RT "Structural basis of the adaptive molecular recognition by MMP9.";
RL J. Mol. Biol. 320:1065-1079(2002).
RN [28]
RP 3D-STRUCTURE MODELING.
RA Mallena S.C., Sagajkar R.D.;
RT "Theoretical model of human type IV collagenase precursor.";
RL Submitted (APR-2002) to the PDB data bank.
RN [29]
RP VARIANTS VAL-20; LYS-82 AND ARG-279.
RX PubMed=10598806; DOI=10.1007/s004390051124;
RA Zhang B., Henney A., Eriksson P., Hamsten A., Watkins H., Ye S.;
RT "Genetic variation at the matrix metalloproteinase-9 locus on
RT chromosome 20q12.2-13.1.";
RL Hum. Genet. 105:418-423(1999).
CC -!- FUNCTION: May play an essential role in local proteolysis of the
CC extracellular matrix and in leukocyte migration. Could play a role
CC in bone osteoclastic resorption. Cleaves KiSS1 at a Gly-|-Leu
CC bond. Cleaves type IV and type V collagen into large C-terminal
CC three quarter fragments and shorter N-terminal one quarter
CC fragments. Degrades fibronectin but not laminin or Pz-peptide.
CC -!- CATALYTIC ACTIVITY: Cleavage of gelatin types I and V and collagen
CC types IV and V.
CC -!- COFACTOR: Binds 2 zinc ions per subunit.
CC -!- COFACTOR: Binds 3 calcium ions per subunit.
CC -!- ENZYME REGULATION: Inhibited by histatin-3 1/24 (histatin-5).
CC Inhibited by ECM1.
CC -!- SUBUNIT: Exists as monomer or homodimer; disulfide-linked. Exists
CC also as heterodimer with a 25 kDa protein. Macrophages and
CC transformed cell lines produce only the monomeric form. Interacts
CC with ECM1.
CC -!- INTERACTION:
CC Self; NbExp=2; IntAct=EBI-1382326, EBI-1382326;
CC Q16819:MEP1A; NbExp=2; IntAct=EBI-1382326, EBI-8153734;
CC Q16820:MEP1B; NbExp=2; IntAct=EBI-1382326, EBI-968418;
CC Q8IX30:SCUBE3; NbExp=2; IntAct=EBI-1382326, EBI-4479975;
CC P13611:VCAN; NbExp=3; IntAct=EBI-1382326, EBI-8515977;
CC -!- SUBCELLULAR LOCATION: Secreted, extracellular space, extracellular
CC matrix (Probable).
CC -!- TISSUE SPECIFICITY: Produced by normal alveolar macrophages and
CC granulocytes.
CC -!- INDUCTION: Activated by 4-aminophenylmercuric acetate and phorbol
CC ester. Up-regulated by ARHGEF4, SPATA13 and APC via the JNK
CC signaling pathway in colorectal tumor cells.
CC -!- DOMAIN: The conserved cysteine present in the cysteine-switch
CC motif binds the catalytic zinc ion, thus inhibiting the enzyme.
CC The dissociation of the cysteine from the zinc ion upon the
CC activation-peptide release activates the enzyme.
CC -!- PTM: Processing of the precursor yields different active forms of
CC 64, 67 and 82 kDa. Sequentially processing by MMP3 yields the 82
CC kDa matrix metalloproteinase-9.
CC -!- PTM: N- and O-glycosylated.
CC -!- DISEASE: Intervertebral disc disease (IDD) [MIM:603932]: A common
CC musculo-skeletal disorder caused by degeneration of intervertebral
CC disks of the lumbar spine. It results in low-back pain and
CC unilateral leg pain. Note=Disease susceptibility is associated
CC with variations affecting the gene represented in this entry.
CC -!- DISEASE: Metaphyseal anadysplasia 2 (MANDP2) [MIM:613073]: A bone
CC development disorder characterized by skeletal anomalies that
CC resolve spontaneously with age. Clinical characteristics are
CC evident from the first months of life and include slight shortness
CC of stature and a mild varus deformity of the legs. Patients attain
CC a normal stature in adolescence and show improvement or complete
CC resolution of varus deformity of the legs and rhizomelic
CC micromelia. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- MISCELLANEOUS: In the arthritis patient this enzyme might
CC contribute to the pathogenesis of joint destruction and might
CC constitute a useful marker of disease status.
CC -!- SIMILARITY: Belongs to the peptidase M10A family.
CC -!- SIMILARITY: Contains 3 fibronectin type-II domains.
CC -!- SIMILARITY: Contains 4 hemopexin repeats.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/MMP9ID41408ch20q11.html";
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/mmp9/";
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/mmp9/";
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DR EMBL; J05070; AAA51539.1; -; mRNA.
DR EMBL; M68343; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; M68344; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; M68345; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; M68346; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; M68347; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; M68348; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; M68349; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; M68350; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; M68351; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; M68352; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; M68353; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; M68354; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; M68355; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AK313137; BAG35956.1; -; mRNA.
DR EMBL; AF538844; AAM97934.1; -; Genomic_DNA.
DR EMBL; DQ194553; ABA03169.1; -; Genomic_DNA.
DR EMBL; AL162458; CAC10459.1; -; Genomic_DNA.
DR EMBL; BC006093; AAH06093.1; -; mRNA.
DR EMBL; D10051; BAA20967.1; -; Genomic_DNA.
DR PIR; A34458; A34458.
DR RefSeq; NP_004985.2; NM_004994.2.
DR UniGene; Hs.297413; -.
DR PDB; 1GKC; X-ray; 2.30 A; A/B=107-443.
DR PDB; 1GKD; X-ray; 2.10 A; A/B=107-443.
DR PDB; 1ITV; X-ray; 1.95 A; A/B=513-707.
DR PDB; 1L6J; X-ray; 2.50 A; A=20-444.
DR PDB; 1LKG; Model; -; A=1-707.
DR PDB; 2OVX; X-ray; 2.00 A; A/B=110-443.
DR PDB; 2OVZ; X-ray; 2.00 A; A/B=110-443.
DR PDB; 2OW0; X-ray; 2.00 A; A/B=110-443.
DR PDB; 2OW1; X-ray; 2.20 A; A/B=110-443.
DR PDB; 2OW2; X-ray; 2.90 A; A/B=110-443.
DR PDB; 4H1Q; X-ray; 1.59 A; A/B=110-444.
DR PDB; 4H2E; X-ray; 2.90 A; A/B=107-444.
DR PDB; 4H3X; X-ray; 1.76 A; A/B=107-444.
DR PDB; 4H82; X-ray; 1.90 A; A/B/C/D=110-444.
DR PDB; 4HMA; X-ray; 1.94 A; A/B=110-444.
DR PDBsum; 1GKC; -.
DR PDBsum; 1GKD; -.
DR PDBsum; 1ITV; -.
DR PDBsum; 1L6J; -.
DR PDBsum; 1LKG; -.
DR PDBsum; 2OVX; -.
DR PDBsum; 2OVZ; -.
DR PDBsum; 2OW0; -.
DR PDBsum; 2OW1; -.
DR PDBsum; 2OW2; -.
DR PDBsum; 4H1Q; -.
DR PDBsum; 4H2E; -.
DR PDBsum; 4H3X; -.
DR PDBsum; 4H82; -.
DR PDBsum; 4HMA; -.
DR ProteinModelPortal; P14780; -.
DR SMR; P14780; 26-707.
DR DIP; DIP-29518N; -.
DR IntAct; P14780; 8.
DR MINT; MINT-7709677; -.
DR STRING; 9606.ENSP00000361405; -.
DR ChEMBL; CHEMBL2095216; -.
DR DrugBank; DB01296; Glucosamine.
DR DrugBank; DB00786; Marimastat.
DR DrugBank; DB01017; Minocycline.
DR DrugBank; DB00641; Simvastatin.
DR GuidetoPHARMACOLOGY; 1633; -.
DR MEROPS; M10.004; -.
DR PhosphoSite; P14780; -.
DR UniCarbKB; P14780; -.
DR DMDM; 269849668; -.
DR PaxDb; P14780; -.
DR PeptideAtlas; P14780; -.
DR PRIDE; P14780; -.
DR DNASU; 4318; -.
DR Ensembl; ENST00000372330; ENSP00000361405; ENSG00000100985.
DR GeneID; 4318; -.
DR KEGG; hsa:4318; -.
DR UCSC; uc002xqz.3; human.
DR CTD; 4318; -.
DR GeneCards; GC20P044637; -.
DR H-InvDB; HIX0015874; -.
DR HGNC; HGNC:7176; MMP9.
DR HPA; CAB000348; -.
DR HPA; HPA001238; -.
DR MIM; 120361; gene.
DR MIM; 603932; phenotype.
DR MIM; 613073; phenotype.
DR neXtProt; NX_P14780; -.
DR Orphanet; 1040; Metaphyseal anadysplasia.
DR PharmGKB; PA30889; -.
DR eggNOG; NOG328372; -.
DR HOVERGEN; HBG052484; -.
DR InParanoid; P14780; -.
DR KO; K01403; -.
DR OMA; EGDLKWH; -.
DR OrthoDB; EOG70KGNX; -.
DR PhylomeDB; P14780; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_118779; Extracellular matrix organization.
DR Reactome; REACT_133391; Extracellular matrix organization.
DR EvolutionaryTrace; P14780; -.
DR GeneWiki; MMP9; -.
DR GenomeRNAi; 4318; -.
DR NextBio; 16989; -.
DR PRO; PR:P14780; -.
DR Bgee; P14780; -.
DR CleanEx; HS_MMP9; -.
DR Genevestigator; P14780; -.
DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB.
DR GO; GO:0005578; C:proteinaceous extracellular matrix; IEA:UniProtKB-SubCell.
DR GO; GO:0005518; F:collagen binding; TAS:UniProtKB.
DR GO; GO:0004222; F:metalloendopeptidase activity; IDA:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; TAS:UniProtKB.
DR GO; GO:0030574; P:collagen catabolic process; TAS:Reactome.
DR GO; GO:0007566; P:embryo implantation; IEA:Ensembl.
DR GO; GO:0022617; P:extracellular matrix disassembly; TAS:Reactome.
DR GO; GO:0030225; P:macrophage differentiation; TAS:UniProtKB.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IEA:Ensembl.
DR GO; GO:0051549; P:positive regulation of keratinocyte migration; IMP:BHF-UCL.
DR GO; GO:0006508; P:proteolysis; IDA:UniProtKB.
DR GO; GO:0001501; P:skeletal system development; IEA:Ensembl.
DR Gene3D; 2.10.10.10; -; 3.
DR Gene3D; 2.110.10.10; -; 1.
DR Gene3D; 3.40.390.10; -; 2.
DR InterPro; IPR000562; FN_type2_col-bd.
DR InterPro; IPR000585; Hemopexin-like_dom.
DR InterPro; IPR018487; Hemopexin-like_repeat.
DR InterPro; IPR018486; Hemopexin_CS.
DR InterPro; IPR013806; Kringle-like.
DR InterPro; IPR024079; MetalloPept_cat_dom.
DR InterPro; IPR001818; Pept_M10_metallopeptidase.
DR InterPro; IPR021190; Pept_M10A.
DR InterPro; IPR021158; Pept_M10A_Zn_BS.
DR InterPro; IPR006026; Peptidase_Metallo.
DR InterPro; IPR002477; Peptidoglycan-bd-like.
DR InterPro; IPR006970; PT.
DR Pfam; PF00040; fn2; 3.
DR Pfam; PF00045; Hemopexin; 4.
DR Pfam; PF00413; Peptidase_M10; 1.
DR Pfam; PF01471; PG_binding_1; 1.
DR Pfam; PF04886; PT; 1.
DR PRINTS; PR00138; MATRIXIN.
DR SMART; SM00059; FN2; 3.
DR SMART; SM00120; HX; 4.
DR SMART; SM00235; ZnMc; 1.
DR SUPFAM; SSF47090; SSF47090; 1.
DR SUPFAM; SSF50923; SSF50923; 1.
DR SUPFAM; SSF57440; SSF57440; 3.
DR PROSITE; PS00546; CYSTEINE_SWITCH; 1.
DR PROSITE; PS00023; FN2_1; 3.
DR PROSITE; PS51092; FN2_2; 3.
DR PROSITE; PS00024; HEMOPEXIN; 1.
DR PROSITE; PS51642; HEMOPEXIN_2; 4.
DR PROSITE; PS00142; ZINC_PROTEASE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Calcium; Collagen degradation; Complete proteome;
KW Direct protein sequencing; Disulfide bond; Extracellular matrix;
KW Glycoprotein; Hydrolase; Metal-binding; Metalloprotease; Polymorphism;
KW Protease; Reference proteome; Repeat; Secreted; Signal; Zinc; Zymogen.
FT SIGNAL 1 19
FT PROPEP 20 93 Activation peptide.
FT /FTId=PRO_0000028754.
FT CHAIN 94 ? 67 kDa matrix metalloproteinase-9.
FT /FTId=PRO_0000028755.
FT CHAIN 107 707 82 kDa matrix metalloproteinase-9.
FT /FTId=PRO_0000028756.
FT PROPEP ? 707 Removed in 64 kDa matrix
FT metalloproteinase-9 and 67 kDa matrix
FT metalloproteinase-9.
FT /FTId=PRO_0000028757.
FT DOMAIN 225 273 Fibronectin type-II 1.
FT DOMAIN 283 331 Fibronectin type-II 2.
FT DOMAIN 342 390 Fibronectin type-II 3.
FT REPEAT 518 563 Hemopexin 1.
FT REPEAT 564 608 Hemopexin 2.
FT REPEAT 610 657 Hemopexin 3.
FT REPEAT 658 704 Hemopexin 4.
FT MOTIF 97 104 Cysteine switch (By similarity).
FT ACT_SITE 402 402
FT METAL 99 99 Zinc 2; in inhibited form.
FT METAL 131 131 Calcium 1.
FT METAL 165 165 Calcium 2; via carbonyl oxygen.
FT METAL 175 175 Zinc 1; structural.
FT METAL 177 177 Zinc 1; structural.
FT METAL 182 182 Calcium 3.
FT METAL 183 183 Calcium 3; via carbonyl oxygen.
FT METAL 185 185 Calcium 3; via carbonyl oxygen.
FT METAL 187 187 Calcium 3; via carbonyl oxygen.
FT METAL 190 190 Zinc 1; structural.
FT METAL 197 197 Calcium 2; via carbonyl oxygen.
FT METAL 199 199 Calcium 2; via carbonyl oxygen.
FT METAL 201 201 Calcium 2.
FT METAL 203 203 Zinc 1; structural.
FT METAL 205 205 Calcium 3.
FT METAL 206 206 Calcium 1.
FT METAL 208 208 Calcium 1.
FT METAL 208 208 Calcium 3.
FT METAL 401 401 Zinc 2; catalytic.
FT METAL 405 405 Zinc 2; catalytic.
FT METAL 411 411 Zinc 2; catalytic.
FT SITE 59 60 Cleavage; by MMP3.
FT SITE 106 107 Cleavage; by MMP3.
FT CARBOHYD 38 38 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 120 120 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 127 127 N-linked (GlcNAc...) (Potential).
FT DISULFID 230 256 By similarity.
FT DISULFID 244 271 By similarity.
FT DISULFID 288 314 By similarity.
FT DISULFID 302 329 By similarity.
FT DISULFID 347 373 By similarity.
FT DISULFID 361 388 By similarity.
FT DISULFID 516 704
FT VARIANT 20 20 A -> V (in dbSNP:rs1805088).
FT /FTId=VAR_013780.
FT VARIANT 38 38 N -> S (in dbSNP:rs41427445).
FT /FTId=VAR_037004.
FT VARIANT 82 82 E -> K (in dbSNP:rs1805089).
FT /FTId=VAR_013781.
FT VARIANT 127 127 N -> K (in dbSNP:rs3918252).
FT /FTId=VAR_020054.
FT VARIANT 239 239 R -> H (in dbSNP:rs28763886).
FT /FTId=VAR_025165.
FT VARIANT 279 279 Q -> R (common polymorphism; may be
FT associated with susceptibility to IDD;
FT dbSNP:rs17576).
FT /FTId=VAR_013782.
FT VARIANT 571 571 F -> V (in dbSNP:rs35691798).
FT /FTId=VAR_025166.
FT VARIANT 574 574 R -> P (in dbSNP:rs2250889).
FT /FTId=VAR_024595.
FT VARIANT 668 668 R -> Q (in dbSNP:rs17577).
FT /FTId=VAR_014742.
FT MUTAGEN 402 402 E->Q: Loss of activity.
FT CONFLICT 110 110 F -> L (in Ref. 3; BAG35956).
FT HELIX 41 51
FT HELIX 68 78
FT HELIX 88 94
FT STRAND 103 105
FT STRAND 117 125
FT STRAND 130 132
FT HELIX 134 149
FT STRAND 151 153
FT STRAND 155 158
FT STRAND 165 171
FT STRAND 176 178
FT STRAND 183 186
FT STRAND 189 191
FT STRAND 194 196
FT TURN 197 200
FT STRAND 202 205
FT STRAND 210 214
FT STRAND 221 225
FT STRAND 232 238
FT STRAND 240 243
FT STRAND 255 261
FT HELIX 262 265
FT STRAND 268 270
FT TURN 274 276
FT STRAND 279 283
FT STRAND 290 294
FT STRAND 297 301
FT STRAND 313 319
FT HELIX 320 323
FT STRAND 326 328
FT HELIX 333 335
FT TURN 340 344
FT STRAND 349 353
FT STRAND 356 358
FT STRAND 372 378
FT HELIX 379 382
FT STRAND 385 387
FT STRAND 391 394
FT HELIX 395 406
FT STRAND 408 411
FT STRAND 420 422
FT HELIX 433 443
FT STRAND 444 446
FT HELIX 450 460
FT HELIX 515 517
FT STRAND 522 527
FT STRAND 530 535
FT STRAND 538 542
FT STRAND 545 547
FT STRAND 551 555
FT HELIX 556 559
FT STRAND 568 572
FT TURN 574 576
FT STRAND 579 583
FT STRAND 586 591
FT STRAND 594 600
FT HELIX 601 604
FT STRAND 615 618
FT STRAND 623 628
FT STRAND 631 636
FT TURN 637 640
FT HELIX 644 646
FT HELIX 650 653
FT STRAND 662 667
FT STRAND 670 675
FT STRAND 678 683
FT STRAND 690 696
FT TURN 697 700
SQ SEQUENCE 707 AA; 78458 MW; 2165AC8CA1466209 CRC64;
MSLWQPLVLV LLVLGCCFAA PRQRQSTLVL FPGDLRTNLT DRQLAEEYLY RYGYTRVAEM
RGESKSLGPA LLLLQKQLSL PETGELDSAT LKAMRTPRCG VPDLGRFQTF EGDLKWHHHN
ITYWIQNYSE DLPRAVIDDA FARAFALWSA VTPLTFTRVY SRDADIVIQF GVAEHGDGYP
FDGKDGLLAH AFPPGPGIQG DAHFDDDELW SLGKGVVVPT RFGNADGAAC HFPFIFEGRS
YSACTTDGRS DGLPWCSTTA NYDTDDRFGF CPSERLYTQD GNADGKPCQF PFIFQGQSYS
ACTTDGRSDG YRWCATTANY DRDKLFGFCP TRADSTVMGG NSAGELCVFP FTFLGKEYST
CTSEGRGDGR LWCATTSNFD SDKKWGFCPD QGYSLFLVAA HEFGHALGLD HSSVPEALMY
PMYRFTEGPP LHKDDVNGIR HLYGPRPEPE PRPPTTTTPQ PTAPPTVCPT GPPTVHPSER
PTAGPTGPPS AGPTGPPTAG PSTATTVPLS PVDDACNVNI FDAIAEIGNQ LYLFKDGKYW
RFSEGRGSRP QGPFLIADKW PALPRKLDSV FEERLSKKLF FFSGRQVWVY TGASVLGPRR
LDKLGLGADV AQVTGALRSG RGKMLLFSGR RLWRFDVKAQ MVDPRSASEV DRMFPGVPLD
THDVFQYREK AYFCQDRFYW RVSSRSELNQ VDQVGYVTYD ILQCPED
//

MIM 120361
*RECORD*
*FIELD* NO
120361
*FIELD* TI
*120361 MATRIX METALLOPROTEINASE 9; MMP9
;;COLLAGENASE TYPE IV-B; CLG4B;;
COLLAGENASE TYPE IV, 92-KD;;
read moreCOLLAGENASE TYPE V;;
GELATINASE, 92-KD;;
GELATINASE B; GELB
*FIELD* TX

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.

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 the other 4 families,
they identified heterozygous or homozygous mutations in the MMP13 gene
(600108.0002-600108.0004); see MANDP1 (602111). Lausch et al. (2009)
found that recessive MANDP is caused by homozygous loss of function of
either MMP9 or MMP13, whereas dominant MANDP is associated with missense
mutations in the prodomain of MMP13 that determine autoactivation of
MMP13 and intracellular degradation of both MMP13 and MMP9, resulting in
a double enzymatic deficiency.

- Association Studies

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.

It was 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; dbSNP rs17576) and lumbar disc
herniation (LDH; 603932). An intronic SNP in the THBS2 gene (dbSNP
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.

*FIELD* AV
.0001
METAPHYSEAL ANADYSPLASIA 2, AUTOSOMAL RECESSIVE
MMP9, MET1LYS

In 2 sibs of a nonconsanguineous Pakistani family segregating
metaphyseal anadysplasia (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.

*FIELD* RF
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*FIELD* CN
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

*FIELD* CD
Victor A. McKusick: 3/6/1991

*FIELD* ED
mgross: 04/03/2012
terry: 3/21/2012
wwang: 5/13/2010
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: 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
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

MIM 603932
*RECORD*
*FIELD* NO
603932
*FIELD* TI
#603932 INTERVERTEBRAL DISC DISEASE; IDD
LUMBAR DISC DISEASE, INCLUDED; LDD, INCLUDED;;
read moreLUMBAR DISC HERNIATION, SUSCEPTIBILITY TO, INCLUDED;;
LUMBAR DISC DEGENERATION, SUSCEPTIBILITY TO, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
variations in many genes are involved in susceptibility to
intervertebral disc disease. See MOLECULAR GENETICS section.

DESCRIPTION

Lumbar disc disease is caused by degeneration of intervertebral discs of
the lumbar spine. One of the most common musculoskeletal disorders, it
has strong genetic determinants (Matsui et al., 1998; Battie et al.,
1995; Sambrook et al., 1999).

CLINICAL FEATURES

Sambrook et al. (1999) compared MRI features of degenerative disc
disease in the cervical and lumbar spine of 172 monozygotic and 154
dizygotic twins (mean age 51.7 and 54.4, respectively) who were
unselected for back pain or disc disease. An overall score for disc
degeneration was calculated as the sum of the grades for disc height,
bulge, osteophytosis, and signal intensity at each level. A 'severe
disease' score (excluding minor grades) and an 'extent of disease' score
(number of levels affected) were also calculated. For the overall score,
heritability was 74% at the lumbar spine and 73% at the cervical spine.
For 'severe disease,' heritability was 64% and 79% at the lumbar and
cervical spine, respectively, and for 'extent of disease,' heritability
was 63% and 63%, respectively. These results were adjusted for age,
weight, height, smoking, occupational manual work, and exercise.
Examination of individual features showed that disc height and bulge
were highly heritable at both sites, and osteophytes were heritable in
the lumbar spine.

MOLECULAR GENETICS

- Association with the COL9A2 Gene on Chromosome 1p33-p32

In a study that examined for allelic variation in the COL9A2 gene in
Finnish individuals with sciatica and radiologically documented
intervertebral disc disease, Annunen et al. (1999) found a substitution
of tryptophan for glutamine at codon 326 (120260.0004). This change was
found in 6 of 157 individuals with disc disease but in none of 174
controls. Further analysis of the families of 4 of the original patients
revealed that all individuals heterozygous for the trp substitution
demonstrated the disease phenotype. Many individuals within these
families had IDD but not the trp allele. The authors invoked a high
phenocopy rate to reconcile this observation with the conclusion that
this sequence variant within COL9A2 contributes to the pathogenesis of
disease. In the disease model chosen, this locus accounted for 10% of
disease prevalence. Under these constraints, Annunen et al. (1999)
demonstrated a lod score of 4.5 at a recombination fraction of 0.12.
Subsequent linkage disequilibrium analysis conditional on linkage gave
an additional lod score of 7.1. The authors did not exclude the
possibility that a true disease locus may lie in close physical
proximity to COL9A2.

- Association with the COL11A1 Gene on Chromosome 1p21

Mio et al. (2007) identified an association between a polymorphism of
the COL11A1 gene (120280.0007) and lumbar disc herniation in Japanese
populations. Normally, the COL11A1 gene is highly expressed in the
intervertebral disc; its expression was decreased in the intervertebral
disc in patients with lumbar disc herniation, and the expression level
was inversely correlated with the severity of disc degeneration. Mio et
al. (2007) concluded that type XI collagen is critical for
intervertebral disc metabolism and that its decrease is related to
lumbar disc herniation.

- Association with the THBS2 Gene on Chromosome 6q27

In an association study of 2 independent Japanese populations, involving
a total of 847 patients with lumbar disc herniation (LDH) and 896
controls, Hirose et al. (2008) found a significant association between
an intronic SNP in the THBS2 gene (dbSNP rs9406328; 188061.0001) and
LDH. A missense SNP in the MMP9 gene (dbSNP rs17576) was also strongly
associated with LDH in the Japanese population and showed a
combinatorial effect with THBS2, with an odds ratio of 3.03 for the
genotype that was homozygous for the susceptibility alleles of both
SNPs.

- Association with the ASPN Gene on Chromosome 9q21.3-q22

Song et al. (2008) found an association of the D14 allele of the ASPN
gene (608135.0001) with lumbar disc degeneration in Chinese and Japanese
individuals. The presence of this allele had previously been associated
with susceptibility to knee osteoarthritis (165720).

- Association with the CILP Gene on Chromosome 15q22

Using a case-control association study, Seki et al. (2005) identified a
functional SNP in the CILP gene (I395T; 603489.0001), which encodes the
cartilage intermediate layer protein, that acts as a modulator of
susceptibility to lumbar disc disease.

Virtanen et al. (2007) analyzed the I395T SNP and flanking SNPs in the
CILP gene in 243 Finnish patients with symptoms of lumbar disc disease
and 259 controls, and in 348 Chinese individuals with MRI-defined lumbar
disc disease and 343 controls. The authors found no evidence of
association in the Finnish or Chinese samples and suggested that the
CILP gene is not a major risk factor for symptoms of lumbar disc disease
in Caucasians or in the general population.

- Association with the AGC1 Gene on Chromosome 15q26

In a study of 64 young Japanese women with or without low back problems,
Kawaguchi et al. (1999) demonstrated an association between lumbar disc
degeneration and a shorter variable number of tandem repeat (VNTR)
region in the chondroitin sulfate attachment domain of the AGC1 gene
(155760).

- Association with the COL9A3 Gene on Chromosome 20q13

Paassilta et al. (2001) demonstrated an association between a missense
polymorphism in the COL9A3 gene (120270.0003) and lumbar disc disease in
Finnish patients, with an approximately 3-fold increased risk of disease
with the so-called 'trp3' allele.

- Association with the MMP9 Gene on Chromosome 20q11.2-q13.1

In an association study of 2 independent Japanese populations involving
a total of 847 patients with lumbar disc herniation and 896 controls,
Hirose et al. (2008) found a significant association (corrected p =
0.0083) between LDH and a gln279-to-arg (Q279R) polymorphism (dbSNP
rs17576) in the MMP9 gene, located within the highly conserved
gelatinase-specific fibronectin type II domains. Hirose et al. (2008)
also found that an intronic SNP in the THBS2 gene (120361.0001) was
strongly associated with LDH in the Japanese population and resulted in
decreased THBS2 interaction with MMP2 (120360) and MMP9. They
demonstrated a combinatorial effect of MMP9 and THBS2 for LDH, with an
odds ratio of 3.03 for the genotype that was homozygous for the
susceptibility alleles (G and T, respectively) of both SNPs.

*FIELD* RF
1. Annunen, S.; Paasalita, P.; Lohinlva, J.; Perala, M.; Pihlajamaa,
T.; Karppinen, J.; Tervonen, O.; Kroger, H.; Lahde, S.; Vanharanta,
H.; Ryhanen, L.; Goring, H. H. H.; Ott, J.; Prockop, D. J.; Ala-Kokko,
L.: An allele of COL9A2 associated with intervertebral disc disease. Science 285:
409-411, 1999.

2. Battie, M. C.; Haynor, D. R.; Fisher, L. D.; Gill, K.; Gibbons,
L. E.; Videman, T.: Similarities in degenerative findings on magnetic
resonance images of the lumbar spines of identical twins. J. Bone
Joint Surg. Am. 77: 1662-1670, 1995.

3. 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.

4. Kawaguchi, Y.; Osada, R.; Kanamori, M.; Ishihara, H.; Ohmori, K.;
Matsui, H.; Kimura, T.: Association between an aggrecan gene polymorphism
and lumbar disc degeneration. Spine 24: 2456-2460, 1999.

5. Matsui, H.; Kanamori, M.; Ishihara, H.; Yudoh, K.; Naruse, Y.;
Tsuji, H.: Familial predisposition for lumbar degenerative disc disease:
a case-control study. Spine 23: 1029-1034, 1998.

6. Mio, F.; Chiba, K.; Hirose, Y.; Kawaguchi, Y.; Mikami, Y.; Oya,
T.; Mori, M.; Kamata, M.; Matsumoto, M.; Ozaki, K.; Tanaka, T.; Takahashi,
A.; Kubo, T.; Kimura, T.; Toyama, Y.; Ikegawa, S.: A functional polymorphism
in COL11A1, which encodes the alpha-1 chain of type XI collagen, is
associated with susceptibility to lumbar disc herniation. Am. J.
Hum. Genet. 81: 1271-1277, 2007.

7. Paassilta, P.; Lohiniva, J.; Goring, H. H. H.; Perala, M.; Raina,
S. S.; Karppinen, J.; Hakala, M.; Palm, T.; Kroger, H.; Kaitila, I.;
Vanharanta, H.; Ott, J.; Ala-Kokko, L.: Identification of a novel
common genetic risk factor for lumbar disk disease. JAMA 285: 1843-1849,
2001.

8. Sambrook, P. N.; MacGregor, A. J.; Spector, T. D.: Genetic influences
on cervical and lumbar disc degeneration: a magnetic resonance imaging
study in twins. Arthritis Rheum. 42: 366-372, 1999.

9. Seki, S.; Kawaguchi, Y.; Chiba, K.; Mikami, Y.; Kizawa, H.; Oya,
T.; Mio, F.; Mori, M.; Miyamoto, Y.; Masuda, I.; Tsunoda, T.; Kamata,
M.; Kubo, T.; Toyama, Y.; Kimura, T.; Nakamura, Y.; Ikegawa, S.:
A functional SNP in CILP, encoding cartilage intermediate layer protein,
is associated with susceptibility to lumbar disc disease. Nature
Genet. 37: 607-612, 2005.

10. Song, Y.-Q.; Cheung, K. M. C.; Ho, D. W. H.; Poon, S. C. S.; Chiba,
K.; Kawaguchi, Y.; Hirose, Y.; Alini, M.; Grad, S.; Yee, A. F. Y.;
Leong, J. C. Y.; Luk, K. D. K.; Yip, S.-P.; Karppinen, J.; Cheah,
K. S. E.; Sham, P.; Ikegawa, S.; Chan, D.: Association of the asporin
D14 allele with lumbar-disc degeneration in Asians. Am. J. Hum. Genet. 82:
744-747, 2008.

11. Virtanen, I. M.; Song, Y. Q.; Cheung, K. M. C.; Ala-Kokko, L.;
Karppinen, J.; Ho, D. W. H.; Luk, K. D. K.; Yip, S. P.; Leong, J.
C. Y.; Cheah, K. S. E.; Sham, P.; Chan, D.: Phenotypic and population
differences in the association between CILP and lumbar disc disease.
(Letter) J. Med. Genet. 44: 285-288, 2007.

*FIELD* CN
Marla J. F. O'Neill - updated: 6/10/2008
Victor A. McKusick - updated: 4/14/2008
Victor A. McKusick - updated: 11/28/2007
Marla J. F. O'Neill - updated: 6/5/2007
Victor A. McKusick - updated: 5/9/2005

*FIELD* CD
Victor A. McKusick: 6/23/1999

*FIELD* ED
carol: 10/09/2009
terry: 6/3/2009
carol: 6/11/2008
terry: 6/10/2008
alopez: 5/1/2008
terry: 4/14/2008
alopez: 12/3/2007
terry: 11/28/2007
terry: 9/14/2007
wwang: 6/8/2007
terry: 6/5/2007
wwang: 10/7/2005
wwang: 10/6/2005
terry: 9/19/2005
alopez: 6/13/2005
alopez: 5/10/2005
terry: 5/9/2005
cwells: 11/10/2003
cwells: 5/1/2002
carol: 11/4/1999
carol: 6/23/1999
jlewis: 6/23/1999

MIM 613073
*RECORD*
*FIELD* NO
613073
*FIELD* TI
#613073 METAPHYSEAL ANADYSPLASIA 2; MANDP2
*FIELD* TX
A number sign (#) is used with this entry because metaphyseal
read moreanadysplasia-2 (MANDP2) is caused by mutation in gene encoding matrix
metalloproteinase-9 (MMP9; 120361).

For a general phenotypic description and a discussion of genetic
heterogeneity of metaphyseal anadysplasia, see MANDP1 (602111).

CLINICAL FEATURES

Maroteaux et al. (1991) gave the designation metaphyseal anadysplasia
(ana = prefix meaning return) to an early-onset regressive form of
metaphyseal dysplasia. Diagnosis was possible in the first months when
distal metaphyses of long bones were found to be very irregular. Femoral
necks seemed hypoplastic and the edges of the metaphyses were almost
vertical. The femoral shaft was bowed. These anomalies disappeared after
age 2 years. The main manifestations were a slight shortness and varus
deformity of the lower limbs. Stature was not affected. Maroteaux et al.
(1991) reported 4 boys with this condition. The first patient with this
disorder was reported by Wiedemann and Spranger (1970) and Wiedemann
(1992) provided a follow-up into the patient's fifth decade.

Lausch et al. (2009) studied 5 families segregating metaphyseal
anadysplasia and distinguished 2 types: type 1 (Spranger type), a
clinically more severe type with reduced stature and autosomal dominant
inheritance over several generations in 3 kindreds; and type 2
(Maroteaux type), a milder type with normal stature and autosomal
recessive inheritance. The radiographic presentation of both types was
indistinguishable.

INHERITANCE

Lausch et al. (2009) confirmed autosomal recessive inheritance of MANDP2
by the finding a homozygous mutation in the MMP9 gene in affected
members of a family.

MOLECULAR GENETICS

In 2 sibs of a nonconsanguineous Pakistani family segregating
metaphyseal anadysplasia, 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; 120361.0005) substitution. In affected members of 4
other families, they identified heterozygous or homozygous mutations in
the MMP13 gene (600108.0002-600108.0004). Lausch et al. (2009) found
that recessive metaphyseal anadysplasia is caused by homozygous loss of
function of either MMP9 or MMP13, whereas dominant metaphyseal
anadysplasia is caused by missense mutations in the prodomain of MMP13
that determine autoactivation of MMP13 and intracellular degradation of
both MMP13 and MMP9, resulting in a double enzymatic deficiency.

*FIELD* RF
1. 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.

2. Maroteaux, P.; Verloes, A.; Stanescu, V.; Stanescu, R.: Metaphyseal
anadysplasia: a metaphyseal dysplasia of early onset with radiological
regression and benign course. Am. J. Med. Genet. 39: 4-10, 1991.

3. Wiedemann, H.-R.: Metaphyseal anadysplasia: observation of a patient
from infancy to the fifth decade of life. Dysmorph. Clin. Genet. 6:
123-127, 1992.

4. Wiedemann, H.-R.; Spranger, J.: Chondrodysplasia metaphysaria
(Dysostosis metaphysaria)-ein neuer Typ? Z. Kinderheilk. 108: 171-186,
1970.

*FIELD* CD
Nara Sobreira: 10/7/2009

*FIELD* ED
carol: 10/09/2009
carol: 10/9/2009