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PubMed1997

The proteoglycan metabolism, morphology and viability of articular cartilage treated with a synthetic matrix metalloproteinase inhibitor.

Matrix metalloproteinases (MMP) are among the key enzymes responsible for the proteolytic destruction of articular cartilage during chronic rheumatic diseases. Articular cartilage is one potential target for drugs designed to inhibit the activity of MMPs in order to stop or to slow down the proteolytic destruction of the extracellular matrix of cartilage. The purpose of this study was to investigate the effect of the synthetic inhibitor of MMPs U-24522 for its ability (1) to inhibit in vitro the activity of MMP-proteoglycanases; (2) to modulate the morphology and viability of cartilage explants; and (3) to modify the biosynthesis and release of proteoglycans from articular cartilage explants. U-24522 dose-dependently inhibited the activity of MMP-proteoglycanases and significantly reduced the release of proteoglycans from interleukin-1 treated bovine articular cartilage explants when tested at concentrations ranging from 10(-4) to 10(-9) M. This hydroxamic acid derivative proved not to be harmful to chondrocyte viability and cartilage morphology. In addition, U-24522 had no effect on the rate of proteoglycan biosynthesis of interleukin-1 treated cartilage explants and increased the percentage of newly synthesized proteoglycans to form macromolecular aggregates. Thus U-24522 combines direct inhibitory potential on the activity of MMP-proteoglycanases with the inhibition of interleukin-1 stimulated proteoglycan loss from articular cartilage explants without affecting the morphology, viability and biosynthesis of proteoglycans of bovine articular cartilage explants.

Animals↗
PubMed1998

Cloning of the gene for interstitial collagenase-3 (matrix metalloproteinase-13) from rabbit synovial fibroblasts: differential expression with collagenase-1 (matrix metalloproteinase-1).

Cartilage, bone and the interstitial stroma, composed largely of the interstitial collagens, types I, II and III, are remodelled by three members of the metalloproteinase (MMP) family, collagenase-1 (MMP-1), collagenase-2 (MMP-8) and collagenase-3 (MMP-13). MMP-1 and MMP-13 may contribute directly to disease progression, since they are induced in patients with rheumatoid arthritis and osteoarthritis. The study of MMP-1 and MMP-13 gene regulation in models of arthritic disease has been problematic because mice and rats, which are typically used, only possess a homologue of MMP-13. Here we show that in contrast with mice and rats, rabbits possess distinct genes homologous to human MMP-1 and MMP-13. Furthermore, rabbit MMP-13 is expressed simultaneously with MMP-1 in chondrocytes and synovial fibroblasts in response to the cytokines interleukin-1 and tumour necrosis factor-alpha, or the phorbol ester PMA. The time course of MMP-13 induction is more rapid and transient than that of MMP-1, suggesting that distinct mechanisms regulate the expression of these two collagenases. We have cloned the rabbit MMP-13 gene from synovial fibroblasts and demonstrated that the rabbit gene shares greater homology with human MMP-13 than does the mouse interstitial collagenase. Together with the fact that mice and rats do not possess a homologue to human MMP-1, our data suggest that the rabbit provides an appropriate model for studying the roles of interstitial collagenases in connective-tissue diseases, such as rheumatoid arthritis and osteoarthritis.

Amino Acid Sequence↗
PubMed2002

[The role of matrix metalloproteinases in extracellular matrix remodelling in chronic obstructive pulmonary disease rat models].

OBJECTIVE: To study the role of metalloproteinases(MMPs) in the airway extracellular matrix (ECM) remodelling of chronic obstructive pulmonary disease (COPD) rat models. METHODS: The COPD rat models which was established by intratracheal instillation of 200 microg lipopolysaccharide once for every two weeks(twice), and exposed to 5% smoke for 0.5 h/d for 4 weeks. The pathological changes were observed, lung function and blood gas changes were also deter mined. The fibroblasts, lymphocytes of bronchial walls and alveolar macrophages were counted. The hydroxyproline of bronchial lung tissue homogenates were deter mined by biochemistry method. The expression of MMP-9,MMP-2 and tissue inhibitor of metalloproteinase-1(TIMP-1) in bronchi and lung tissue was verfied by immunohistochemical analysis and by reverse transcription-polymerase chain reaction analysis. The gelatinolytic activities of MMPs of lung tissue were performed by gelatin zymographic analysis. RESULTS: The pathological changes of bronchi and lung tissue, the changes of lung function and blood gas analysis were similar to those of the COPD patients. The number of fibroblasts, lymphocytes and alveolar macrophages of model group were significantly increased than those of control group (P < 0.001). The hydroxyproline of model group was significantly in creased than that of control group (P < 0.001). By using image analyzer, immunoreactivity of MMP-9, MMP-2,TIMP-1 were markedly increased in epithelial cells of bronchi, fibroblasts, macrophages, endothelial cells and pneumocytes in model group as compared with those of control group. The protein expressions of MMP-9, MMP-2 and TIMP-1 in model group were significantly increased than those in control group(P < 0.0001 or P < 0.01). The mRNA expression of MMP-2, MMP-9 and TIMP-1 in COPD model group (1.11 +/- 0.06,1.04 +/- 0.26 and 0.85 +/- 0.34,respectively) were significantly increased than those in control group (0.30 +/- 0.17,0.36 +/- 0.09 and 0.23 +/- 0.08,respectively) as well(P < 0.001 or P < "0.01). The relative gelatinolytic activities of 72 000 MMP-2, 92 000 MMP-9 in model group (3 263.5 +/- 665.1 and 1 338.4 +/- 241.2, respectively) were also significantly higher than those in the model group(388.6 +/- 60.8 and 116.1 +/- 49.8,respectively, P < 0.001). CONCLUSION: The findings suggested that there were up regulations of MMP-9,MMP-2 and TIMP-1 of lung tissue in COPD model group which may contribute to the pathogenesis of airflow limitation through the airway remodelling and alveolar structure destruction(emphysema). The ECM degradation and deposition were imbalanced and abnormally activated. The evaluation of MMP-9,MMP-2 which are responsible for the inflammation and destruction process, and the evaluation of TIMP-1 which is responsible for the repair and remodelling process of the airways, may play an important role in the airway ECM remodelling in COPD.

Animals↗
PubMed1997

[Matrix metalloproteinases].

Matrix-degrading enzymes, matrix metalloproteinases, are members of a unique family of Zinc-binding endopeptidases that are responsible for the metabolism of extracellular components in the tissue stroma. Their controlled expression is essential for normal processes such as wound healing and tissue remodeling, including embryogenesis. However, in many pathological conditions and events such as metastasis of malignant tumors and rheumatoid arthritis, the uncontrolled expression is evident.

Animals↗
PubMed1999

Interleukin 10 (IL-10) inhibition of primary human prostate cell-induced angiogenesis: IL-10 stimulation of tissue inhibitor of metalloproteinase-1 and inhibition of matrix metalloproteinase (MMP)-2/MMP-9 secretion.

In in vitro angiogenesis assays, aggregates of human papilloma virus (HPV)-18-immortalized primary human prostate cancer cells (HPCA-5aHPV-18 or HPCA-10aHPV-18 cells) induced human bone marrow endothelial cells (HBMCE-1 cells) to form microvessels in three-dimensional collagen I gels after 1-2 days incubation at 37 degrees C. The microvessels aligned perpendicular to the tumor aggregates and abutted on the edges of the aggregates. The number and length of the microvessels increased significantly from day 1 to 2 (i.e., by approximately 30%). ELISAs showed that the HPCA-5aHPV-18 cells normally secreted low levels of tissue inhibitor of metalloproteinase (TIMP)-2, matrix metalloproteinase (MMP)-2, and MMP-9 but relatively high levels of TIMP-1. In contrast, HPCA-10aHPV-18 cells secreted high levels of MMP-2 and MMP-9 (>40 pg/microg protein) but low levels of TIMP-1 and TIMP-2 (<5 pg/microg protein). Interleukin 10 (IL-10) (15 ng/ml) induced TIMP-1 production (>15 pg/microg protein) but reduced MMP-2 and MMP-9 secretion (<5 pg/microg protein) by the HPCA-5aHPV-18 and HPCA-10aHPV-18 cells. IL-10 (15 ng/ml) and MMP-9/MMP-2 antibodies all blocked induction of microvessel formation in the coculture experiments. In contrast, IL-10 receptor antibodies and TIMP-1 antibodies countered IL-10's effects and promoted angiogenesis. The data demonstrated that IL-10 stimulation of TIMP-1 and inhibition of MMP-2 and MMP-9 secretion by prostate tumor cells can control induction of angiogenesis in vitro.

Antibodies↗
PubMed1997

Mighty mice: transgenic technology "knocks out" questions of matrix metalloproteinase function.

Matrix metalloproteinases (MMP) comprise a family of structurally related proteinases that are believed to play a critical role in many physiological and pathological processes. Transgenic technology offers the possibility of determining whether MMPs contribute directly to these processes. For example, gain of function and loss of function models have confirmed causative roles of MMPs in the development of pulmonary emphysema and unexpectedly uncovered an MMP-dependent mechanism of inflammatory cell recruitment. Limitations of these techniques and powerful applications on the horizon are also presented as we embark on an era where controlled experiments can be performed in complex mammalian models.

Animals↗
PubMed1996

In vivo collagen turnover following experimental balloon angioplasty injury and the role of matrix metalloproteinases.

Extracellular matrix formation is the major component of the restenosis lesion that develops after balloon angioplasty. Although ex vivo studies have shown that the synthesis of collagen is stimulated early after balloon angioplasty, there is a delay in accumulation in the vessel wall. The objectives of this study were to assess collagen turnover and its possible regulation by matrix metalloproteinases (MMPs) in a double-injury iliac artery rabbit model of restenosis. Rabbits were killed at four time points (immediately and at 1, 4, and 12 weeks) after balloon angioplasty. In vivo collagen synthesis and collagen degradation were measured after a 24-hour incubation with [14C]proline. Arterial extracts were also run on gelatin zymograms to determine MMP (gelatinase) activity. Collagen turnover studies were repeated in a group of 1-week postangioplasty rabbits that were treated with daily subcutaneous injections of either a nonspecific MMP inhibitor, GM6001 (100 mg/kg per day), or placebo. Collagen synthesis and degradation showed similar temporal profiles, with significant increases in the balloon-injured iliac arteries compared with control nondilated contralateral iliac arteries immediately after angioplasty and at 1 and 4 weeks. Peak collagen synthesis and degradation occurred at 1 week and were increased (approximately four and three times control values, respectively). Gelatin zymography was consistent with the biochemical data by showing an increase of a 72-kD gelatinase (MMP-2) in the balloon-injured side immediately after the second injury, peaking at 1 week, and still detectable at 4 and 12 weeks (although at lower levels). In balloon-injured arteries, the MMP inhibitor reduced both collagen synthesis and degradation. Overall, at 1 week after balloon angioplasty, GM6001 resulted in a 33% reduction in collagen content in balloon-injured arteries compared with placebo (750 +/- 143 to 500 +/- 78 micrograms hydroxyproline per segment, P < .004), which was associated with a nonsignificant 25% reduction in intimal area. Our data suggest that degradation of newly synthesized collagen is an important mechanism regulating collagen accumulation and that MMPs have an integral role in collagen turnover after balloon angioplasty.

Angioplasty, Balloon↗
PubMed1998

Matrix metalloproteinase inhibitors.

Matrix metalloproteinases (MMPs) are a family of enzymes responsible for the breakdown of proteins of connective tissue. Through this action they play an important role in growth, development and tissue repair. Recent studies also suggest that MMPs are utilised in cancer, facilitating both local tumour invasion and metastasis. Levels of certain MMPs such as stromelysin-3 and gelatinase are elevated in tumour-associated stroma compared to non-involved tissue. A series of synthetic low molecular weight MMP inhibitors have been produced. Early inhibitors were based on the peptide structure of collagen, although more recently non-peptide inhibitors have also been developed. The inhibitors are selective for the MMP family and are active at low nanomolar concentrations. Experiments in models of breast cancer have shown that MMP inhibitors can significantly reduce the growth rate of both primary and secondary tumours, and can block the process of metastasis. Several MMP inhibitors have now started clinical trials in patients with advanced malignancy. Although not the optimum setting for a tumouristatic agent, early results suggest this approach may be effective in slowing tumour growth. Trials in the adjuvant setting will provide the most important test of these inhibitors and should determine their potential to complement existing cytoreductive treatments and prolong survival.

Antineoplastic Agents↗
PubMed1999

Clinical studies with matrix metalloproteinase inhibitors.

Matrix metalloproteinases (MMPs) have been implicated in the invasive growth and spread of tumours. Potent and selective inhibitors of MMPs have been synthesized. These inhibitors can prevent tumour invasion in vitro and have suppressed tumour growth and metastasis in animal cancer models. Several MMP inhibitors have now reached clinical trials. Phase I studies indicate that the inhibitors can be given by mouth and that over the short term they are well tolerated. Longer, randomised studies in cancer patients are now underway.

Antineoplastic Agents↗
PubMed1998

New Drugs on the Horizon: Matrix Metalloproteinase Inhibitors.

Matrix metalloproteinases (MMPs) are a family of enzymes involved in a number of normal cellular processes, such as regulation of endometrial growth and menstruation, and abnormal processes, such as tumor growth, invasion, and metastasis. There are now 18 distinct enzymes that fall into three functional classifications based on their substrate target: collagenases which degrade fibrillar collagen; gelatinases which degrade denatured and basement membrane collagens, and stromelysins which degrade proteoglycans and glycoproteins. The MMPs can also be separated into five categories based on structural and functional similarities.

Journal Article↗
PubMed2003

Pneumococcal zinc metalloproteinase ZmpC cleaves human matrix metalloproteinase 9 and is a virulence factor in experimental pneumonia.

The ZmpC zinc metalloproteinase of Streptococcus pneumoniae, annotated in the type 4 genome as SP0071, was found to cleave human matrix metalloproteinase 9 (MMP-9). The previously described IgA protease activity was confirmed to be specifically linked to the IgA1-protease/SP1154 zinc metalloproteinase. MMP-9 is a protease cleaving extracellular matrix gelatin and collagen and is activated by proteolytic cleavage like most proteases. MMP-9 is a human protease and is involved in a variety of physiological and pathological matrix degrading processes, including tissue invasion of metastases and opening of the blood-brain barrier. While TIGR4 (serotype 4) and G54 (serotype 19) pneumococcal genome strains have a highly conserved copy of zmpC, the genome of R6 (a derivative of serotype 2 D39 strain) lacks zmpC. Both the analysis for zmpC presence and MMP-9 cleavage activity in various pneumococcal strains showed correlation of ZmpC with MMP-9 cleavage activity. When assaying clinical isolates of S. pneumoniae, the zmpC gene was not found in any of the nasal and conjunctival swab isolates, but it was present in 1 out of 13 meningitis isolates and in 6 out of 11 pneumonia isolates. In a murine pneumonia model, infection with a zmpC-mutant reduced mortality at 3-4 days post-infection by 75%, when compared with infection with wild-type strains. These data indicate that the ZmpC pneumococcal protease may play a role in pneumococcal virulence and pathogenicity in the lung.

Administration, Intranasal↗
PubMed2004

Low levels of tissue inhibitors of metalloproteinases with a high matrix metalloproteinase-9/tissue inhibitor of metalloproteinase-1 ratio are present in tracheal aspirate fluids of infants who develop chronic lung disease.

OBJECTIVE: The pathogenesis of chronic lung disease (CLD) involves inflammation with proteolytic damage to lung extracellular matrix. Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that, acting in concert with their tissue inhibitors, tightly orchestrate extracellular matrix morphogenesis and repair after injury. Imbalances in their levels relative to that of their inhibitors have been implicated in diseases characterized by matrix disruption and remodeling. We investigated the possibility that imbalances in MMP-9 and MMP-2 relative to their tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2, respectively, in tracheal aspirates of preterm infants may be involved in the development of CLD. METHODS: Serial tracheal aspirates collected from birth until extubation in 49 ventilated preterm infants (24-32 weeks' gestations) were analyzed for MMP-2, MMP-9, TIMP-1, and TIMP-2. Data normalized by TA values of free secretory component of immunoglobulin A were compared for CLD (n = 22) versus no CLD (n = 27). Also, known clinical predictors of CLD (gestational age, birth weight, and sex) were assessed for both groups. Association of predictors with the outcome CLD was assessed by logistic regression. RESULTS: Mean gestational age was lower in CLD infants, but birth weight and gender were comparable for both groups. CLD infants had significantly lower TIMP-1 level with higher MMP-9/TIMP-1 ratio during the first 2 weeks of life and low TIMP-2 and MMP-2 levels during the first 3 days of life compared with no-CLD infants. Logistic regression analysis indicated that the findings are predictive of CLD. CONCLUSIONS: We conclude that low tracheal aspirate levels of TIMPs, with a high MMP-9/TIMP-1 ratio early in life, are associated with subsequent development of CLD.

Bronchopulmonary Dysplasia↗
PubMed2005

Effects of age, gender, ethnicity, diurnal variation and exercise on circulating levels of matrix metalloproteinases (MMP)-2 and -9, and their inhibitors, tissue inhibitors of matrix metalloproteinases (TIMP)-1 and -2.

BACKGROUND: Circulating metalloproteinases (MMP) and their inhibitors (TIMP) are indices of vascular and cardiac tissue matrix turnover. However, the temporal changes and relationship of these parameters to age, gender, ethnicity and exercise have been poorly defined. We therefore studied these aspects on plasma levels of MMP-2 and -9 and TIMP-1 and -2, as the major metalloproteinases (and their inhibitors) implicated in pathophysiology of vascular disease. METHODS: Venous citrated blood was collected from 93 normal healthy volunteers from four ethnic groups (Afro-Caribbean, South Asian, Caucasian and Far Eastern) for a cross-sectional study. In addition, 20 separate healthy volunteers were studied during supine rest, before and immediately following peak treadmill stress using a Bruce protocol. MMP-2 and -9 and TIMP-1 and -2 were all measured by ELISA. RESULTS: There was a categorical distribution of MMP-2 concentration with individual subjects showing high levels, yet others being undetectable, although these changes were unrelated to age, gender or ethnicity. TIMP-1 and -2 showed a modest negative correlation with age (r=-0.251, p=0.015; r=-0.254, p=0.014). There was a positive correlation between MMP-2 and TIMP-2 (r=0.399, p<0.001), MMP-9 and TIMP-1 (r=0.45, p<0.001) and between TIMP-1 and TIMP-2 (r=0.275, p=0.008). When adjusted for age and gender, there were no significant differences in MMP-2 and TIMP-1 and -2 between the four ethnic groups. MMP-9 was significantly lower in the Far Eastern group compared to the other three ethnic groups (p=0.012). Only TIMP-1 (p=0.042) and TIMP-2 (p=0.024) were significantly altered after exercise. CONCLUSION: Age and exercise both have modest effects on circulating concentrations of TIMP-1 and-2. MMP-9 appears lower in individuals of Far Eastern/Chinese origin regardless of age or gender. The positive association between MMPs and TIMPs suggests that in healthy individuals, enzyme activity may be regulated by this interaction. The reasons for the categorical distribution of MMP-2 remain unclear but this would be important in any studies designed to use circulating MMPs as a surrogate for tissue MMPs around clinical events, such as myocardial infarction or in response to therapies affecting extracellular matrix composition.

Adult↗
PubMed2001

Rat hepatic stellate cells contribute to the acute-phase response with increased expression of alpha1(I) and alpha1(IV) collagens, tissue inhibitor of metalloproteinase-1, and matrix-metalloproteinase-2 messenger RNAs.

The acute-phase response (APR) represents a systemic reaction of the organism to multiple nonspecific inflammatory stimuli. In general, it is protective for the host, and hepatocytes are the main cells responding with alterations in the expression of a set of liver-specific proteins named the acute-phase proteins. We have previously shown that although a turpentine-induced APR is not fibrogenic per se, it enhances collagen deposition in rats treated with CCl(4) and up-regulates expression of hepatic alpha1(I) collagen and tissue inhibitor of metalloproteinases 1 (TIMP-1) messenger RNAs (mRNAs). In this report we extended our studies and showed that turpentine induced, in a time-dependent manner, expression of alpha1(I) and alpha1(IV) collagens, TIMP-1, and matrix-metalloproteinase 2 (MMP-2) mRNAs. We further showed that expression of these mRNAs occurs in hepatic stellate cells, but not in hepatocytes obtained 6 hours after the induction of an APR episode. These changes were accompanied by increased blood levels of tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) without noticeable immediate changes in the expression of their respective mRNAs in the liver. In contrast to CCl(4)-induced liver damage, turpentine alone, whether administered as a single dose or as a weekly dose for 3 weeks did not up-regulate expression of transforming growth factor beta1 (TGF-beta1) mRNA and did not result in excess collagen deposition. Overall, these findings suggest that collagen deposition in the livers of rats with repeated APR episodes may be enhanced only when given together with a fibrogenic stimulus that activates hepatic stellate cells (HSCs) and/or up-regulates TGF-beta1 mRNA expression.

Acute-Phase Reaction↗
PubMed2005

Prevention of progressive joint destruction in adjuvant induced arthritis in rats by a novel matrix metalloproteinase inhibitor, FR217840.

Matrix metalloproteinase (MMP) has been implicated in joint destruction of chronic arthritis diseases, such as rheumatoid arthritis. FR217840 (2R)-1-([5-(4-fluorophenyl)-2-thienyl]sulfonyl)-N-hydroxy-4-(methylsulfonyl)-2-piperazinecarboxamide is a potent, orally active synthetic MMP inhibitor that inhibits human collagenases (MMP-1, MMP-8 and MMP-13), gelatinases (MMP-2 and MMP-9) and membrane type MMP (MT-MMP) (MT1-MMP/MMP-14). FR217840 also inhibits rat collagenase and gelatinase. We studied the effect of FR217840 on a rat adjuvant induced arthritis model. Although oral administration (days 1-21) of FR217840 (3.2, 10, 32 mg/kg) to adjuvant injected Lewis rats did not affect inflammation, as indicated by both hind paw swelling and histological inflammatory infiltration, FR217840 suppressed both bone destruction and serum pyridinoline content in a dose-dependent manner. Also, FR217840 (32 mg/kg) reduced tartrate-resistant acid phosphatase (TRAP) cell number in the ankle joints of rats with arthritis. These results indicate that FR217840 successfully suppressed joint destruction and suggest that FR217840 may have potential as a novel anti-rheumatic drug.

Acid Phosphatase↗