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PubMed2003

Expression and localization of extracellular matrix metalloproteinase inducer in giant cell tumor of bone.

Matrix metalloproteinases (MMPs) are regarded as a significant regulator in tumor invasion and metastasis. Previous studies have shown that extracellular matrix metalloproteinase inducer (EMMPRIN) in tumor cells induces the synthesis of MMPs. EMMPRIN is abundantly present on the surface of tumor cells and stimulate adjacent stromal cells to synthesize MMPs to induce tumor progression. Giant cell tumor (GCT) of bone is a benign but locally aggressive primary neoplasm of bone. The spindle-shaped mononuclear stromal cells are considered to be the tumor components of GCT, which are capable of inducing osteoclast formation by recruiting the circulating monocyte and macrophage. In this study, we proposed that EMMPRIN is associated with the biological progression and aggressiveness of GCT. We have conducted semi-quantitative RT-PCR to determine the correlation of EMMPRIN expression with the clinical stage of GCT. We have also examined the cellular localization of EMMPRIN in GCT using in-situ hybridization (ISH) and Immunohistochemistry (IH). The results showed that EMMPRIN was present in GCT and its mRNA levels were associated with the clinical stage of GCT. Higher expression level of EMMPRIN was observed in GCT with advanced stage (stage III). There was a great significance (P < 0.05) of EMMPRIN expression between stage I & II and stage III GCTs. Both ISH and IH demonstrated that EMMPRIN is present at the multinuclear osteoclast-like giant cells of GCT, with strong immunostaining on the cell membrane. The stromal-like tumor cells were also positively stained but the intensity was weaker. Interestingly, the production of EMMPRIN in osteoclast-like cells of GCT seems to be regulated by stromal-like tumor cells. Receptor activator of NF-kappaB ligand (RANKL), which has been previously shown to be produced by the stromal-like tumor cells for the recruitment of osteoclast-like giant cells in GCT, enhanced the expression of EMMPRIN mRNA during the differentiation of macrophage-like RAW(264.7) cells into osteoclasts. In short, our studies suggest that EMMPRIN may be an important regulatory factor involved in the biological behaviors of GCT.

Animals↗
PubMed2002

Matrilysin (matrix metalloproteinase-7) selects for apoptosis-resistant mammary cells in vivo.

Overexpression of the matrix metalloproteinase matrilysin (matrix metalloproteinase-7) in the mouse mammary gland promotes mammary hyperplasia and accelerates the onset of oncogene-induced mammary tumors. In cell culture models, acute exposure of cells coexpressing Fas and Fas ligand (FasL) to matrilysin induces apoptosis, whereas chronic exposure to matrilysin selects for apoptosis-resistant cells. We now demonstrate that matrilysin promotes resistance to apoptosis in vivo. Matrilysin expression increased apoptosis in the involuting mammary gland of mice that had undergone a single pregnancy and lactation cycle. Premature basement membrane disruption was detected in matrilysin-expressing mice, which could account for the increase in apoptosis. However, multiparous mice, in which the involuting mammary epithelial cells have been repeatedly exposed to matrilysin, show a significant decrease in apoptosis. Mammary tissue from multiparous matrilysin-expressing mice showed decreased FasL expression, suggesting that loss of FasL is at least one mechanism of matrilysin-induced resistance to apoptosis. We propose that matrilysin promotes mammary tumor formation by enhancing the selection of cells that are resistant to apoptosis.

Animals↗
PubMed2006

Comprehensive profiling and localisation of the matrix metalloproteinases in urothelial carcinoma.

The matrix metalloproteinases (MMPs) are endopeptidases which break down the extracellular matrix and regulate cytokine and growth factor activity. Several MMPs have been implicated in the promotion of invasion and metastasis in a broad range of tumours including urothelial carcinoma. In this study, RNA from 132 normal bladder and urothelial carcinoma specimens was profiled for each of the 24 human MMPs, the four endogenous tissue inhibitors of MMPs (TIMPs) and several key growth factors and their receptors using quantitative real time RT-PCR. Laser capture microdissection (LCM) of RNA from 22 tumour and 11 normal frozen sections was performed allowing accurate RNA extraction from either stromal or epithelial compartments. This study confirms the over expression in bladder tumour tissue of well-documented MMPs and highlights a range of MMPs which have not previously been implicated in the development of urothelial cancer. In summary, MMP-2, MT1-MMP and the previously unreported MMP-28 were very highly expressed in tumour samples while MMPs 1, 7, 9, 11, 15, 19 and 23 were highly expressed. There was a significant positive correlation between transcript expression and tumour grade for MMPs 1, 2, 8, 10, 11, 12, 13, 14, 15 and 28 (P < 0.001). At the same confidence interval, TIMP-1 and TIMP-3 also correlated with increasing tumour grade. LCM revealed that most highly expressed MMPs are located primarily within the stromal compartment except MMP-13 which localised to the epithelial compartment. This work forms the basis for further functional studies, which will help to confirm the MMPs as potential diagnostic and therapeutic targets in early bladder cancer.

Biomarkers, Tumor↗
PubMed1999

Expression of membrane type 1-matrix metalloproteinase in laryngeal carcinoma.

Membrane type 1-matrix metalloproteinase (MT1-MMP) is a member of the recently identified unique membrane-type subgroup in the matrix metalloproteinase (MMP) family. MT1-MMP has proteolytic activity against components of the extracellular matrix and activates progelatinase A (MMP-2) at the cell surface. In this study, we analyzed the expression of MT1-MMP mRNA in 45 cases of laryngeal carcinoma by RT-PCR and investigated the relationship between MT1-MMP expression and survival in 18 cases. The result showed that the expression of MT1-MMP mRNA was higher in tumor tissue than in corresponding normal tissue. The tumoral expression in clinical stage III was higher than in stage II. The tumoral expression level of MT1-MMP mRNA in patients with lymph node metastasis was signigicantly higher than those with negative lymph nodes. The patients with high expression level showed significantly poorer 5 year survival than those with low expression level. Collectively, our findings suggest that the high level of MT1-MMP expression is closely related to the invasion and metastasis of laryngeal carcinoma, and indicates poorer prognosis.

Actins↗
PubMed1996

Relaxed specificity of matrix metalloproteinases (MMPS) and TIMP insensitivity of tumor necrosis factor-alpha (TNF-alpha) production suggest the major TNF-alpha converting enzyme is not an MMP.

Tumor necrosis factor-alpha is released from cells by a proteolytic cleavage. Previous work suggested that a specific, non-matrix metalloproteinase carries out this cleavage, but matrix metalloproteinases have also been implicated. In this paper, we report that none of the matrix metalloproteinases tested cleaved peptide substrates as specifically as the non-matrix metalloproteinase. A matrix metalloproteinase did process tumor necrosis factor-alpha extracted from COS cells, but neither tissue inhibitor of metalloproteinases-1 nor -2 blocked tumor necrosis factor-alpha processing by human monocytes. Moreover, tissue inhibitor of metalloproteinases-1 had at most a partial effect on the in vivo release of the cytokine in mice. We conclude that a non-matrix metalloproteinase is the major physiological tumor necrosis factor-alpha convertase.

ADAM Proteins↗
PubMed1996

Suppression of matrix metalloproteinase production by hCG in cultures of human luteinized granulosa cells as a model for gonadotrophin-induced luteal rescue.

Granulosa cells were isolated from follicular aspirates collected at ovum recovery for in vitro fertilization. Cells were cultured in a defined medium on artificial extracellular matrix (Matrigel) in the presence or absence of hCG as a model for corpus luteum function. Release of cells from this culture system is reduced by hCG and this effect may be mediated through an inhibition of extracellular matrix degradation. Using zymography and western blot analysis, we confirm the identity of matrix metalloproteinases-2 and -9 in culture media. Matrix metalloproteinase-9 was the predominant gelatinase in freshly prepared granulosa cells and in culture media, and also represented a major metalloproteinase component in homogenates of early and mid-luteal phase samples of corpora lutea. Quantitative analysis of matrix metalloproteinases in culture media, obtained throughout the 14 day culture period and expressed per microgram of DNA, showed that matrix metalloproteinase-2, undetectable on day 2, rose throughout the culture period and that this rise was significantly inhibited by hCG. In contrast, matrix metalloproteinase-9 was clearly detectable on day 2 and remained relatively constant throughout much of the culture (day 2 to day 12) in the presence of gonadotrophin. Significantly increased production of matrix metalloproteinase-9 (day 6 to day 12) was evident in the absence of hCG. Our results provide further evidence for the hypothesis that the rescue of the corpus luteum in early pregnancy involves the maintenance of cellular function through the stabilization of the extracellular matrix.

Blotting, Western↗
PubMed1999

Differential regulation of platelet aggregation by matrix metalloproteinases-9 and -2.

We have recently found matrix metalloproteinase-2 (MMP-2) in human platelets and reported that the release of this enzyme during platelet activation stimulates aggregation. We have now identified matrix metalloproteinase-9 (MMP-9) in human platelets and resistance-sized (approximately 200 microm) arteries. Resting platelets released small quantities of pro-MMP-9. Maximal release of MMP-9 was detected during partial (appr. 30% maximum) aggregation with thrombin. However, maximal release of MMP-2 was associated with maximal aggregation. MMP-9 antibodies induced aggregation of resting platelets and potentiated aggregation of platelets induced by thrombin and collagen. Moreover, MMP-9 microisolated from arteries as well as recombinant human MMP-9 (0.1-30 ng/ml) inhibited thrombin and collagen-induced aggregation. We conclude that MMP-9 is an inhibitor of aggregation and in this action opposes the effects of MMP-2. The MMP-2/MMP-9 system may play an important role in the regulation of platelet-platelet and platelet-vessel wall interactions.

Arteries↗
PubMed2001

Production of matrix metalloproteinases in response to mycobacterial infection.

Matrix metalloproteinases (MMPs) constitute a large family of enzymes with specificity for the various proteins of the extracellular matrix which are implicated in tissue remodeling processes and chronic inflammatory conditions. To investigate the role of MMPs in immunity to mycobacterial infections, we incubated murine peritoneal macrophages with viable Mycobacterium bovis BCG or Mycobacterium tuberculosis H37Rv and assayed MMP activity in the supernatants by zymography. Resting macrophages secreted only small amounts of MMP-9 (gelatinase B), but secretion increased dramatically in a dose-dependent manner in response to either BCG or M. tuberculosis in vitro. Incubation with mycobacteria also induced increased MMP-2 (gelatinase A) activity. Neutralization of tumor necrosis alpha (TNF-alpha), and to a lesser extent interleukin 18 (IL-18), substantially reduced MMP production in response to mycobacteria. Exogenous addition of TNF-alpha or IL-18 induced macrophages to express MMPs, even in the absence of bacteria. The immunoregulatory cytokines gamma interferon (IFN-gamma), IL-4, and IL-10 all suppressed BCG-induced MMP production, but through different mechanisms. IFN-gamma treatment increased macrophage secretion of TNF-alpha but still reduced their MMP activity. Conversely, IL-4 and IL-10 seemed to act by reducing the amount of TNF-alpha available to the macrophages. Finally, infection of BALB/c or severe combined immunodeficiency (SCID) mice with either BCG or M. tuberculosis induced substantial increases in MMP-9 activity in infected tissues. In conclusion, we show that mycobacterial infection induces MMP-9 activity both in vitro and in vivo and that this is regulated by TNF-alpha, IL-18, and IFN-gamma. These findings indicate a possible contribution of MMPs to tissue remodeling processes that occur in mycobacterial infections.

Animals↗
PubMed1998

Expression of matrix metalloproteinases by human plasma cells and B lymphocytes.

Matrix metalloproteinases (MMP) are proteolytic enzymes that play a key role in tissue remodelling during physiological and pathological processes, by initiating the degradation of extracellular matrix. MMP overexpression can lead to tissue destruction which is characteristic of chronic inflammatory diseases such as rheumatoid arthritis and scleritis. Plasma cells are often abundant at such sites of chronic inflammation. In the present study we investigated whether plasma cells could contribute to matrix degradation by their expression of MMP In situ hybridization and immunohistochemical analyses on diseased synovial and scleral tissue demonstrated the expression of stromelysin-1 (MMP-3) and gelatinase B (MMP-9), but little or no tissue inhibitor of matrix metalloproteinase 1 (TIMP-1) mRNA, by IgG-positive plasma cells. Northern blot analysis of RNA extracted from a human plasma cell line (ARH-77), Epstein-Barr virus-transformed B cells, and purified peripheral blood B cells, demonstrated expression of stromelysin mRNA. TIMP-1 mRNA was only detected by the more sensitive reverse transcription PCR method in these cell types. Plasma cells and B lymphocytes cultured in the presence of monensin demonstrated cytoplasmic gelatinase B. Gelatin and casein zymography on conditioned media (CM) derived from cytokine treated plasma cells revealed the induction of secreted gelatinase and stromelysin activity. Western blotting confirmed the presence of stromelysin-1 and TIMP-1 proteins in plasma cell CM. These data suggest that plasma cells are not only capable of modulating an inflammatory response by antibody and cytokine production, but also by their ability to produce MMP. Secretion of MMP from focal aggregates of plasma cells may play a critical role in tissue destructive diseases such as rheumatoid synovitis and scleritis.

Arthritis, Rheumatoid↗
PubMed2005

Apoptotic efficacy and inhibitory effect of dexamethasone on matrix metalloproteinase.

BACKGROUND: There is now accumulating evidence that matrix metalloproteinases and apoptosis may play an important role in inflammation processes. This study was undertaken to determine the effect of dexamethasone on apoptosis and matrix metalloproteinase 2 (MMP-2) activity compared with two nonsteroidal anti-inflammatory drugs (NSAIDs), piroxicam and diclofenac. MATERIAL/METHODS: A fibrosarcoma (WEHI-164) cell line was used for evaluating tolerability, MMP-2 activity, and apoptosis. Dexamethasone, piroxicam, and diclofenac were used at concentrations of 10-200 microg/ml in triplicate, two-fold dilutions. MMP-2 activity was assessed using zymography. For assessment of apoptosis, terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) was used. RESULTS: Cytotoxicity analysis of dexamethasone showed a greater tolerability than diclofenac at concentrations of 10-100 microg/ml, whereas the cytotoxic effect of dexamethasone and piroxicam were parallel at doses of 5-80 microg/ml. The dose-dependent inhibitory effect of dexamethasone on MMP-2 activity was significantly less than that of the tested NSAIDs at concentrations of 10-80 microg/ml, while it increased at doses of >100 microg/ml compared with piroxicam. Moreover, the rate of apoptosis for dexamethasone-treated cells was 20.92%, the values for diclofenac and piroxicam being 78% and 28.15%, respectively. CONCLUSIONS: Our findings suggest that dexamethasone is able to induce apoptosis and suppress MMP-2 activity. Collectively, dexamethasone might be assumed as an agent which could be recommended for chemopreventive purposes.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2000

Biomechanical regulation of matrix metalloproteinase-9 in cultured chondrocytes.

Abnormal mechanical loading of joints may induce degeneration of articular cartilage. Shear stress is one mode of mechanical loading that may regulate chondrocyte metabolism. We investigated the mechanism by which shear stress induces the gene encoding matrix metalloproteinase-9, a mediator of the progressive degradation of articular cartilage in osteoarthritis. In vitro experiments using passaged rabbit chondrocytes in monolayer culture subjected to a shear stress of 16 dyn/cm2 (1.6 Pa) in a flow channel showed increased expression of the matrix metalloproteinase-9 gene. The induction of matrix metalloproteinase-9 appeared to depend on a region in the 5' promoter of the gene that contains a 12-0-tetradecanoylphorbol 13-acetate-responsive element. Transfection experiments using a construct containing a luciferase reporter driven by a 12-0-tetradecanoylphorbol 13-acetate-responsive element indicated that shear stress activated a 12-0-tetradecanoylphorbol 13-acetate-responsive element-mediated transcription in chondrocytes. Similar experiments showed that shear stress induced a matrix metalloproteinase-9 promoter construct (matrix metalloproteinase-9-luciferase). Shear stress activated c-Jun NH2-terminal kinase, extracellular signal-regulated kinase, and p38. Transfection of matrix metalloproteinase-9-luciferase together with the dominant negative mutant of c-Jun NH2-terminal kinase, but not with that of extracellular signal-regulated kinase or p38, attenuated the shear-induced matrix metalloproteinase-9 promoter activity. In addition, transfection of constructs encoding dominant negative mutants of Ras, Rac, and Cdc42 attenuated the induction of c-Jun transcriptional activity by shear stress. Thus. shear stimulation of chondrocytes stimulates Ras, Rac, and Cdc42, which subsequently activate c-Jun NH2-terminal kinase to induce a 12-0-tetradecanoylphorbol 13-acetate-responsive element-mediated expression of matrix metalloproteinase-9.

Animals↗
PubMedDate not supplied

TGF beta-like regulation of matrix metalloproteinases by anti-transforming growth factor-beta, and anti-transforming growth factor-beta 1 antibodies in dermal fibroblasts: Implications for wound healing.

Transforming growth factor beta (TGF-beta) stimulates collagen and matrix metalloproteinase-2 expression and inhibits MMP-1 expression in dermal fibroblasts. Anti-TGF-beta antibodies have been proposed in the prevention of wound scars. The goal of this research was to investigate the regulation of matrix metalloproteinases-1 and -2 expression at the protein, mRNA, and transcriptional levels using an anti-TGF-beta antibody to TGF-beta 1, 2, 3, and 5 (all isoforms), and specifically by an anti-TGF-beta 1 antibody. Both antibodies, though at doses lower than the recommended neutralization dose, stimulated the expression of TGF-beta, and exhibited TGF-beta-like regulation of the matrix metalloproteinases. The antibodies inhibited matrix metalloproteinase-1 protein, mRNA, and promoter activity. The protein levels of matrix metalloproteinase-2 were up-regulated to a greater extent than the matrix metalloproteinase-2 mRNA level by both antibodies. These effects of anti-TGF-beta and anti-TGF-beta 1 antibodies on matrix metalloproteinase regulation were mimicked by exogenous TGF-beta 1 but not rabbit or chicken IgG. We infer that the anti-TGF-beta1 isoform that forms part of the composition of the anti-TGF-beta antibody to all isoforms may be responsible for the feedback stimulation of TGF-beta and the resultant alterations in the expression of the matrix metalloproteinases by the anti-TGF-beta antibodies.

Antibodies↗
PubMed2002

Effects of the antirheumatic remedy hox alpha--a new stinging nettle leaf extract--on matrix metalloproteinases in human chondrocytes in vitro.

Inflammatory joint diseases are characterized by enhanced extracellular matrix degradation which is predominantly mediated by cytokine-stimulated upregulation of matrix metalloproteinase (MMP) expression. Besides tumour necrosis factor-alpha (TNF-alpha), Interleukin-1beta (IL-1beta) produced by articular chondrocytes and synovial macrophages, is the most important cytokine stimulating MMP expression under inflammatory conditions. Blockade of these two cytokines and their downstream effectors are suitable molecular targets of antirheumatic therapy. Hox alpha is a novel stinging nettle (Urtica dioica/Urtica urens) leaf extract used for treatment of rheumatic diseases. The aim of the present study was to clarify the effects of Hox alpha and the monosubstance 13-HOTrE (13-Hydroxyoctadecatrienic acid) on the expression of matrix metalloproteinase-1, -3 and -9 proteins (MMP-1, -3, -9). Human chondrocytes were cultured on collagen type-II-coated petri dishes, exposed to IL-1beta and treated with or without Hox alpha and 13-HOTrE. A close analysis by immunofluorescence microscopy and western blot analysis showed that Hox alpha and 13-HOTrE significantly suppressed IL-1beta-induced expression of matrix metalloproteinase-1, -3 and -9 proteins on the chondrocytes in vitro. The potential of Hox alpha and 13-HOTrE to suppress the expression of matrix metalloproteinases may explain the clinical efficacy of stinging nettle leaf extracts in treatment of rheumatoid arthritis. These results suggest that the monosubstance 13-HOTrE is one of the more active antiinflammatory substances in Hox alpha and that Hox alpha may be a promising remedy for therapy of inflammatory joint diseases.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2001

Amniotic fluid matrix metalloproteinase-8 in preterm labor with intact membranes.

OBJECTIVE: Intra-amniotic inflammation is a major determinant of maternal and neonatal outcome in patients with preterm labor. Matrix metalloproteinase-8 is a sensitive marker of inflammation in body fluids. This study was conducted to examine the value of amniotic fluid matrix metalloproteinase-8 determinations in patients with preterm labor and intact membranes. STUDY DESIGN: Amniotic fluid was obtained by transabdominal amniocentesis from 371 patients with preterm labor. Fluid was cultured for aerobic and anaerobic bacteria and Mycoplasmas. Amniotic fluid analysis included Gram stain examination, white blood cell count, and matrix metalloproteinase-8 (enzyme-linked immunosorbent assay) determination. Nonparametric statistics were used for analysis. RESULTS: The rate of preterm delivery was 54% (200/371) and that of intra-amniotic infection was 9.2% (34/371). The median amniotic fluid matrix metalloproteinase-8 concentration was more than 50-fold higher in patients with intra-amniotic infection than in patients with no intra-amniotic infection (median, 605.6 ng/mL; range, 0.65-15,000 ng/mL vs median, 10.6 ng/mL; range, <0.06-16,600 ng/mL, respectively; P <.0001). The matrix metalloproteinase-8 amniotic fluid concentrations were significantly higher in patients who delivered preterm than in patients who delivered at term (median, 19.5 ng/mL; range, <0.06-16,600 ng/mL vs median, 2.1 ng/mL; range, <0.06-500 ng/mL, respectively; P <.001). After exclusion of patients with intra-amniotic infection, patients who delivered preterm had a significantly higher median amniotic fluid matrix metalloproteinase-8 than patients who delivered at term (P <.05). An amniotic fluid matrix metalloproteinase-8 level of >30 ng/mL was an independent predictor for the occurrence of neonatal morbidity (odds ratio, 3.4; 95% CI, 1.9-5.8; P <.01). CONCLUSION: Increased amniotic fluid matrix metalloproteinase-8 concentrations identify patients at risk for intra-amniotic infection, impending preterm delivery, and adverse neonatal outcome.

Amniocentesis↗
PubMed1995

Matrix metalloproteinase inhibitors: a novel class of anticancer agents.

Matrix metalloproteinase inhibitors represent a new therapeutic approach to the treatment of advanced cancer. These inhibitors block the activity of proteolytic enzymes, matrix metalloproteinases, used by tumor cells to break down and remodel tissue matrices during the process of metastatic spread. As such they were regarded initially as inhibitors of metastasis. However, recent studies have shown that these inhibitors can also act to inhibit tumor growth by (i) preventing local invasion and promoting stromal encapsulation and (ii) by inhibiting tumor neovascularization. Matrix metalloproteinase inhibitors therefore have the potential to halt tumor progression and it is possible to envision their use as a low toxicity complement to cytotoxic therapies. Batimastat (BB-94) is the first inhibitor of this class to enter clinical trial in cancer patients. In a phase I/II trial in patients with malignant ascites batimastat was well tolerated and there were preliminary signs of efficacy.

Animals↗
PubMed2000

Identification of matrix metalloproteinases in canine neoplastic tissue.

OBJECTIVE: To identify matrix metalloproteinases (MMP) 2 and 9 in canine tumor tissue and to compare the amount of activity to that in unaffected stromal tissue. ANIMALS: 30 dogs with spontaneously developing, high-grade osteosarcoma. PROCEDURE: Tumor and nearby stromal tissue (muscle) were obtained at the time of surgery. Specimens were homogenized, and supernatants were assayed, using gelatin zymography. Human derived standards were run concurrently. Densitometry was done to obtain a semiquantitative arbitrary unit value for each specimen. The amount of activity in tumor tissue was compared with the amount in stromal tissue. RESULTS: Gelatinolytic bands were observed from the analysis of all tumor tissues and in most stromal tissues. These bands migrated in the same molecular weight area as the human MMP 2 and 9 standards. Gelatinolytic activity could be quenched by the addition of 50 mM EDTA and 1 microg of synthetic tissue inhibitor of metalloproteinase (TIMP) 2 per 100 ml. There was significantly more gelatinolytic activity in tumor tissue than in stromal tissue. CONCLUSIONS AND CLINICAL RELEVANCE: MMP 2 and 9 are detectable in canine neoplastic tissue. Matrix metalloproteinases activity in tumor tissue is higher than in unaffected stromal tissue, indicating that canine MMP may be involved in the pathogenesis of tumor growth and metastasis.

Animals↗
PubMed2006

A single nucleotide polymorphism in the matrix metalloproteinase 9 gene (-8202A/G) is associated with thoracic aortic aneurysms and thoracic aortic dissection.

OBJECTIVE: Matrix metalloproteinase 9 plays an important role in the maintenance of the aortic extracellular matrix. Genetic variations that affect protease expression or activity might contribute to thoracic aortic disease. The purpose of this study was to determine whether 3 single nucleotide polymorphisms in the matrix metalloproteinase 9 gene are associated with thoracic aortic aneurysms and dissection. METHODS: Genomic DNA was isolated from blood or aortic tissue from 28 patients with degenerative thoracic aortic aneurysms, 60 patients with thoracic aortic dissection, and 111 control patients. The frequency distributions of 3 matrix metalloproteinase 9 single nucleotide polymorphisms (-8202A/G, IVS4+3G/T, and 2003A/G [Q668R]) were determined by using genotyping accomplished with a real-time detection system. Associations between polymorphisms and disease were estimated with odds ratios and their 95% confidence intervals. RESULTS: The frequency of the -8202G allele was significantly higher in patients with thoracic aortic aneurysms and aortic dissection (0.52 and 0.56, respectively) than in control subjects (0.36, P < .001). Patients with thoracic aortic aneurysms or dissection were nearly 5 times more likely than control subjects to have the G allele (adjusted odds ratio, 4.87; 95% confidence interval, 2.04-11.64). There were no significant associations between the IVS4+3G/T or 2003A/G polymorphisms and thoracic aortic disease. CONCLUSIONS: The matrix metalloproteinase 9 -8202A/G polymorphism is associated with thoracic aortic aneurysms and dissection. Further studies are warranted to elucidate the functional role of the -8202A/G variant in matrix metalloproteinase 9 expression.

Adolescent↗
PubMed1999

Design and synthesis of phosphinamide-based hydroxamic acids as inhibitors of matrix metalloproteinases.

A new series of hydroxamic acid-based matrix metalloproteinase (MMP) inhibitors containing a unique phosphinamide motif derived from D-amino acid was designed, synthesized, and tested for enzyme inhibition. Compounds with an R configuration at phosphorus were found to be potent MMP inhibitors while molecules with the S configuration were almost inactive. Structure-activity relationship studies of the series led to the discovery of the potent inhibitor 16 with IC50 = 20.5 nM and 24.4 nM against fibroblast collagenase (MMP-1) and stromelysin (MMP-3), respectively. The binding mode of this novel phosphinamide-based series of MMP inhibitors was established based on X-ray crystallography of the complex of stromelysin and 16.

Binding Sites↗