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PubMed2006

Ethanol stimulates the secretion of matrix metalloproteinases 2 and 9 in MCF-7 human breast cancer cells.

Alcohol consumption is a well-established risk factor for hormone-dependent breast cancer. In vitro studies performed to understand the mechanisms by which ethanol acts on breast cancer cells have shown that this compound stimulates both proliferation and migration. In the present study, we show by gelatin zymography that, when exposed to ethanol, MCF-7 human breast cancer cells display a higher amount of active metalloproteinases (MMP) 2 and 9 in their culture medium. This increase is somewhat higher than those observed in the case of 17beta-estradiol (E2) exposure. As expected, anti-estrogen ICI 182,780 inhibits the E2-induced overexpression of a well-known estrogen responsive gene, the progesterone receptor, in MCF-7 cells. ICI 182,780 also inhibits the E2-induced increase in MMP-2 and -9 secretion. Nevertheless, in the case of ethanol exposure, this ER ant-agonist was only efficient on MMP-9 secretion. In addition, although MMP-9 transcription was not sensitive to E2 or ethanol, MMP-2 transcription was stimulated in MCF-7 cells exposed to ethanol. Collectively, these results give new insights into the effects of alcohol on breast cancer cell migration, which are not due solely to an estrogen-like activity of alcohol.

Breast Neoplasms↗

PubMed2002

Genotype association of C(-735)T polymorphism in matrix metalloproteinase 2 gene with G(8002)A endothelin 1 gene with plaque psoriasis.

BACKGROUND: Excessive angiogenesis is one of the characteristic features of psoriasis. OBJECTIVE: To determine the possible genetic background of neo-angiogenesis in plaque psoriasis, frequent polymorphisms in matrix metalloproteinase 2 (MMP-2) and endothelin 1 (ET-1) genes were studied. METHODS: The case group (n = 119) included patients with plaque psoriasis, aged 44 +/- 15 years. The age of onset of psoriasis was 27 +/- 11 years. The control group (n = 184) consisted of healthy subjects without any individual history of psoriasis, aged 37 +/- 15 years. C(-735)T MMP-2 and G(8002)A ET-1 polymorphisms were determined by PCR reaction with subsequent restriction analyses. RESULTS: A significant difference in genotype distribution of C(-735)T MMP-2 between psoriatic and control patients was found (p(corr) = 0.008). Two associated genotypes (CCGG and CTGG) of the two polymorphisms were significantly less frequent in psoriatic patients (p(corr) = 0.03 and p(corr) = 0.008, respectively). CONCLUSION: The results seem to reflect a different susceptibility of MMP-2 as well as of some associated MMP-2 and ET-1 genotypes to psoriasis.

Adult↗

PubMed2004

Expression and importance of matrix metalloproteinase 2 and 9 (MMP-2 and -9) in human trophoblast invasion.

BACKGROUND: The aim of this study was to examine the invasiveness of first trimester trophoblasts according to the secretion profile of MMP-2 and -9 at different gestational stages, and to test the similarity between primary trophoblast cell-culture and the JAR choriocarcinoma cell-line. METHODS: First trimester trophoblasts were divided into two groups: 6-8 weeks (early) and 9-12 w (late) of gestation. The two trophoblast groups and JAR cells were cultured in medium, with various concentrations of forskolin and Epidermal Growth Factor (EGF). Proteolytic activity was detected by zymography and invasiveness was assessed by Matrigel invasion assay. Student's T-test was used for statistical analysis. RESULTS: In 6-8 w trophoblast, proMMP-2 was only slightly dominant over proMMP-9 (53.2% vs. 46.8% respectively), whereas in 9-12 w, proMMP-9 was clearly dominant over proMMP-2 (61.7% vs.38.3% respectively). In JAR cells proMMP-2 was strongly dominant (90.2% vs.9.8% respectively). In JAR cells forskolin significantly increased proMMP-2 and -9 secretion (128.5% +/- 12 and 183.2% +/- 27.9 of control, respectively). EGF had a dual effect on JAR cells: at 8 ng/ml both proMMP-2 and -9 were increased (133.5% +/-15 and 223.9% +/- 32.4 of control, respectively) while at 80 ng/ml both proMMP-2 and -9 were decreased (65.1% +/- 18.3 and 66.6% +/- 37 of control, respectively). Forskolin significantly increased both proMMP-2 and -9 secretion in 6-8 w and 9-12 w trophoblasts (125.9% +/- 6.3,128.4% +/- 6.4; 169.7% +/- 20.3, 120.3% +/- 4.5 of control, respectively). EGF also significantly increased both proMMP-2 and -9 secretion in 6-8 w and 9-12 w trophoblasts (141.22% +/- 14.8, 138.8% +/- 10.3; 168.3% +/- 18.2, 117.3 +/- 3.8 of control, respectively). Both forskolin and EGF increased trophoblast cells invasiveness in all groups. The invasive ability of trophoblast cells, induced by forskolin, was reduced by MMP-2 antibody in: JAR cells, 6-8 w and 9-12 w trophoblasts. Likewise trophoblast invasion induced by EGF was reduced by MMP-2 antibody in all groups. However the invasive ability induced by forskolin or EGF was inhibited by MMP-9 antibody only in trophoblasts from 9-12 w. CONCLUSIONS: First trimester trophoblasts express differential gelatinase secretion profile according to the gestational week. In JAR and early trophoblasts (6-8 w) MMP-2 is the main gelatinase and the key enzyme in trophoblast invasion. Thereafter in late first trimester trophoblasts (9-12 w), both MMP-2 and -9 participate in trophoblast invasion.

Cell Line, Tumor↗

PubMed1994

Immunohistochemical localization of matrix metalloproteinase 2 and its specific inhibitor TIMP-2 in neoplastic tissues with monoclonal antibodies.

Matrix metalloproteinase-2 (MMP-2), synthesized as a 631 amino-acid proenzyme, is activated by cleavage of the first 80 amino acids and naturally inhibited by tissue inhibitor of metalloproteinase-2 (TIMP-2). We report here the production of MAbs against MMP-2 and TIMP-2 and their use in localizing the respective antigens on tumor tissues. The anti-MMP-2 MAb recognized the latent and activated MMP-2 mutant protein (mutein) with C-terminal deletion at amino acid 425, indicating that both N- and C-terminal amino acids of MMP-2 are not important for its binding. The binding study of anti-TIMP-2 MAb, using several C-terminally truncated TIMP-2 muteins, showed that the amino acids 111-126 of TIMP-2 are essential for the binding of this antibody. Besides their respective antigens, both MAbs also recognized the MMP-2/TIMP-2 complex. On frozen sections of breast tumor, anti-MMP-2 MAb stained mainly tumor-cell cytoplasm with varying intensity, while anti-TIMP-2 MAb gave a stromal staining of varying intensity and a weak or absent staining of tumor-cell cytoplasm, suggesting different localization of the proteins in these tumors. In addition, in 1/3 of the breast cases both antibodies also localized on tumor-cell membranes. Similar cytoplasmic and stromal but not membrane staining patterns were observed in colon, gastric, endometrial, squamous-cell, prostatic and ovarian carcinoma as well. Since MMP-2 degrades type-IV collagen, the major component of basement membranes, the differences between MMP-2 and TIMP-2 levels and localization in individual tumors may relate to the invasiveness of the tumor and thus provide predictive information. However, this aspect could not be discussed in this study because no biological and clinical parameters such as lymph-node involvement or Dukes' stage of the tumors were available.

Animals↗

PubMed2001

Lysophosphatidylcholine increases the secretion of matrix metalloproteinase 2 through the activation of NADH/NADPH oxidase in cultured aortic endothelial cells.

Matrix metalloproteinases (MMPs) play a pivotal role in angiogenesis, atherogenesis, vascular remodeling after vascular injury, and instability of atherosclerotic plaque. The present study was undertaken to investigate the effect of lysophosphatidylcholine, a major component of oxidized low density lipoprotein (LDL), on the regulation of MMPs in cultured bovine aortic endothelial cells (BAECs). Furthermore, we explored the potential role of oxidative stress in the regulation of MMP. LPC increased the secretion of gelatinolytic activity, as well as, protein of MMP-2 from BAECs. The stimulation of BAEC with superoxide increased the production of MMP-2 and it also induced its activation. Electron spin resonance (ESR) with 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) as spin trap agent demonstrated that lysophosphatidycholine (LPC) induced generation of reactive oxygen (ROS) species from BAECs. The inhibition of NADH/NADPH oxidase, one of the potential sources of superoxide in endothelial cells, attenuated the effect of LPC. Our findings suggest that LPC might activate the endothelial NADH/NADPH oxidase to enhance superoxide production, and it might, in turn, enhance MMP-2 induction.

Animals↗

PubMed1995

Steps involved in activation of the complex of pro-matrix metalloproteinase 2 (progelatinase A) and tissue inhibitor of metalloproteinases (TIMP)-2 by 4-aminophenylmercuric acetate.

Tissue inhibitor of metalloproteinases (TIMP)-2 forms a noncovalent complex with the precursor of matrix metalloproteinase 2 (proMMP-2, progelatinase A) through interaction of the C-terminal domain of each molecule. We have isolated the proMMP-2-TIMP-2 complex from the medium of human uterine cervical fibroblasts and investigated the processes involved in its activation by 4-aminophenylmercuric acetate (APMA). The treatment of the complex with APMA-activated proMMP-2 by disrupting the Cys73-Zn2+ interaction of the zymogen. This is triggered by perturbation of the proMMP-2 molecule, but not by the reaction of the SH group of Cys73 with APMA. The 'activated' proMMP-2 (proMMP-2*) formed a new complex with TIMP-2 by binding to the N-terminal inhibitory domain of the inhibitor without processing the propeptide. Thus the APMA-treated proMMP-2*-TIMP-2 complex exhibited no gelatinolytic activity. In the presence of a small amount of free MMP-2, however, proMMP-2* in the complex was converted into the 65 kDa MMP-2 by proteolytic attack of MMP-2, but the complex did not exhibit gelatinolytic activity. The gelatinolytic activity detected after APMA treatment was solely derived from the activation of free proMMP-2. The removal of the propeptide of the proMMP-2* bound to TIMP-2 was also observed by MMP-3 (stromelysin 1), but not by MMP-1 (interstitial collagenase). MMP-3 cleaved the Asn80-Tyr81 bond of proMMP-2*. On the other hand, when MMP-3 was incubated with the proMMP-2-TIMP-2 complex, it bound to TIMP-2 and rendered proMMP-2 readily activatable by APMA. These results indicate that the blockage of TIMP-2 of the complex with an active MMP is essential for the activation of proMMP-2 when it is complexed with TIMP-2.

Cervix Uteri↗

PubMed1997

Membrane-type-2 matrix metalloproteinase can initiate the processing of progelatinase A and is regulated by the tissue inhibitors of metalloproteinases.

Membrane-type-1 matrix metalloproteinase has been identified as an activator of the matrix metalloproteinase progelatinase A at cell surfaces. We report here that a soluble active form of membrane-type-2 matrix metalloproteinase can also process progelatinase A in a comparable fashion to the type-1 at rates which are dependent on the concentration of the proenzyme. Activation is inhibited by tissue inhibitors of metalloproteinases TIMP-2 and TIMP-3, but only partially by TIMP-1. These results suggest that cellular activation of progelatinase A may be initiated by different members of the membrane-type matrix metalloproteinase family depending on tissue distribution.

Amino Acid Sequence↗

PubMed1997

Prostaglandin E2 stimulates expression of matrix metalloproteinase 2 in cultured rat mesangial cells.

Prostaglandins of the E-series have been demonstrated to reduce extracellular accumulation of collagens in some models of glomerulonephritis. This effect is partially due to reduction of collagen formation by mesangial cells. The potential effects of prostaglandins on the expression of collagen degrading enzymes in mesangial cells are largely unknown. Since rat mesangial cells generate a matrix metalloproteinase 2 (MMP-2) that specifically degrades collagen type IV, the effects of prostaglandin E2 (PGE2) on transcription, steady-state mRNA levels, extracellular enzyme activity and protein concentration of this proteinase were evaluated. Mesangial cells (MC) were incubated with PGE2 (2 microM) for different time-periods (1 to 48 hr), and steady-state mRNA levels of MMP-2 were determined by Northern blotting. PGE2 increased MMP-2 mRNA levels beginning at one hour of incubation and remained elevated up to 24 hours. Nuclear run off experiments revealed that the PGE2-induced increase in mRNA expression for MMP-2 is due to stimulated gene transcription. Western blot analysis and zymography revealed that MMP-2 protein production and enzyme activity was also enhanced by PGE2. The cAMP analogue 8-bromo-cAMP increased MMP-2 mRNA levels, suggesting that PGE2-induced generation of intracellular cAMP plays a role in MMP-2 induction in MC. These studies demonstrate that PGE2 stimulates the transcription, protein formation and enzyme activity of MMP-2 in cultured rat MC. This effect may contribute to the prostaglandin mediated reduction of extracellular collagen deposition in glomerulonephritis.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed2002

Matrix metalloproteinase 2 is involved in the regulation of the antimicrobial peptide parasin I production in catfish skin mucosa.

A 19-residue antimicrobial peptide parasin I is generated from histone H2A in the skin mucus of catfish by the action of cathepsin D activated by a procathepsin D-processing enzyme induced upon epidermal injury. Here we report the isolation and characterization of the procathepsin D-processing enzyme in the mucus of wounded catfish. Sequence analysis of the cDNA identified the purified procathepsin D-processing enzyme as matrix metalloproteinase 2 (MMP 2). By acting as a procathepsin D convertase upon epidermal injury, MMP 2 is involved in the regulation of parasin I production in catfish skin mucosa.

Amino Acid Sequence↗

PubMed1997

Characterisation of equine matrix metalloproteinase 2 and 9; and identification of the cellular sources of these enzymes in joints.

The cellular production by resident articular cells and infiltrating inflammatory cells of the gelatinase matrix metalloproteinases (MMP) was investigated by tissue culture methods and analysis of cell supernatants by gelatin zymography. Peripheral blood neutrophils in short term culture produced MMP-9, as did peripheral blood monocytes in culture. Isolated articular chondrocytes in monolayer culture produced both MMP-2 and MMP-9, although articular cartilage maintained as explant culture produced MMP-2 alone. Synovial fibroblasts grown in monolayer culture produced MMP-2 alone, although synovial membrane in explant culture produced both MMP-2 and the active form of MMP-2. Lysis of blood polymorph neutrophils produced large quantities of MMP-9, but lysis of blood monocytes, synovial fibroblasts and articular chondrocytes produced little enzyme indicating that, unlike the other cell types, polymorph neutrophils store MMPs intracellularly. Equine MMP-2 was purified from synovial fibroblast cell culture supernatant, and equine MMP-9 from polymorph neutrophil cell culture supernatant, by gelatin-sepharose affinity chromatography. The 2 enzymes were identified from their molecular weights and by their respective N-terminal amino acid sequences which showed homology with the enzymes from other species. The demonstration that invasive cells and resident articular cells can produce enzymes which are capable of digestion of certain component molecules of the articular cartilage matrix, shows that therapeutic targeting of these enzymes could be a valid proposition in the prevention of cartilage destruction in osteoarthritis.

Amino Acid Sequence↗

PubMed2003

Cyclosporine A up-regulates expression of matrix metalloproteinase 2 and vascular endothelial growth factor in rat heart.

Cyclosporine A (CsA) is the first immunosuppressant universally used in allotransplantation. However, it has been demonstrated that this drug produces side effects in several organs, particularly in the kidney and in the heart. Since the immunosuppressive therapy induces myocardial toxicity, the aim of this study was to evaluate in the myocardium of CsA-treated rats the expression variations of vascular endothelial growth factor (VEGF) and matrix metalloproteinase 2 (MMP2), to verify if: VEGF increased, VEGF increase was associated with MMP2 increase and they could be considered as repair proteins. The study was carried out on 28 Wistar rats divided into two groups. The group I animals served as control and so they were subcutaneously injected daily with castor oil for 21 days; group II: animals were subcutaneously injected daily with CsA (Sandimmun, Sandoz) at the therapeutic dose (15 mg/kg) for 21 days. The group I animals (control) showed normal heart architecture and low levels of MMP2 and VEGF. The group II animals (CsA-treated) showed structural degenerative changes with myocardial fibrosis and a clear increase both in MMP2 and VEGF. These data show that the immunosuppressant therapy induces a high increase in both the proteins and that VEGF variations are associated with MMP2 variations. These findings suggest that these proteins are involved in the endogenous emergency cell mechanisms induced by stress conditions, probably playing a role against myocardial injury as repair proteins.

Animals↗

PubMed2005

Winchester syndrome caused by a homozygous mutation affecting the active site of matrix metalloproteinase 2.

The inherited osteolysis syndromes are a heterogeneous group of skeletal disorders whose classification is still uncertain. Three osteolysis syndromes show autosomal recessive inheritance and multicentric involvement: Torg syndrome (OMIM 259600), Winchester syndrome (OMIM 277950) and Nodulosis-Arthropathy-Osteolysis syndrome (NAO; OMIM 605156). The 2001 Nosology of the International Skeletal Dysplasia Society (Hall CM, Am J Med Genet 2002: 113: 65) classifies NAO as a variant of Torg syndrome, while Winchester syndrome is considered as a separate disorder. Recently, mutations in the matrix metalloproteinase 2 (MMP2) gene were identified in affected individuals with a clinical diagnosis of NAO in two Arab families. We report a homozygous missense mutation (E404K) in the active site of MMP2 in a 21-year-old woman with a severe form of osteolysis best compatible with a diagnosis of Winchester syndrome. The clinical and molecular findings suggest that Torg, NAO and Winchester syndromes are allelic disorders that form a clinical spectrum.

Adult↗

PubMed1997

Unaltered secretion of beta-amyloid precursor protein in gelatinase A (matrix metalloproteinase 2)-deficient mice.

The beta-amyloid peptide, which forms extracellular cerebral deposits in Alzheimer's disease, is derived from a large membrane-spanning glycoprotein referred to as the beta-amyloid precursor protein (APP). The APP is normally cleaved within the beta-amyloid region by a putative proteinase (alpha-secretase) to generate large soluble amino-terminal derivatives of APP, and this event prevents the beta-amyloid peptide formation. It has been suggested that the gelatinase A (matrix metalloproteinase 2, a 72-kDa type IV collagenase) may act either as alpha-secretase or as beta-secretase. Mice devoid of gelatinase A generated by gene targeting develop normally, except for a subtle delay in their growth, thus providing a useful system to examine the role of gelatinase A in the cleavage and secretion of APP in vivo. We show here that APP is cleaved within the beta-amyloid region and secreted into the extracellular milieu of brain and cultured fibroblasts without gelatinase A activity. The data suggest that gelatinase A does not play an essential role in the generation and release of soluble derivatives of APP at physiological conditions.

Amyloid beta-Protein Precursor↗

PubMed1997

Primate smooth muscle cell migration from aortic explants is mediated by endogenous platelet-derived growth factor and basic fibroblast growth factor acting through matrix metalloproteinases 2 and 9.

BACKGROUND: Migration of arterial smooth muscle cells (SMCs) is regulated by basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), and matrix metalloproteinases (MMPs) in the injured rat carotid artery. We have recently shown that migration of SMCs from baboon aortic explants depends on the activity of MMPs, but the identity of the stimulatory MMPs and the role of bFGF and PDGF in this primate system are not known. METHODS AND RESULTS: These experiments were designed to determine whether MMP2, MMP9, bFGF, or PDGF plays a role in SMC migration from medial explants of baboon aorta. Explants were cultured in serum-free medium with insulin, transferrin, and ovalbumin. Neutralizing antibodies to MMP2 and antibodies that inhibit activation of proMMP9 decreased SMC migration from the aortic explants. Antibodies to bFGF and to the alpha- and beta-subunits of the PDGF receptor also inhibited migration from the explants. Addition of bFGF and PDGF-BB but not PDGF-AA increased migration. The antibodies to bFGF but not the antibodies to the PDGF receptor subunits decreased the levels of MMP9, whereas all the antibodies decreased activated MMP2. CONCLUSIONS: These data demonstrate that SMC migration from primate aortic explants is dependent on endogenous MMP2, MMP9, PDGF, and bFGF. The data also suggest that PDGF-induced (PDGF-BB or possibly PDGF-AB) migration is dependent on MMP2, whereas bFGF-induced migration depends on both MMP2 and MMP9.

Animals↗

PubMed2003

Matrix metalloproteinases 2 and 9 mediate epidermal growth factor receptor transactivation by gonadotropin-releasing hormone.

Rapid engagement of the extracellular signal-regulated kinase (ERK) cascade via the Gq/11-coupled GnRH receptor (GnRHR) is mediated by transactivation of the epidermal growth factor receptor (EGFR). Here we show that the cross-talk between GnRHR and EGFR in gonadotropic cells is accomplished via gelatinases A and B (matrix metalloproteinases (MMPs) 2 and 9), identifying gelatinases as the first distinct members of the MMP family mediating EGFR transactivation by G protein-coupled receptors. Using a specific MMP2 and MMP9 inhibitor, Ro28-2653, GnRH-dependent EGFR transactivation was abrogated. Proving the specificity of the effect, transient transfection of alphaT3-1 cells with ribozymes directed against MMP2 or MMP9 specifically blocked EGFR tyrosine phosphorylation in response to GnRH stimulation. GnRH challenge of alphaT3-1 cells furthered the release of active MMP2 and MMP9 and increased their gelatinolytic activities within 5 min. Rapid release of activated MMP2 or MMP9 was inhibited by ribozyme-targeted down-regulation of MT1-MMP or MMP2, respectively. We found that GnRH-induced Src, Ras, and ERK activation were also gelatinase-dependent. Thus, gelatinase-induced EGFR transactivation was required to engage the extracellular-signal regulated kinase cascade. Activation of c-Jun N-terminal kinase and p38 MAPK by GnRH was unaffected by EGFR or gelatinase inhibition that, however, suppressed GnRH induction of c-Jun and c-Fos. Our findings suggest a novel role for gelatinases in the endocrine regulation of pituitary gonadotropes.

Animals↗

PubMed1995

Release of gelatinase A (matrix metalloproteinase 2) induced by photolysis of caged phosphatidic acid in HT 1080 metastatic fibrosarcoma cells.

Phosphatidic acid (PA) is a putative novel messenger in signal transduction and membrane traffic. We have synthesized a photolyzable derivative of PA, termed caged PA (cPA), which may be utilized as a new tool in studies of PA-mediated cellular events. 1-(2-Nitrophenyl)diazoethane, synthesized from 2-nitroacetophenone, was reacted with dipalmitoyl-PA to yield a 1-(2-nitrophenyl)ethyl ester of PA. Photolysis of the compound by ultraviolet light resulted in the formation of phosphatidic acid. The structure of the compound and of its photolytic products was verified by NMR spectroscopy. The utility of cPA was examined in HT 1080 metastatic fibrosarcoma cells, in which the formation of PA by phospholipase D was implicated in laminin-induced release of gelatinase A (matrix metalloproteinase 2 (MMP-2)). The uptake of cPA by HT 1080 cells reached a plateau after 120 min of incubation. Ultraviolet illumination of cPA-loaded cells for 5 s resulted in photolysis of 1.8% of the cell-incorporated cPA. The photolysis of cPA caused a 2-fold elevation in the release of MMP-2 to the medium, whereas nonphotolyzed cPA caused no change in MMP-2 release. Moreover, the effect of cPA photolysis was significantly higher than that obtained with extracellularly introduced PA. Thus, the effect of laminin on MMP-2 secretion can be mimicked by photolysis of cPA, suggesting a pivotal role for phospholipase D in laminin-induced cancer cell invasiveness and metastasis. These results indicate that cPA could serve as a unique tool for studying the cellular roles of PA.

Cell Line↗

PubMed2003

A new approach for the treatment of malignant melanoma: enhanced antitumor efficacy of an albumin-binding doxorubicin prodrug that is cleaved by matrix metalloproteinase 2.

The progression of malignant melanoma is characterized by overexpression of a number of matrix metalloproteinases (MMPs), especially MMP-2, which play a critical role in the degradation of basement membranes and the extracellular matrix. Consequently, we assessed a drug targeting strategy in which the protease activity of MMP-2 is exploited to release an anticancer agent from a macromolecular carrier, i.e., circulating albumin. For this purpose, a water-soluble maleimide derivative of doxorubicin (1) incorporating a MMP-2 specific peptide sequence (Gly-Pro-Leu-Gly-Ile-Ala-Gly-Gln) was developed that binds rapidly and selectively to the cysteine-34 position of circulating albumin. The albumin-bound form of 1 was efficiently and specifically cleaved by MMP-2 liberating a doxorubicin tetrapeptide (Ile-Ala-Gly-Gln-DOXO) and subsequently doxorubicin. In vivo, 1 was superior to the parent compound doxorubicin in the A375 human melanoma xenograft, which is characterized by a high expression of MMP-2.

Albumins↗

PubMed2005

Al-Aqeel Sewairi syndrome, a new autosomal recessive disorder with multicentric osteolysis, nodulosis and arthropathy. The first genetic defect of matrix metalloproteinase 2 gene.

OBJECTIVE: We report a distinctive autosomal recessive multicentric osteolysis in Saudi Arabian families with distal arthropathy of the metacarpal, metatarsal and interphalangeal joints, with ultimate progression to the proximal joints with decreased range of movements and deformities with ankylosis and generalized osteopenia. In addition, they had large, painful to touch palmar and plantar pads. Hirsutism and mild dysmorphic facial features including proptosis, a narrow nasal bridge, bulbous nose and micrognathia. METHODS: Using a genome-wide search for microsatellite markers from 11 members of the family from the Armed Forces Hospital and King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia, localized the disease gene to chromosome 16q12-21. Haplotype analysis with additional markers narrowed the critical region to 1.2cM and identified the matrix metalloproteinase 2 (MMP-2), (gelatinase A, collagenase type IV, EC 3.4, 24,24) gene as a disease candidate at Mount Sinai School of Medicine, New York, United States of America in April 2000. RESULTS: Some affected individuals were homoallelic for a nonsense mutation (TCA>TAA) in codon 244 of exon 5, predicting the replacement of a tyrosine residue by a stop codon in the first fibronectin type II domain (Y244X). Other affected members had a missense mutation in exon 2 arginine 101-histidine (R101H) leading to no MMP-2 enzyme activity in serum or fibroblast or both of affected individuals. In other affected members, a non-pathogenic homoallelic GT transversion resulted in the substitution of an aspartate with a tyrosine residue in codon 210 of exon 4 (D210Y). The MMP-2-null mouse has no developmental defects, but are small, which may reflect genetic redundancy. CONCLUSION: The discovery that deficiency of this well-characterized gelatinase/collagenase results in an inherited form of an osteolytic and arthritic disorder provides an invaluable insights for the understanding of osteolysis and arthritis and is the first genetic evidence that MMP2 deficiency is important in growth and development.

Child, Preschool↗