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PubMed2005

Human mesenchymal stem cell derived osteoblasts degrade organic bone matrix in vitro by matrix metalloproteinases.

Some recent studies have suggested that cells of mesenchymal origin might participate in the organic bone matrix dissolution. In the present study, collagen synthesis and degradation by human mesenchymal stem cell (MSC) derived cells were studied at early stage of osteoblast differentiation using a special two-stage in vitro culture model. In this model, cells were cultured on bovine bone slices, which were first resorbed by osteoclasts. Synthesis of type I collagen was markedly enhanced when mesenchymal cells were cultured on bone matrix. After thorough osteoclast removal, MSC derived cells were capable of degrading the organic bone matrix, and caused a release of type I collagen degradation product (ICTP) into the culture medium. This was inhibited by matrix metalloproteinase (MMP) inhibitor, while cysteine proteinase inhibitor or estrogen had no inhibitory effect. Western blot analysis or gelatin zymography confirmed the presence of MMP-2, -8, -13 and -14, but not MMP-1 or -9, in the differentiated cells. 17beta-Estradiol was found to increase the expression of MMP-2 and -14 by these cells. Finally, scanning electron microscopy showed that the differentiating human MSCs were capable of degrading organic bone matrix remnants from the bottom of the resorption lacunae. These data support the hypothesis that collagen cleavage by the same cells that are subsequently responsible for bone formation is MMP mediated process and is an important step coupling bone formation into bone resorption.

Animals↗
PubMed2004

Sputum matrix metalloproteases: comparison between chronic obstructive pulmonary disease and asthma.

Asthma and chronic obstructive pulmonary disease (COPD) are different conditions with contrasting airway inflammation and parenchymal disease patterns. A number of matrix metalloproteases (MMPs) are implicated in the pathophysiology of COPD and asthma. Different profiles of airway MMPs may, therefore, be expected in asthma and COPD. The present study compared MMP profiles in the airways of non-smokers, non-symptomatic cigarette smokers, and patients with COPD or asthma (n = 15 subjects per group). Induced sputum was assessed for MMP-1, -2, -3, -8 and -9, and tissue inhibitor of metalloproteases (TIMP)-1 by ELISA. Gelatinase activity was determined by zymography. Sputum from COPD patients contained increased levels of MMP-1, -8 and -9 compared with the other groups (2-7-fold, depending upon group). MMP-9 activity was elevated in COPD sputum by 3-12-fold above the other groups. Sputum from COPD patients had 3-fold higher levels of TIMP-1 than samples from asthmatics or controls, but was not different to smokers. FEV1 correlated negatively with MMP-1, -8, -9, MMP-9 activity and TIMP-1, whereas percent neutrophils in sputum correlated positively with MMP-1, -8, -9, TIMP-1 and MMP-9 activity. The MMP profile in COPD differs to that in asthma and cigarette smokers. This may contribute to, or be a marker of, different pathophysiologies of asthma and COPD.

Adult↗
PubMed2006

Action of matrix metalloproteinases at restricted sites in colon anastomosis repair: an immunohistochemical and biochemical study.

BACKGROUND: Dehiscence of colon anastomosis is a common, serious and potentially life-threatening complication after colorectal operation. In experimental models, impaired biomechanic strength of colon anastomoses is preventable by general inhibitors of matrix metalloproteinases (MMPs) and associated with collagen loss, which indicates a possible link between MMP-mediated collagen degradation and dehiscence. The precise localization of collagen degradation within the anastomotic area and the specific MMPs responsible are unknown. METHODS: We have analyzed distinct zones within anastomoses using a novel microdissection technique for collagen levels, collagenolytic activity exerted directly by endogenous proteinases, and MMP-8 and MMP-9 immunoreactivity and their collagenolytic activity. RESULTS: The most pronounced collagen loss was observed in the suture-holding zone, showing a 29% drop compared with adjacent micro-areas of 3-day-old anastomoses. Only this specific tissue compartment underwent a dramatic and significant increase in collagenolysis, amounting to a loss of 10% of existing collagen molecules in 24 hours, and was abolished by metalloproteinase inhibitors. The tissue surrounding suture channels was heavily infiltrated with CD68-positive histiocytes that expressed MMP-8 and to a lesser extent MMP-9. The collagenolytic effect of the interstitial collagenase MMP-8 was synergistically potentiated by the gelatinase MMP-9 when added to colon biopsies incubated in vitro. CONCLUSIONS: The unique finding of this study was that the specific tissue holding the sutures of a colon anastomosis lost the most collagen presumably through induction and activation of multiple MMPs that may explain the beneficial effects of treatment with non-selective MMP antagonists.

Anastomosis, Surgical↗
PubMed2005

Alpha v beta 6 integrin down-regulates the MMP-13 expression in oral squamous cell carcinoma cells.

The integrin alphavbeta6, a receptor for fibronectin, vitronectin, tenascin and TGF-beta latency-associated peptide (LAP), is not detectable on normal oral epithelium but is neo-expressed in oral squamous cell carcinomas (OSCC) and epithelial dysplasia. Previously it has been shown that alphavbeta6 integrin can up-regulate MMP-3 and -9 expression in OSCC cells. Using beta6-transfected and control OSCC cells we demonstrate that alphavbeta6 integrin down-regulates MMP-13 expression at both mRNA and protein level. Although expressing less MMP-13, beta6-transfected cells were found to have similar collagenolytic activity as control cells and invade at similar levels through type I collagen. Growth of the tumour cells in organotypic culture and confocal microscopy confirmed low levels of MMP-13 in cells with high alphavbeta6 expression. Furthermore, human squamous cell carcinomas of the tongue with high expression of alphavbeta6 showed lower MMP-13 levels than carcinomas with low levels of alphavbeta6. Our results suggest that alphavbeta6 down-regulates MMP-13 expression in OSCC cells and that MMP-13 is not essential for the degradation of type I collagen by OSCC cells.

Antigens, Neoplasm↗
PubMed1999

Collagenolysis in the lower uterine segment during parturition at term: correlations with stage of cervical dilatation and duration of labor.

OBJECTIVE: The objective of this study was to quantify the extent of neutrophil infiltration and the concentrations of enzymes involved in collagenolysis in the lower uterine segment in relation to the degree of cervical dilatation and the duration of labor. STUDY DESIGN: Biopsy specimens of the lower uterine segment were obtained from 62 women undergoing cesarean section at term. The number of extravascular neutrophils was assessed with enzyme histochemical evaluation, and the concentrations of matrix metalloproteinase-8, matrix metalloproteinase-9, and tissue inhibitor of metalloproteinases-1 by were assessed by enzyme-linked immunosorbent assay. RESULTS: The neutrophil count and the concentrations of matrix metalloproteinase-8, matrix metalloproteinase-9, and tissue inhibitor of metalloproteinases-1 increased with increasing cervical dilatation. At >6 cm the neutrophil count and the concentrations of matrix metalloproteinase-8, matrix metalloproteinase-9, and tissue inhibitor of metalloproteinases-1 were significantly higher than at <2 cm. An association with the duration of labor was found for the neutrophil count and the concentrations of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinases-1. Multiple linear regression analysis showed that the degree of cervical dilatation is more closely related to the 4 laboratory parameters investigated than to the duration of labor. CONCLUSION: The findings support the hypothesis that local changes (ie, collagenolysis) in the lower uterine segment unrelated to uterine activity play a crucial role in cervical dilatation at term.

Cervix Uteri↗
PubMed2003

Adenoviral gene transfer of interleukin-1 in combination with oncostatin M induces significant joint damage in a murine model.

Oncostatin M (OSM) is an interleukin (IL)-6 family cytokine that we have previously shown can synergize with a number of proinflammatory cytokines to promote the release of collagen from cartilage in explant culture. However, the effects of this potent cytokine combination in vivo are not known. Using adenoviral gene transfer, we have overexpressed murine IL-1 (AdmIL-1) and murine OSM (AdmOSM) intraarticularly in the knees of C57BL/6 mice. Histological analyses indicated marked synovial hyperplasia and inflammatory cell infiltration for both AdmIL-1 and AdmOSM but not in control joints. This inflammation was even more pronounced for the AdmIL-1+AdmOSM combination with evidence of cartilage and bone destruction. Significant loss of both proteoglycan and collagen was also seen for this combination, and immunohistochemistry revealed an increased expression of matrix metalloproteinases (MMPs) with decreased tissue inhibitor of metalloproteinases (TIMPs) in both articular cartilage and synovium. Similar expression profiles for MMPs/TIMPs were found in IL-1+OSM-stimulated human articular chondrocytes. Taken together, these data confirm that, in vivo, OSM can exacerbate the effects of IL-1 resulting in inflammation and tissue destruction characteristic of that seen in rheumatoid arthritis. We provide further evidence to implicate the up-regulation of MMPs as a key factor in joint pathology.

Adenoviridae↗
PubMed2000

pH- and temperature-dependence of functional modulation in metalloproteinases. A comparison between neutrophil collagenase and gelatinases A and B.

Metalloproteases are metalloenzymes secreted in the extracellular fluid and involved in inflammatory pathologies or events, such as extracellular degradation. A Zn(2+) metal, present in the active site, is involved in the catalytic mechanism, and it is generally coordinated with histidyl and/or cysteinyl residues of the protein moiety. In this study we have investigated the effect of both pH (between pH 4.8 and 9.0) and temperature (between 15 degrees C and 37 degrees C) on the enzymatic functional properties of the neutrophil interstitial collagenase (MMP-8), gelatinases A (MMP-2) and B (MMP-9), using the same synthetic substrate, namely MCA-Pro-Leu-Gly approximately Leu-DPA-Ala-Arg-NH(2). A global analysis of the observed proton-linked behavior for k(cat)/K(m), k(cat), and K(m) indicates that in order to have a fully consistent description of the enzymatic action of these metalloproteases we have to imply at least three protonating groups, with differing features for the three enzymes investigated, which are involved in the modulation of substrate interaction and catalysis by the enzyme. This is the first investigation of this type on recombinant collagenases and gelatinases of human origin. The functional behavior, although qualitatively similar, displays significant differences with respect to what was previously observed for stromelysin and porcine collagenase and gelatinase (Stack, M. S., and R. D. Gray. 1990. Arch. Biochem. Biophys. 281:257-263; Harrison, R. K., B. Chang, L. Niedzwiecki, and R. L. Stein. 1992. Biochemistry. 31:10757-10762). The functional characterization of these enzymes can have some relevant physiological significance, since it may be related to the marked changes in the environmental pH that collagenase and gelatinases may experience in vivo, moving from the intracellular environment to the extracellular matrix.

Amino Acid Sequence↗
PubMed2000

Evolution of matrix metalloprotease and tissue inhibitor expression during heart failure progression in the infarcted rat.

OBJECTIVE: Characterize the timecourse of matrix metalloproteinase (MMP-1, -2, -3, -7, -9, -11, -12, -13, and -14) and endogenous tissue inhibitors of MMPs (TIMP-1, -2, -3, and -4) upregulation during left ventricular (LV) remodeling following myocardial infarction (MI) in rats. METHODS: The descending left coronary artery of male rats (Rattus norvegicus) was ligated to produce a MI. LV function and dilation were assessed from 1 day to 16 weeks post-MI. Protein and mRNA extraction was done on LV samples containing scar and myocardium together. Gelatinase activity was measured by zymography. Westerns were run on the MMPs known to cleave fibrillar collagen in the rat (MMP-8, -13, and -14) as well as TIMP-1, -2, and -4. RESULTS: Average infarct size was 38.6+/-1.1%, and produced LV dysfunction and progressive LV dilation. Thoracic ascites, a marker of congestive heart failure (HF), was not present until 12 weeks post-MI. Upregulation of MMP-2, -8, -9, -13, and -14 and TIMP-1 and TIMP-2 was detected at different timepoints during HF progression. Increased MMP protein levels occurred sometimes without a corresponding elevation in mRNA levels, and increased TIMP mRNA levels without increased protein levels. MMP-13 active form was elevated during the first 2 weeks post-MI while TIMP-1 and TIMP-2 protein levels were not significantly elevated until 2 weeks post-MI. MMP-8 and MMP-14 protein levels increased later during heart failure progression. CONCLUSION: MMP/TIMP upregulation evolves over time following infarction in the rat LV. Some MMPs were significantly elevated during the first week post-MI (MMP-13, -2, and -9) and another was not until 16 weeks post-MI (MMP-14). The dissociation between LV MMP/TIMP mRNA and protein levels shows that post-translation processing occurs in the rat heart.

Animals↗
PubMed2001

MMP-TIMP interaction depends on residue 2 in TIMP-4.

Extracellular matrix remodeling and degradation are of great importance in both physiological and pathological situations. Matrix metalloproteinases (MMPs) and their natural occurring inhibitors - tissue inhibitors of metalloproteinases (TIMPs) - are involved in matrix turnover. Among the TIMPs there is only little specificity for inhibiting individual MMPs. In this report we describe the mutational analysis of the interaction of human TIMP-4 with several MMPs. The effects of different substitutions of residue 2 (Ser(2)) in the inhibitory domain of TIMP-4 were determined by kinetic measurements. Size, charge and polarity of residue 2 in the TIMP structure are key factors in MMP inhibition.

Amino Acid Substitution↗
PubMed1998

Hydroxamate derivatives of substrate-analogous peptides containing aminomalonic acid are potent inhibitors of matrix metalloproteinases.

Novel peptides containing the sequence -Pro-Leu-Ama(NHOH)- were synthesized and characterized by spectroscopic techniques. Their inhibitory properties towards the activated form of native human gelatinase B (MMP-9) and the catalytic domain of neutrophil collagenase (cdMMP-8) were determined. The most effective inhibitor synthesized exhibits Ki values of 2 x 10(-6) M (cdMMP-8) and 5 x 10(-9) M (MMP-9) thus attaining interesting discrimination between the tested metalloproteinases. A most important feature of this type of inhibitor is its peptide nature making the compounds similar to natural substrates. In spite of the peptide character of the inhibitors synthesized, the P1-P1'-peptide bond shows a high resistance to cleavage by the proteinases.

Humans↗
PubMed2003

Expression of matrix metalloproteinases, sICAM-1 and IL-8 in CSF from children with meningitis.

The combined expression of the inflammatory mediators, matrix metalloproteinases (MMPs), soluble form of intracellular adhesion molecule ICAM-1 (sICAM-1) and interleukin (IL)-8, was evaluated in children infected with bacterial or viral meningitis. MMP-2 and IL-8 were detected in all CSF samples and were enhanced in both bacterial and viral infected samples, compared to those from control children. The expression of MMP-9 as well as sICAM-1 was not detected in control CSF while observed in viral infected and further elevated in bacterial infected samples. This pilot study supports a role for MMPs, IL-8 and sICAM in infectious meningitis and suggests further research to determine their possible use as biomarkers for various forms of meningeal infection as well as the use of their specific antagonists as potential therapeutic agents for central nervous system (CNS) inflammatory processes.

Biomarkers↗
PubMed1997

Zymographic measurement of gelatinase activity in brain tissue after detergent extraction and affinity-support purification.

Several methods have been developed for the measurement of gelatinase activity from various tissues using detergent extraction. Gelatin-affinity chromatography has been employed for the large-scale purification of gelatinases from conditioned medium obtained from cultured cells. The objective of this paper was to develop a rapid method whereby gelatinase activity could be extracted from regional brain tissues without tedious, intervening purification steps. After Triton X-100 extraction and gelatin-Sepharose 4B purification of rat brain tissue extracts, two major activities were observed on gelatin zymograms. These were identified as gelatinase A and B using co-migration with astrocyte-derived enzymes and inhibition of activity by tissue inhibitor of matrix metalloproteinase-1 (TIMP-1). The non-ionic detergents, Triton X-100 and 3-[(3-cholamidopropyl)dimethylammonio]-1-propane-sulfonate (CHAPS) were equally effective in extracting activities from brain tissue. Little difference in recovery was observed among 0.1, 1 and 10% concentrations of Triton X-100. The method developed here was capable of recovering gelatinase activities from rat brain tissue over a 4-10-fold range using gelatin zymography for the measurement of activity. It is possible that this method may be modified for the measurement of gelatinases in tissues such as biopsy samples of gliomas or astrocytomas or other cancers where gelatinases are thought to play a role in tumor invasion and/or metastasis.

Animals↗
PubMed2002

Stress-related modulation of matrix metalloproteinase expression.

Matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs), whose expression can be controlled by cytokines, play a role in extracellular matrix remodeling in physiological and pathological processes. Using a blister chamber wound model on UV-B-exposed human forearm skin, we examined whether stress or mood-associated neuroendocrine alteration is sufficient to modulate MMP and TIMP expression. We did not find evidence that depressive symptoms were reliably associated with modulation of either MMP or TIMP expression. However, we did find that activation of the hypothalamic-pituitary-adrenal (HPA) and sympathetic-adrenal medullary (SAM) axes can modulate levels of MMPs. A positive association between plasma norepinephrine levels and MMP-2 protein levels, and a negative correlation between plasma cortisol levels and MMP-2 levels were found. The data suggest that activation of the HPA and SAM axes, even in individuals within the normal range of depressive symptoms, could mediate MMP levels and wound healing in blister wounds.

Adrenal Medulla↗
PubMed1998

Overview of matrix metalloproteinase expression in cultured human cells.

The matrix metalloproteinases (MMP) have been implicated in tumor invasion and metastasis both by immunohistochemical studies and from the observation that specific metalloproteinase inhibitors block tumor invasion and metastasis. Oligonucleotide primers for thirteen MMPs (MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-11, MMP-12, MMP-13, MMP-14, MMP-15, MMP-16) were optimized for use in RT-PCR. A semi-quantitative RT-PCR assay was used to determine the pattern of MMP mRNA expression in 84 normal and transformed or carcinogen transformed human cell lines and strains derived from different tissues. The results demonstrate one or more cell lines which express thirteen members of the MMP family. In addition, various oncogene transfected human fibroblast cell strains were analyzed for MMP expression. We confirm that over-expression of the H-ras oncoprotein correlates with up-regulation of MMP-9 and demonstrate that over-expression of v-sis also up-regulates MMP-9. A cell line immortalized following myc expression was found to up-regulate MMP-7, MMP-11 and MMP-13. Inappropriate expression of several MMP mRNAs was detected in breast, prostate, bone, colon and oral tumor derived cell lines. Identification of at least one cell line expressing each of thirteen MMPs and the observation of oncogene induced expression of several MMPs should facilitate analysis of the transcriptional mechanisms controlling each MMP.

Cell Line↗
PubMed1999

Collagen breakdown in soft connective tissue explants is associated with the level of active gelatinase A (MMP-2) but not with collagenase.

Recent data suggest that gelatinase A (matrix metalloproteinase-2, MMP-2) plays an important role in the degradation of collagen of soft connective tissues. In an attempt to investigate its participation in more detail we assessed the digestion of collagen in cultured rabbit periosteal explants and compared this with the level of active MMP-2 and collagenases. The data demonstrated that both collagen degradation and MMP activity increased with time. Conditioned medium obtained from explants cultured for 72 h showed that the level of active MMP-2 correlated with collagen degradation (r = 0.80, d.f. = 23, P < 0.0001). Such a relationship was not found with collagenase activity (r = -0.08, d.f. = 21, NS). The possible involvement of MMP-2 in collagen degradation was investigated further by incubating explants with selective gelatinase inhibitors (CT1166, CT1399 and CT1746). In the presence of these compounds breakdown of collagen was almost completely abolished (approximately 80%). Finally we assessed whether periosteal fibroblasts had the capacity to degrade collagen type I that conferred resistance to collagenase activity. Breakdown of this collagen did not differ from degradation of normal collagen. Taken together, our data provide support for the view that MMP-2 plays a crucial role in collagen degradation of soft connective tissue.

Animals↗
PubMed2001

Novel 5,5-disubstitutedpyrimidine-2,4,6-triones as selective MMP inhibitors.

The 5,5-disubstitutedpyrimidine-2,4,6-triones represent a new class of MMP inhibitors showing selectivity for the gelatinases A and B, collagenase-3, and human neutrophil collagenase. The SAR presented here is in good agreement with an X-ray structure of compound 5 bound to the catalytic domain of stromelysin-1. While of the barbiturate structural class, compound 5 did not show any toxic or sedative effects.

Animals↗
PubMed2002

Oxal hydroxamic acid derivatives with inhibitory activity against matrix metalloproteinases.

Several amines, amino acid derivatives and low molecular weight peptides containing an amide-bound oxal hydroxamic acid moiety have been synthesized and tested for their inhibitory effects towards native human gelatinase B (MMP-9) and the catalytic domains of the membrane type MT1-MMP (MMP-14) and of neutrophil collagenase (MMP-8). A number of these compounds exhibited considerable inhibitory activity against the tested metalloproteinases.

Amines↗