Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.23 (MMP)
 4,246 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Differentiation between age (physiological) and disease-induced changes in the nucleus pulposus will facilitate our understanding of the mechanism(s) leading to the development of degenerative disc disease. The aim of this study was to develop an in vitro model that would allow the study of age-induced alterations of cell function in nucleus pulposus. Nucleus pulposus (NP) cells were isolated from intervertebral discs obtained from either calves (<9 months) or cows (>18 months). The cells were placed in culture and grown for 19 days. Although nucleus pulposus tissue was formed by the cells of the two different ages the more mature (older) cells formed less tissue as determined histologically by light microscopy. This was confirmed biochemically as the wet weight and proteoglycan content of the tissue formed by the older cells were significantly less than that of the younger tissue. The older cells accumulated less proteoglycans as determined by quantifying radioisotope incorporation. The older cells showed lower constitutive gene expression of collagen type II and aggrecan whereas collagen type I and link protein levels were similar to those of the younger cells. Metalloprotease (MMP) 13 gene and protein expression increased with age. There was no change in the levels of gene expression of MMP 2 and TIMP 1, 2, or 3 with age. Cells obtained from NP tissue harvested from younger or mature animals showed both genotypic and phenotypic differences in vitro that resulted in the inability of the older cells to reconstitute their extracellular matrix to the same extent as the younger cells. This suggests that this in vitro NP tissue model will be suitable to determine the mechanism(s) regulating age-induced changes.
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PMID:An in vitro tissue model to study the effect of age on nucleus pulposus cells. 1771 Apr 48

Elevated oxidative stress has been characterized in numerous disorders including systemic hypertension, arterial stiffness, left ventricular hypertrophy (LVH) and heart failure. The peroxisome proliferator activated receptor gamma (PPARgamma) ameliorates oxidative stress and LVH. To test the hypothesis that PPARgamma decreased LVH and cardiac fibrosis in chronic pressure overload, in part, by increasing SOD, eNOS and elastin and decreasing NOX4, MMP and collagen synthesis and degradation, chronic pressure overload analogous to systemic hypertension was created in C57BL/6J mice by occluding the abdominal aorta above the kidneys (aortic stenosis-AS). The sham surgery was used as controls. Ciglitazone (CZ, a PPARgamma agonist, 4 microg/ml) was administered in drinking water. LV function was measured by M-Mode Echocardiography. We found that PPARgamma protein levels were increased by CZ. NOX-4 expression was increased by pressure-overload and such an increase was attenuated by CZ. SOD expression was not affected by CZ. Expression of iNOS was induced by pressure-overload, and such an increase was inhibited by CZ. Protein levels for MMP2, MMP-9, MMP-13 were induced and TIMP levels were decreased by pressure-overload. The CZ mitigated these levels. Collagen synthesis was increased and elastin levels were decreased by pressure-overload and CZ ameliorated these changes. Histochemistry showed that CZ inhibited interstitial and perivascular fibrosis. Echocardiography showed that CZ attenuated the systolic and diastolic LV dysfunction induced by pressure-overload. These observations suggested that CZ inhibited pressure-overlaod-induced cardiac remodeling, and inhibition of an induction of NOX4, iNOS, MMP-2/MMP-13 expression and collagen synthesis/degradation may play a role in pressure-overload induced cardiac remodeling.
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PMID:Reversal of systemic hypertension-associated cardiac remodeling in chronic pressure overload myocardium by ciglitazone. 1784 84

Kinetics of mRNA expression following a single loading event was measured using an in vivo rat tail model. Animals were instrumented and loaded in compression for 1.5 h at 1 MPa and 1 Hz. Real-time RT-PCR was used to measure mRNA levels 0, 8, 24 and 72 h after mechanical stimulation for genes associated with matrix proteins (aggrecan, collagen-I, collagen-II), proteases (MMP-2, MMP-3, MMP-13, ADAMTS-4), and their inhibitors (TIMP-1, TIMP-3) in anulus fibrosus and nucleus pulposus regions. Baseline mRNA levels were of greatest abundance for matrix proteins and lowest for proteases. The mRNA levels reached maximum levels 24 h following mechanical stimulation for the majority of genes evaluated, but some had maximum levels 8 and 72 h following loading. The mRNA levels returned to baseline levels for all genes in the nucleus 72 h following loading, but the majority of genes in the anulus remained upregulated. Results support a coordinated strategy of relative mRNA expression that varied over time beginning with inhibition of tissue breakdown, followed by synthesis of aggrecan and matrix degrading enzymes, and eventually collagen metabolism days following loading. Consequently, optimal time for tissue harvest for mRNA measurements depends on genes of interest. Results suggest attempts at anabolic remodeling must be given adequate time for metabolic processes and protein synthesis to occur, and that changes in TIMP and MMP levels may have greater potency in affecting structural protein abundance than direct changes in the structural protein messages. Results have important implications for disc remodeling and tissue engineering.
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PMID:In vivo intervertebral disc remodeling: kinetics of mRNA expression in response to a single loading event. 1817 44

Due to an imbalance in the MMP:TIMP ratio determined a tissue damage in arthritis, it is hypothesized that polymorphic variations of the TIMP genes are associated with regulation of the MMP:TIMP balance. To test this hypothesis, the presence of single nucleotide polymorphisms (SNPs) located in the human TIMP-2 and TIMP-4 genes was confirmed in the Korean RA and OA patients. We performed a case-control study comprising 109 unrelated Korean OA patients, 177 unrelated Korean RA patients and 175 healthy subjects. There were statistically significant differences in the genotype distribution and allele frequencies of the C/T polymorphism of TIMP-4 gene between OA and control groups (P = 0.0002 and P = 0.001, respectively). However, no significant association between TIMP-2 polymorphisms and OA was observed. Also, no difference was observed when allele or genotype frequencies of both TIMP-2 and TIMP-4 gene polymorphisms were compared between RA and controls. We demonstrated that the C/T polymorphism which is located on the 3'-untranslational regions of the TIMP-4 gene might be associated with susceptibility to OA patients.
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PMID:Association of TIMP-4 gene polymorphism with the risk of osteoarthritis in the Korean population. 1830 98

Remodeling of the pulmonary artery is a major feature of pulmonary artery hypertension, and CPU86017, a derivative of berberine, is known to effectively alleviate hypoxic pulmonary hypertension (HPH). CPU86017 is a racemate, possessing two chiral centers: 7N and 13aC. We have compared the effects of four CPU86017 isomers, SS [(+)-7S, 13aS-CPU86017], SR [(-)-7S, 13aR-CPU86017], RR [(-)-7R, 13aR-CPU86017] and RS [(+)-7R, 13aS-CPU86017], on HPH. Sprague-Dawley rats were exposed to hypoxic conditions (10 +/- 0.5% O2 for 8 h per day) for 4 weeks and treated with CPU86017, SS, SR, RR or RS (4 mg/kg, subcutaneously) from day 15 to 28. After 4 weeks of exposure to hypoxia, remodeling of the right ventricle and the small pulmonary arteries (<150 microm) was very pronounced, and extra-cellular matrix (ECM) had been excessively produced in association with abnormal mRNA and protein expression of matrix metalloproteinase 9 (MMP9) and mRNA of tissue inhibitor of matrix metalloproteinase 1 and 2 (TIMP1, TIMP2). Expression of endothelin receptor A was upregulated, while that connexin 40 was downregulated. The administration of CPU86017 and its four isomers attenuated the changes, with the isomer RS exhibiting the most favorable effect on HPH rats. We propose that an activated endothelin pathway associated with an unbalanced MMP-TIMP system may contribute to the over-accumulation of ECM and the remodeling of the pulmonary arterioles in HPH. CPU86017 and its four isomers attenuate ECM accumulation and vascular remodeling by normalizing both the MMP-TIMP system and the ET system. The RS isomer is superior to the racemate CPU86017 in attenuating HPH.
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PMID:CPU86017 and its isomers improve hypoxic pulmonary hypertension by attenuating increased ETA receptor expression and extracellular matrix accumulation. 1854 32

To gain insight into the pathogenesis of hepatic fibrosis related to insulin resistance, we have examined the effects of euglycemic hyperinsulinemia on three matrix metalloproteinases (MMP-2, MMP-9, and MT1-MMP) and on two major tissue inhibitors of MMPs (TIMP-1 and TIMP-2) in liver of insulin-sensitive and insulin-resistant rats. Four hours of insulin infusion (4.8 mU.kg(-1).min(-1)) without or with lipid-heparin infusion (to produce insulin resistance) decreased hepatic MMP-2 mRNA (by RT-PCR), pro-MMP-2, MMP-2, MMP-9, and MT1-MMP (all by Western blots) and the gelatinolytic activity of MMP-2 (by gelatin zymography) by approximately 60-80%. Hyperinsulinemia ( approximately 1.6 mmol/l) increased TIMP-1 and TIMP-2 concentrations (by ELISA) in insulin-sensitive and insulin-resistant rats. Phosphoinositide 3-kinase was activated by insulin in insulin-sensitive rats and inhibited in insulin-resistant rats. Extracellular signal-regulated kinases 1/2 (ERK1/2) were activated by insulin in insulin-sensitive rats and partially inhibited in insulin-resistant rats; c-jun NH(2)-terminal kinase-1 (JNK1), JNK2/3, or p38 MAPK were only activated by lipid but not by insulin. We conclude that hyperinsulinemia, whether or not associated with insulin resistance, shifts the MMP/TIMP balance toward reduction of extracellular matrix degradation and thus may promote the development of hepatic fibrosis.
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PMID:Effects of hyperinsulinemia on hepatic metalloproteinases and their tissue inhibitors. 1866 96

Recent studies have demonstrated the efficacy of targeted therapy combined with radiotherapy in head and neck squamous cell carcinoma (HNSCC). We hypothesized that a combination treatment including a replicating adenovirus armed with tissue inhibitor of metalloproteinase-2 (TIMP-2), radiation and Cisplatin will augment treatment response and reduce tumor growth in vivo of HNSCC xenografts. Both single-agent (TIMP-2 virus, radiation and Cisplatin) and the combination therapies were evaluated in vitro and in vivo. The efficacy of both single-agent and combination therapies in vivo was determined by monitoring tumor growth and immunohistochemistry. Treatment with replicative Ad-TIMP-2 virus and radiation decreased cell viability in vitro and resulted in an additional antiangiogenic response in vivo. Tumor response rates to treatment with replicative Ad-TIMP-2, radiation, Cisplatin or combination therapies ranged from limited inhibition of tumor growth of the single-agent therapy to a statistically significant additive antitumor response with the combination therapies. Replicative Ad-TIMP-2+radiation+Cisplatin in the SCC1 nude mice demonstrated the greatest response rates in tumor growth and angiogenesis. Combination of Ad-TIMP-2 gene therapy with radiation and the triple treatment group resulted in an augmented therapeutic response. This is the first report of the potential benefits of combining radiation and MMP inhibitor treatment.
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PMID:Therapy of head and neck squamous cell carcinoma with replicative adenovirus expressing tissue inhibitor of metalloproteinase-2 and chemoradiation. 1884 12

In chronic arthritis cartilage and bone destruction occur as a consequence of synovial inflammation. It is mainly mediated by matrix metalloproteinases and RANKL-OPG pathways. Data on synovial fluid levels of these mediators in enthesitis related arthritis subtype (ERA) of JIA are not available. MMP-1, MMP-3, TIMP, sRANKL and OPG levels were measured in synovial fluid from patients with ERA and compared with other arthritides, polyarticular (Poly) JIA, RA and osteoarthritis (OA). sRANKL was detectable in 25/41 of ERA patients, 4/16 of Poly JIA patients. Median SF sRANKL level in patients with ERA was higher as compared to OA (p < 0.001) and poly JIA (p < 0.05) but were comparable to RA. The median OPG level in ERA was lower as compared to OA (p < 0.001), comparable to RA but was higher than poly JIA (p < 0.001). sRANKL/OPG ratio was significantly higher in ERA and Poly JIA compared to OA (p < 0.0001, p < 0.0001 respectively). The median MMP3 levels in ERA (74 microg/ml) was lower as compared to poly JIA (410 microg/ml; p < 0.0001) and RA (340 ug/ml; p < 0.0001) but was comparable to OA (107 microg/ml). The median level of ProMMP1 in ERA (0.70 microg/ml) was lower as compared to RA (2.9 microg/ml; p < 0.0001) and poly JIA but was elevated as compared to OA patients (0.1 microg/ml; p < 0.0001). TIMP1 levels in ERA were higher than poly JIA and RA patients. MMP3/TIMP1 ratio was lower in ERA compared to polyarticular JIA patients (p < 0.05). Ours is the first study reporting elevated sRANKL and reduced OPG levels and elevated sRANKL/OPG ratio in SF of children with JIA resulting in a mileu associated with bone loss. In addition, ERA patients had lower MMP level as well as MMP/TIMP ratio as compared to poly JIA which may partly explain lesser degree of joint damage seen in ERA as compared to poly JIA.
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PMID:Synovial fluid RANKL and matrix metalloproteinase levels in enthesitis related arthritis subtype of juvenile idiopathic arthritis. 1905 52

The purpose of the study was to examine the specific features of morphological manifestations and molecular mechanisms of controlling the processes of proliferation, apoptosis, cell differentiation, neoangiogenesis, and fibrosis, which result in lung tissue rearrangement in different types of idiopathic fibrosing alveolitis (IFA). Open and transbronchial biopsy specimens obtained from 103 patients with IFA and intact lung tissue biopsy specimens taken from those clinically diagnosed as having sarcoidosis as a control group were examined. The serial paraffin sections immunohistochemically revealed the following antigens: cytokeratins 5, 6, 7, 8, 19 (Uni-Heidelberg, DAKO), MMP 1, MMP 2, MMP 7, and TIMP 4, Apo-protein (Novocastra), Ki67, PCNA, PDGF, EGFR, CD34, SMA (smooth muscle actin), FGFb (LabVision). Biotin-conjugated antibodies to murine and rabbit immunoglobulins (Dako LSAB + KIT, PEROXIDASE) were used as secondary antibodies. The nuclei were stained with hematoxylin. Positive and negative control tests were carried out. The results of immunohistochemical tests were estimated in percentage of cells showing positive reactions (Ki67, PCNA), as well as those of a semiquantitative analysis in scores and statistical analyses (Mann-Whitney U-test, Fisher's test, and Spearman's rank correlation coefficient) were employed. OIP was ascertained to differ from other IFA in higher values of the cytokines under study, as well as in the predominant rearrangement of the lung interstice and dysregeratory epithelial changes at the site of respiratory bronchiolar transformation. At the same time there was an intensive proliferation of the epithelium and stromal cells (high expression of PCNA, PDGF by hyperplastic alveolocytes, alveolar macrophages, fibroblasts and myofibroblasts), and neogenesis (the high density of newly formed vessels with endothelial expression of CD34). Elevated alveolocytic apoptosis (from Apo-protein expression) was also observed. Cell proliferation and neoangiogenesis was attained by high MMPs expression. The practical value of the study is that the expression of the study markers may serve as a criterion for differential diagnosis and determination of prognosis in different types of IFA.
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PMID:[Molecular bases for the development of variants of idiopathic fibrosing alveolitis]. 1951 52

Collagen IV is the major matrix component associated with differentiating adipocytes in adipose tissues, and the understanding of its contribution in adipogenic differentiation could be important for elucidation of mechanisms and processes driving the obesity. Therefore, in the light of our previous findings of differential effects of structural conformation of collagen I matrix on differentiation of bone marrow stromal cells, we investigated whether similar phenomenon occurs on collagen IV matrix in native and denatured structural states. The results of the present study show that native collagen IV is unsupportive of adipogenic differentiation and very little if any adipogenesis occurs on this matrix in the presence of adipogenic stimuli. In sharp contrast to native collagen IV, the same matrix in denatured structural state drives highly efficient adipogenic differentiation suggesting that it might be the major driver of adipogenesis in adipose tissues and that the ratio of native to denatured matrix might regulate the intensity of adipogenesis and possibly underlies the obesity. In contrast to observations that adipogenesis on denatured collagen I (collagen I is the major matrix component in musculoskeletal tissues) is suppressed by stress, adipogenesis on denatured collagen IV appears to be stress-resistant suggesting an explanation for the observed ineffectiveness of physical exercise, i.e. mechanical stress, in the reduction of adipose tissues. The obesity was shown to be associated with overproduction of MMPs and decline in levels of TIMPs. Such a shift in MMP/TIMP balance was considered a consequence of the pathology. In the light of the present study, however, this shift might constitute the primary source of the decease. The findings of the present study suggest strategies for the treatment of obesity, raise significant questions and indicate directions for further experimentation.
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PMID:Human bone marrow-derived stromal cells show highly efficient stress-resistant adipogenesis on denatured collagen IV matrix but not on its native counterpart: implications for obesity. 1976 44


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