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PubMed1990

Interleukin 6 enhances the production of tissue inhibitor of metalloproteinases (TIMP) but not that of matrix metalloproteinases by human fibroblasts.

We have investigated the effect of interleukin 6 (IL-6) on the synthesis of tissue inhibitor of metalloproteinases (TIMP) and matrix metalloproteinases (MMPs), collagenase (MMP-1) and stromelysin (MMP-3) using human skin and uterine cervical fibroblasts. IL-6 did not modulate the expression of MMPs by these fibroblasts, but the production of TIMP was enhanced by IL-6 in a dose dependent manner, whereas IL-1 stimulated the production of both MMPs and TIMP. The combination of IL-6 and IL-1 further augmented IL-1-induced MMPs and TIMP production. The results provide the first evidence that IL-6 participates in the catabolism of the extracellular matrix components by modulating the effects of IL-1 on MMPs and TIMP synthesis as well as its direct effects on the synthesis of TIMP by connective tissue cells.

Cells, Cultured↗
PubMedDate not supplied

Matrix metalloproteinase expression in malignant melanomas: tumor-extracellular matrix interactions in invasion and metastasis.

Structural changes in the extracellular matrix (ECM) are necessary for cell migration during tissue remodeling and tumor invasion. The matrix metalloproteinases (MMPs) and their inhibitors have been shown to be critical modulators of ECM composition and are, thus, crucial in neoplastic cell invasion and metastasis. Expression of MMP-2, -3, -9, -10, and -13 was investigated in human malignant melanomas (MMs) employing an indirect alkaline phosphatase conjugated immunocytochemical technique. Evaluation of the results was based on (a) the percent of neoplastically transformed cells/surrounding stroma that reacted positively and (b) a measure of staining intensity [graded from A (highest) to D]. The two forms of stromelysin, MMP-3 and -10, share 82% sequence homology, but exhibit differences in cellular synthesis and inducibility by cytokines and growth factors in vitro. Strong overall expression of MMP-3 and -10 was found in MMs, especially in the ECM adjacent to blood vessels. Positive immunoreactivity could be seen for these two MMPs in the ECM surrounding over 90% of the neoplastically transformed cells (++++), and the staining intensity was also the strongest possible (A,B). Focal (+), high intensity (A,B) staining could be detected for MMP-2, -9, and -13. Thus, it seems that the stromelysins are involved in the generalized growth and expansion of the neoplastic cell mass, while MMP-2, -9 and -13 are involved in the neoangiogenic and focal clonal selection and expansion phenomena associated with in situ tumor progression, invasion of the microvasculature, and metastasis.

Antibodies, Monoclonal↗
PubMed2000

Interplay of matrix metalloproteinases, tissue inhibitors of metalloproteinases and their regulators in cardiac matrix remodeling.

Myocardial fibrosis due to maladaptive extracellular matrix remodeling contributes to dysfunction of the failing heart. Further elucidation of the mechanism by which myocardial fibrosis and dilatation can be prevented or even reversed remains of great interest as a potential means to limit myocardial remodeling and dysfunction. Matrix metalloproteinases (MMPs) are the driving force behind extracellular matrix degradation during remodeling and are increased in the failing human heart. MMPs are regulated by a variety of growth factors, cytokines, and matrix fragments such as matrikines. In the present report, we discuss the regulation of MMPs, the role of MMPs in the development of cardiac fibrosis, and the modulation of MMP activity using gene transfer and knockout technologies. We also present recent findings from our laboratory on the regulation of the extracellular MMP inducer (EMMPRIN), MMPs, and transforming growth factor-beta(1) in the failing human heart before and after left ventricular assist device support, as well as the possibility of preventing ventricular fibrosis using different anti-MMP strategies. Several studies suggest that such modulation of MMP activity can alter ventricular remodeling, myocardial dysfunction, and the progression of heart failure. It is therefore suggested that the interplay of MMPs and their regulators is important in the development of the heart failure phenotype, and myocardial fibrosis in heart failure may be modified by modulating MMP activity.

Animals↗
PubMed2006

Activity and expression of urokinase-type plasminogen activator and matrix metalloproteinases in human colorectal cancer.

BACKGROUND: Matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), and urokinase-type plasminogen activator (uPA) are involved in colorectal cancer invasion and metastasis. There is still debate whether the activity of MMP-2 and MMP-9 differs between tumors located in the colon and rectum. We designed this study to determine any differences in the expression of MMP-2, MMP-9 and uPA system between colon and rectal cancer tissues. METHODS: Cancer tissue samples were obtained from colon carcinoma (n = 12) and rectal carcinomas (n = 10). MMP-2 and MMP-9 levels were examined using gelatin zymography and Western blotting; their endogenous inhibitors, tissue inhibitor of metalloproteinase-2 (TIMP-2) and tissue inhibitor of metalloproteinase-1 (TIMP-1), were assessed by Western blotting. uPA, uPAR and PAI-1 were examined using enzyme-linked immunosorbent assay (ELISA). The activity of uPA was assessed by casein-plasminogen zymography. RESULTS: In both colon and rectal tumors, MMP-2, MMP-9 and TIMP-1 protein levels were higher than in corresponding paired normal mucosa, while TIMP-2 level in tumors was significantly lower than in normal mucosa. The enzyme activities or protein levels of MMP-2, MMP-9 and their endogenous inhibitors did not reach a statistically significant difference between colon and rectal cancer compared with their normal mucosa. In rectal tumors, there was an increased activity of uPA compared with the activity in colon tumors (P = 0.0266), however urokinase-type plasminogen activator receptor (uPAR) and plasminogen activator inhibitor-1 (PAI-1) showed no significant difference between colon and rectal cancer tissues. CONCLUSION: These findings suggest that uPA may be expressed differentially in colon and rectal cancers, however, the activities or protein levels of MMP-2, MMP-9, TIMP-1, TIMP-2, PAI-1 and uPAR are not affected by tumor location in the colon or the rectum.

Aged↗
PubMed1997

Matrix metalloproteinases in skin.

Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases collectively capable of degrading essentially all extracellular matrix components. These enzymes can be produced by several different types of cells in skin such as fibroblasts, keratinocytes, macrophages, endothelial cells, mast cells, and eosinophils and their activity can be specifically inhibited by TIMPs (tissue inhibitors of metalloproteinases), which bind to active MMPs with 1:1 stoichiometry. In general, MMPs are not constitutively expressed in skin but are induced temporarily in response to exogenous signals such as various cytokines, growth factors, cell matrix interactions and altered cell-cell contacts. At present, more evidence is accumulating that MMPs play an important role in proteolytic remodeling of extracellular matrix in various physiologic situations, including developmental tissue morphogenesis, tissue repair, and angiogenesis. On the other hand, MMPs play an important pathogenetic role in excessive breakdown of connective tissue components, e.g. in rheumatoid arthritis, osteoarthritis, chronic ulcers, dermal photoageing, and periodontitis, as well as in tumor cell invasion and metastasis. In this review we discuss the role of MMPs and TIMPs in human skin based on new observations on the regulation of the expression of MMPs, on their substrate specificity, and MMP expression in physiologic and pathologic conditions of skin involving matrix remodeling. Furthermore, therapeutic modalities based on regulating MMP activity will be reviewed.

Basal Cell Carcinoma↗
PubMed2001

Matrix metalloproteinases: they're not just for matrix anymore!

The matrix metalloproteinases (MMPs) have been viewed as bulldozers, destroying the extracellular matrix to permit normal remodeling and contribute to pathological tissue destruction and tumor cell invasion. More recently, the identification of specific matrix and non-matrix substrates for MMPs and the elucidation of the biological consequence of cleavage indicates that perhaps MMPs should be viewed more as pruning shears, playing sophisticated roles in modulating normal cellular behavior, cell-cell communication and tumor progression.

Animals↗
PubMed1997

Involvement of a region near valine-69 of tissue inhibitor of metalloproteinases (TIMP)-1 in the interaction with matrix metalloproteinase 3 (stromelysin 1).

Tissue inhibitors of metalloproteinases (TIMPs) inhibit matrix metalloproteinases (MMPs) by forming a 1:1 stoichiometric complex, but the inhibition mechanism of these inhibitors is not known. Here we have investigated the reactive site of TIMP-1 by its proteinase susceptibility before and after forming a complex with MMP-3 (stromelysin 1). When TIMP-1 was allowed to react with human neutrophil elastase, its inhibitory activity was destroyed. This resulted from cleavage of the Val69-Cys70 bond. However, cleavage of this bond by neutrophil elastase was prevented when TIMP-1 formed a complex with the catalytic domain of MMP-3, and full TIMP-1 activity was restored after dissociation of the complex at pH 3.0 in the presence of EDTA. These results indicate that the region around Val69 closely associates with an active MMP. The three-dimensional structure of the N-terminal domain of TIMP-2 elucidated by NMR studies [Williamson, Martorell, Carr, Murphy, Docherty, Freedman and Feeney (1994) Biochemistry 33, 11745-11759] reveals that Val69 and Cys70 form part of an extended ridge that also includes the N-terminal section of the inhibitor. This region is probably involved in the interaction with the catalytic domains of MMPs.

Binding Sites↗
PubMed2006

Extracellular matrix metalloproteinase inducer in interstitial pneumonias.

Extracellular matrix metalloproteinase inducer (EMMPRIN), a glycosylated transmembrane protein that induces matrix metalloproteinases (MMPs), is minimally expressed in the normal adult lung. We previously reported that it is up-regulated in murine bleomycin-induced lung injury. In this study, we determined the expression of EMMPRIN and its association with MMP-2, MMP-7, and MMP-9 in interstitial pneumonias (IPs). We performed immunohistochemistry for EMMPRIN and MMPs on lung tissue from 22 subjects with various IPs. We did bronchoalveolar lavage (BAL) on 9 of these subjects and 13 others with IPs to measure the soluble EMMPRIN in BAL fluid. For comparison, immunohistochemistry or BAL was done on 14 subjects without IPs. The staining intensity for each protein was scored from 0 to 3 in various epithelial cell types. Soluble EMMPRIN in BAL fluid was measured by an enzyme-linked immunosorbent assay. Extracellular matrix metalloproteinase inducer was prominent in abnormal epithelial cells. It was more prominent in hyperplastic type II cells, compared with epithelium in alveolar bronchiolization. It was also elevated in BAL fluid from the subjects with IPs. Matrix metalloproteinases were expressed in cells expressing EMMPRIN, although the profile of MMPs varied among the different abnormal epithelial cell types with MMP-2 and MMP-7 in hyperplastic type II cells and MMP-7 and MMP-9 in cells showing squamous metaplasia and cells comprising bronchiolization. These results suggest a role of EMMPRIN in reepithelialization in IPs.

Basigin↗
PubMed2006

Effect of recombinant human tissue inhibitor of matrix metalloproteinase-1 in rabbit mandibular distraction osteogenesis: a histological and immunohistochemical study.

BACKGROUND: Bone matrix metalloproteinases are capable of degrading bone matrix during the remodelling, and their degradation activities can be down regulated by the tissue inhibitors of matrix metalloproteinases. This study evaluated the influence of exogenous tissue inhibitor of matrix metalloproteinase-1 on the expression of matrix metalloproteinases and endogenous tissue inhibitor of matrix metalloproteinases in mandibular distraction osteogenesis. MATERIAL AND METHODS: Fifteen New Zealand white rabbits were assigned to three groups: a negative control; a sham control group implanted with a collagen sheet; and an experimental group implanted with recombinant human tissue inhibitor of matrix metalloproteinase-1 impregnated in a collagen sheet. Rabbits were sacrificed at 6 weeks, 12 weeks and 24 weeks of consolidation. RESULTS: Major expression of matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases was observed at the early stage of consolidation, only positive signals of tissue inhibitors of matrix metalloproteinases were observed at 24 weeks. The addition of recombinant human tissue inhibitor of matrix metalloproteinases-1 did not affect bone maturation and remodelling. CONCLUSIONS: An equilibrium of bone formation and resorption was reached at 24 weeks of consolidation in the rabbit mandible. No obvious influence of recombinant human tissue inhibitor of matrix metalloproteinase-1 on bone remodelling of mandibular distraction osteogenesis was noted.

Animals↗
PubMed1997

Mutational study of the amino-terminal domain of human tissue inhibitor of metalloproteinases 1 (TIMP-1) locates an inhibitory region for matrix metalloproteinases.

A bacterial expression system for the inhibitory N-terminal domain of human tissue inhibitor of metalloproteinases 1 (N-TIMP-1) (Huang, W., Suzuki, K., Nagase, H., Arumugam, S., Van Doren, S. R., and Brew, K. (1996) FEBS Lett. 384, 155-161) has been used to produce 20 single- and double-site mutants that probe the roles of different residues in its inhibitory action on metalloproteinases. Mutations that produce the largest increases in the Ki for a C-terminally truncated form of stromelysin 1, MMP-3(DeltaC), but do not disturb the conformation involve substitutions of residues that are located in a ridge that is centered around the disulfide bond between Cys1 and Cys70. Specific residues that have a large influence on activity include Cys1, Thr2, Met66, Val69, and Cys70. Of the mutations introduced, the greatest functional disturbances, reflected in Ki increases of 2-4 orders of magnitude, are generated by changes that disrupt the Cys1-Cys70 disulfide bond and by substitution of Ala for Thr2. Most mutations that perturb the interaction with MMP-3 have parallel effects on the affinity of N-TIMP-1 for MMP-1 (interstitial collagenase) and MMP-2 (gelatinase A). However, the Thr2 to Ala mutation produces an inhibitor that is 17-fold more effective against MMP-3 than MMP-1, suggesting that it is feasible to engineer TIMP-1 variants that are more specifically targeted to selected matrix metalloproteinases. The reactive site identified by these studies is a structurally constrained but elongated region of TIMP that can fit the matrix metalloproteinase substrate-binding site.

Binding Sites↗
PubMed2003

Tissue inhibitor of metalloproteinase (TIMP)-1: the TIMPed balance of matrix metalloproteinases in the central nervous system.

Astrocytes are intimately involved in the mechanisms of neural injury and repair. They participate in a variety of homeostatic functions and elicit repair responses as balance mechanisms. Currently, there is a growing appreciation of a more active role of astrocytes in neuronal signaling and function. One key homeostatic mechanism of astrocytes in tissue repair is maintained through their production of tissue inhibitors of metalloproteinases (TIMPs). The family of TIMPs (1-4) plays a central regulatory role as inhibitors of matrix metalloproteinases (MMPs), enzymes involved in extracellular matrix maintenance and remodeling. Recently, TIMP-1, the inducible form, has been identified as a multifunctional molecule with divergent functions. It participates in wound healing and regeneration, cell morphology and survival, tumor metastasis, angiogenesis, and inflammatory responses. An imbalance of MMP/TIMP regulation has been implicated in several inflammatory diseases of the central nervous system (CNS). Here we review the conundrums of TIMP-1 regulation in CNS pathophysiology. We propose that astrocyte-TIMP-1 may play an important role in CNS homeostasis and disease. Astrocyte TIMP-1 expression is differentially regulated in inflammatory neurodegenerative diseases and may have significant therapeutic relevance.

Animals↗
PubMed2005

[The effect of matrix metalloproteinase-1 on root surface dentin matrix: a scanning electron microscope observation].

OBJECTIVE: To observe the effect of matrix metalloproteinase-1 (MMP-1) from human host on degradation of dentin organic matrix of root dentin. METHODS: The freshly extracted caries-free impacted teeth were selected. Teeth were cut transversely under the enamel-cementum junction into dentin sections with a thickness of about 5 mm. Then all sections with removal of cementum, pulp and predentin were randomly divided into four groups. In the first group, dentin sections were demineralized with acid solution for 21 days, and then incubated with MMP-1 solution for 7 days; the second group were only treated with acid solution for 21 days; the third group were only attacked by MMP-1 solution for 7 days; and the fourth group were untreated as a control. Then all sections were dehydrated in ascending strength of alcohol, critically dried, coated with platinum, and then observed under scanning electron microscope(SEM). RESULTS: The dentin sections of root surface attacked by acid and MMP-1 showed that demineralization of dentin mineral and degradation of dentin matrix fibrae synchronously happened. The dentin matrix fibrae wasn't degradated in the groups treated with acid or MMP-1. CONCLUSION: The proteinases from human host may play an important role in the development of root surface caries. MMP-1 may distinctly degradate the organic matrix of demineralized dentin.

Dental Cementum↗
PubMed2002

Tissue levels of active matrix metalloproteinase-2 and -9 in colorectal cancer.

The bioactivity of matrix metalloproteinases was studied in tissues from colorectal cancer patients by means of both quantitative gelatin zymography and a fluorometric activity assay. Next to paired samples of tumour tissue and distant normal mucosa (n=73), transitional tissue was analysed from a limited (n=33) number of patients. Broad-spectrum matrix metalloproteinase activity and both the active and latent forms of the gelatinases matrix metalloproteinase-2 and -9 were higher in tumour than in normal mucosa. The ratio's between active and latent forms of matrix metalloproteinase-2 and -9 were highest in tumour tissue and normal mucosa, respectively. Matrix metalloproteinase-2 levels, both active and latent forms, correlated inversely with stage of disease, the tumours without synchronous distant metastases containing significantly (P=0.005) more active matrix metalloproteinase-2 than the others. At much lower levels of activity, the same trend was observed in distant normal mucosa. The level of latent form of matrix metalloproteinase-9 in tumour depended on tumour location. Neither the active form of matrix metalloproteinase-9 nor broad-spectrum matrix metalloproteinase activity in tumour tissue did correlate with any of the clinicopathological parameters investigated. The results demonstrate explicit differences between the activity of matrix metalloproteinase-2 and -9, indicating different roles for both gelatinases in tumour progression. Such data are necessary in order to develop rational anti-cancer therapies based on inhibition of specific matrix metalloproteinases.

Adenocarcinoma, Mucinous↗
PubMed2001

Occurrence of matrix metalloproteinases and tissue inhibitors of metalloproteinases in tuberculous pleuritis.

OBJECTIVE: Matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP) have been found in high concentrations in pleural effusions. Because MMP and TIMP may play a part in the causation of the fibrosis seen in tuberculous (TB) pleuritis their occurrence was examined. DESIGN: Pleural effusion fluid and plasma concentrations of MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, TIMP-1 and TIMP-2 were determined by ELISA in 21 patients with TB pleuritis. To adjust for the total protein content, respective ratios were calculated. Activities of MMP-2 and MMP-9 were measured by gelatine zymography and the MMP-9/MMP-2 ratios calculated. Pleural effusions and plasma of 15 patients with congestive heat failure (CHF) and plasma of 15 healthy persons (CON) served as controls. RESULTS: Immunoreactive pleural fluid concentrations of MMP-1, MMP-2, MMP-8, and MMP-9 were higher in TB compared to CHF, but plasma concentrations were not different between the groups. TB pleural fluid concentrations of MMP-1, MMP-2, TIMP-1, and TIMP-2 were higher compared to TB plasma. MMP-3 was found in trace amounts only. The MMP-9/total protein ratios in pleural fluid were higher in TB compared to CHF (0.4492+/-0.1633 vs 0.0364+/-0.0145, P<0.005) but the TIMP-1 ratios were lower (139.0+/-28.7 vs 517.8+/-183.7, P<0.0005). In TB pleural fluid vs TB plasma, the respective MMP-1, MMP-2, TIMP-1, and TIMP-2 ratios were increased (0.46+/-0.10 vs 0.17+/-0.02; 25.2+/-2.8 vs 4.2+/-0.9; 139.0+/-28.7 vs 27.8+/-8.2; 0.67+/-0.13 vs 0.18+/-0.04, P<0.0005 each). Gelatine zymography demonstrated MMP-2 and MMP-9 bands of different brightness in TB effusions but in CHF effusions the MMP-9 band was barely visible. The MMP-9/MMP-2 effusion ratios were therefore higher in TB compared to CHF (0.46+/-0.15 vs 0.05+/-0.04, P<0.0005). CONCLUSION: Compartmentalized MMP-1, MMP-2, TIMP-1, and TIMP-2 and, compared to CHF, a surplus of MMP-1, MMP-2, MMP-8, and MMP-9 in the pleural space obviously contribute to the fibrotic reactions in TB pleuritis.

Adult↗
PubMed1998

Complex role of matrix metalloproteinases in angiogenesis.

Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) play a significant role in regulating angiogenesis, the process of new blood vessel formation. Interstitial collagenase (MMP-1), 72 kDa gelatinase A/type IV collagenase (MMP-2), and 92 kDa gelatinase B/type IV collagenase (MMP-9) dissolve extracellular matrix (ECM) and may initiate and promote angiogenesis. TIMP-1, TIMP-2, TIMP-3, and possibly, TIMP-4 inhibit neovascularization. A new paradigm is emerging that matrilysin (MMP-7), MMP-9, and metalloelastase (MMP-12) may block angiogenesis by converting plasminogen to angiostatin, which is one of the most potent angiogenesis antagonists. MMPs and TIMPs play a complex role in regulating angiogenesis. An understanding of the biochemical and cellular pathways and mechanisms of angiogenesis will provide important information to allow the control of angiogenesis, e.g. the stimulation of angiogenesis for coronary collateral circulation formation; while the inhibition for treating arthritis and cancer.

Animals↗
PubMed1993

Matrix metalloproteinases: a review.

Matrix metalloproteinases (MMPs) are a family of nine or more highly homologous Zn(++)-endopeptidases that collectively cleave most if not all of the constituents of the extracellular matrix. The present review discusses in detail the primary structures and the overlapping yet distinct substrate specificities of MMPs as well as the mode of activation of the unique MMP precursors. The regulation of MMP activity at the transcriptional level and at the extracellular level (precursor activation, inhibition of activated, mature enzymes) is also discussed. A final segment of the review details the current knowledge of the involvement of MMP in specific developmental or pathological conditions, including human periodontal diseases.

Amino Acid Sequence↗
PubMed2003

Unveiling the surface epitopes that render tissue inhibitor of metalloproteinase-1 inactive against membrane type 1-matrix metalloproteinase.

Membrane type 1-matrix metalloproteinase (MT1-MMP) is a zinc-dependent, membrane-associated endoproteinase of the metzincin family. The enzyme regulates extracellular matrix remodeling and is capable of cleaving a wide variety of transmembrane proteins. The enzymatic activity of MT1-MMP is regulated by endogenous inhibitors, the tissue inhibitor of metalloproteinases (TIMP). To date, four variants of mammalian TIMP have been identified. Whereas TIMP-2-4 are potent inhibitors against MT1-MMP, TIMP-1 displays negligible inhibitory activity against the enzyme. The rationale for such selectivity is hitherto unknown. Here we identify the surface epitopes that render TIMP-1 inactive against MT1-MMP. We show that TIMP-1 can be transformed into an active inhibitor against MT1-MMP by the mutation of a single residue, namely threonine 98 to leucine (T98L). The resultant mutant displayed inhibitory characteristics of a typical slow, tight binding inhibitor. The potency of the mutant could be further enhanced by the introduction of valine 4 to alanine (V4A) and proline 6 to valine (P6V) mutations. Indeed, the inhibitory profile of the triple mutant (V4A/P6V/T98L) is indistinguishable from those of other TIMPs. Our findings suggest that threonine 98 is critical in initiating MMP binding and complex stabilization. Our findings also provide a potential mechanistic explanation for MMP-TIMP selectivity.

Amino Acid Sequence↗