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PubMed1996

Secretion of matrix metalloproteinase-2 (72 kD gelatinase/type IV collagenase = gelatinase A) by malignant human glioma cell lines: implications for the growth and cellular invasion of the extracellular matrix.

Human glioma cells (T98G and A172 cell lines) were cultured on various extracellular matrix (ECM) components including type I, IV and V collagens, fibronectin, laminin, and reconstituted basement membrane (Matrigel), and the role of matrix metalloproteinases (MMPs) in their growth and invasion was examined. T98G glioma cells grew well on these ECM components and invaded the reconstituted basement membrane. In contrast, A172 glioma cells showed growth inhibition on collagen types IV and V and Matrigel without invasion of the Matrigel. Gelatin zymography and enzyme immunoassays demonstrated that T98G glioma cells, but not A172 cells, secrete a large amount of matrix metalloproteinase-2 (MMP-2, 72 kD gelatinase/type IV collagenase = gelatinase A), and this was confirmed by immunoblotting and immunohistochemistry. Of the two different tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2), T98G cells produced only TIMP-1 during culture on Matrigel, whereas A172 cells secreted both. Although both human recombinant TIMP-1 and TIMP-2 stimulated T98G cell growth slightly on Matrigel, the in vitro invasiveness was significantly reduced by only recombinant TIMP-2. These results suggest that MMP-2 plays an important role in the ECM invasion of T98G human glioma cells in vitro.

Brain Neoplasms↗
PubMed2004

Association of matrix metalloproteinase-9 and Purkinje cell degeneration in mouse cerebellum caused by Angiostrongylus cantonensis.

Angiostrongylosis is a neurological disorder caused by invasion of the central nervous system by developing larvae of Angiostrongylus cantonensis. Purkinje cells in infected mouse cerebellums are small and irregular with degenerative atrophy or partial loss. Ultrastructural changes in degenerative cells included enlarged vacuolar structures and swollen mitochondria within the cytoplasm. The matrix metalloproteinase-9 mRNA which is low in normal cerebellums was expressed in A. cantonensis-infected mice cerebellum prior to Purkinje cell degeneration. Matrix metalloproteinase-9 protein level and enzyme activity increased when the Purkinje cells appeared degenerated. Using immunohistochemistry, matrix metalloproteinase-9 was localised within degenerative Purkinje cells. In addition, when the specific matrix metalloproteinase inhibitor, GM6001, was added, matrix metalloproteinase-9 enzyme activity was reduced by 41.6%. The numbers of degenerative Purkinje cells increased significantly upon establishment of infection but subsided upon inhibition. These results suggested that the expression of matrix metalloproteinase-9 may be associated with degeneration of Purkinje cells in mouse cerebellum infected by A. cantonensis.

Angiostrongylus cantonensis↗
PubMed2004

Mutations in two matrix metalloproteinase genes, MMP-2 and MT1-MMP, are synthetic lethal in mice.

The matrix metalloproteinase (MMP) family (approximately 25 members in mammals) has been implicated in extracellular matrix remodeling associated with embryonic development, cancer formation and progression, and various other physiological and pathological events. Inactivating mutations in individual matrix metalloproteinase genes in mice described so far, however, are nonlethal at least up to the first few weeks after birth, suggesting functional redundancy among MMP family members. Here, we report that mice lacking two MMPs, MMP-2 (nonmembrane type) and MT1-MMP (membrane type), die immediately after birth with respiratory failure, abnormal blood vessels, and immature muscle fibers reminiscent of central core disease. In the absence of MMP-2 and MT1-MMP, myoblast fusion in vitro is also significantly retarded. These findings suggest functional overlap in mice between the two MMPs with distinct molecular natures.

Animals↗
PubMed1993

Detection and localization of mRNAs encoding matrix metalloproteinases and their tissue inhibitor in human breast pathology.

Matrix metalloproteinases (MMPs) are a group of enzymes thought to be responsible for both normal connective-tissue-matrix remodelling and the accelerated breakdown associated with tumor development. These MMPs and tissue inhibitor of MMPs (TIMP1) could be expressed by either the cancer or the stromal cells. Expression of mRNAs encoding interstitial collagenase (MMP1), 72-kD type IV collagenase (MMP2) and stromelysin (MMP3), which are probably involved in tumor invasion and metastasis, and of TIMP1 were studied in human mammary pathology by in situ hybridization and Northern blot analysis. Out of 6 benign lesions, 2 expressed MMP2 mRNAs. mRNAs encoding MMP1 and MMP3 were detectable in occasional stromal and tumor cells in 2 out of 17 carcinomas. Thirteen out of 17 cancers expressed MMP2 mRNA throughout the tumor in stromal cells close to noninvasive tumor clusters and well-differentiated invasive cancer cells. TIMP1 mRNA expression was detected in noninvasive and well-differentiated invasive tumor cells. These data suggest that there is a cooperation between tumor and stromal cells, in particular for the production of 72-kD type IV collagenase, involved in the disruption of basement membranes. A lack of TIMP1 expression from invasive cancer cells would also contribute to matrix destruction.

Blotting, Northern↗
PubMed1998

The interglobular domain of cartilage aggrecan is cleaved by hemorrhagic metalloproteinase HT-d (atrolysin C) at the matrix metalloproteinase and aggrecanase sites.

Two primary cleavage sites have been identified within the interglobular domain of the cartilage aggrecan core protein: one is between amino acid residues Asn 341 and Phe342, where many matrix metalloproteinases (MMP) have been shown to cleave; and the other is between amino acid residues Glu373 and Ala374. Although cleavage at the Glu373-Ala374 site is believed to play a critical role in cartilage aggrecan degradation in arthritic diseases, the enzyme responsible for cleavage at this site, "aggrecanase," has not been identified. Members of the ADAM (a disintegrin and metalloproteinase) family of proteins, which shows structural homology to the snake venom hemorrhagic metalloproteinases (reprolysins), have recently been demonstrated to be expressed in articular chondrocytes. Because many ADAM family members have a putative proteinase function, this raises the possibility that aggrecanase may be a member of this family of proteases. To examine whether reprolysins have the ability to cleave aggrecan at either the aggrecanase site or the MMP site, the snake venom hemorrhagic toxin metalloproteinase HT-d (atrolysin C) was tested for its ability to cleave bovine aggrecan monomer. Cleavage was monitored using the BC-3 antibody, which recognizes aggrecan fragments with the new NH2 terminus ARGSV generated by cleavage at the aggrecanase site, and with the AF-28 antibody, which recognizes aggrecan fragments with the new NH2 terminus FFGVG generated by cleavage at the MMP site. Cleavage at both the aggrecanase and MMP sites occurred in a concentration-dependent manner with 100 nM atrolysin C or greater. AF-28-reactive fragments were generated by 30 min of incubation, and levels were maximal by 8 h; BC-3-reactive fragments were detected at 2 h and continued to increase through 48 h, thus suggesting that atrolysin C can cleave at the MMP and aggrecanase sites. NH2-terminal aggrecan fragments generated by cleavage at the aggrecanase site were also detected using antisera recognizing the new COOH terminus, NITEGE, formed by cleavage at the Glu373-Ala374 bond, indicating that cleavage at this site does not require prior cleavage at the MMP site. These data provide the first demonstration that a reprolysin can cleave the core protein of aggrecan and the first example of a specific protease that can cleave at the aggrecanase site independent of cleavage at the MMP cleavage site.

Aggrecans↗
PubMed2004

Rapid inactivation of alpha-1-proteinase inhibitor by neutrophil specific leukolysin/membrane-type matrix metalloproteinase 6.

Leukolysin/MT6-MMP is a GPI-anchored matrix metalloproteinase (MMP) primarily expressed by neutrophils. It is stored in intracellular granules at resting state, but rapidly discharged upon stimulations into the extracellular milieu, presumably to promote tissue remodeling or destruction. The proteolytic targets for leukolysin at the inflammatory sites remain unknown. Here, we show that alpha-1-proteinase inhibitor, or alpha1-PI, a known protective shield against destructive serine proteinases, is a physiological target for leukolysin. We show that alpha1-PI failed to accumulate in media conditioned by cells co-expressing alpha1-PI and leukolysin. Purified leukolysin cleaves alpha1-PI efficiently at the Phe376Leu and Pro381Met bonds and the cleaved alpha1-PI lost its anti-proteolytic activity against human neutrophil elastase, cathepsin G (CatG) and proteinase 3 (PR3). In fact, leukolysin preferentially cleaves alpha1-PI when co-incubated with other extracellular molecules such as laminin and gelatin. Kinetically, leukolysin is more active than two known neutrophil MMPs, MMP8 and MMP9, in cleaving and inactivating alpha1-PI. Taken together, these results suggest that neutrophils may mediate tissue destruction by deploying leukolysin to weaken the alpha1-PI protective shield at inflammatory sites.

Animals↗
PubMed2001

The relationship between amniotic fluid matrix metalloproteinase-8 and funisitis.

OBJECTIVE: The fetal inflammatory response syndrome is a multisystem disorder associated with impending preterm delivery and adverse neonatal outcome. Inflammation of the umbilical cord--funisitis--is the histologic counterpart of fetal inflammatory response syndrome and has been associated with an increased risk for the development of cerebral palsy. Neutrophils found in the amniotic cavity are of fetal origin. Therefore, neutrophil secretory products may be an index of the fetal inflammatory response syndrome. To test this hypothesis, we examined the relationship between levels of amniotic fluid matrix metalloproteinase-8 and funisitis. STUDY DESIGN: The relationship between the presence of funisitis and concentrations of amniotic fluid matrix metalloproteinase-8 was examined in 255 consecutive patients who delivered preterm singleton neonates (gestational age, <36 weeks) within 72 hours of amniocentesis. Amniotic fluid was cultured for aerobic and anaerobic bacteria and for mycoplasmas. Funisitis was diagnosed in the presence of neutrophil infiltration into the umbilical vessel walls or Wharton jelly. Matrix metalloproteinase-8 was measured by use of a specific immunoassay. Nonparametric statistics were used for analysis. RESULTS: Funisitis was present in 23% (59/255) of cases. Patients with funisitis had a significantly higher median concentration of amniotic fluid matrix metalloproteinase-8 than those without funisitis (median, 433.7 ng/mL [range, 1.5-3836.8 ng/mL] vs median, 1.9 ng/mL [range, <0.3-4202.7 ng/mL]; P <.001). The diagnostic indices of matrix metalloproteinase-8 (cutoff, 23 ng/mL) in the identification of funisitis were: sensitivity of 90% (53/59), specificity of 78% (153/196), positive predictive value of 55% (53/96), and negative predictive value of 96% (153/159). CONCLUSIONS: There is a strong association between increased levels of amniotic fluid matrix metalloproteinase-8 and funisitis. We propose that determination of amniotic fluid matrix metalloproteinase-8 concentrations may assist the assessment of the fetal inflammatory status, thereby eliminating the need for fetal blood sampling.

Adult↗
PubMedDate not supplied

Effect of in vitro mechanical compression on Epilysin (matrix metalloproteinase-28) expression in hypertrophic scars.

Epilysin, designated matrix metalloproteinase (MMP)-28, is the newest member of this family of proteases expressed by keratinocytes in response to an injury. MMP-28's physiological role and specific substrates are unknown, but its expression pattern suggests that it may serve a role in both tissue homeostasis and wound healing. The aim of this preliminary study was to observe the presence of MMP-28 protein in normotrophic and hypertrophic scars and to evaluate the effect of in vitro mechanical compression on its expression. Biopsies from normotrophic and hypertrophic scars resulting from burns were divided into two samples, one to be used as control (uncompressed) and the other to be compressed in an oxygenated organ chamber for 24 hours in the presence of a serum-free medium, using an electromechanical load transducer (stable pressure = 35 mmHg). Analysis of MMP-28 protein secretion, assessed by Western blot and beta-casein zymography in scar conditioned media, revealed that normotrophic scar did not release MMP-28 in any condition while hypertrophic scar released active MMP-28 both in control conditions and after compression. MMP-28 immunohistochemistry revealed a light protein presence in normotrophic scar keratinocytes and a strong MMP-28 positivity in hypertrophic scar keratinocytes in control conditions, while compression increased MMP-28 staining in normotrophic scar and induced a significant reduction of the protein presence in hypertrophic scar keratinocytes. As it has been suggested that MMP-28 may restructure the skin basal membrane (Saarialho-Kere et al., 2002), our data indicate that mechanical compression directly acts to modulate the remodeling phase of wound healing, altering release and activity of MMP-28 in hypertrophic scars.

Adolescent↗
PubMed1998

Matrix metalloproteinases in cerebrovascular disease.

Cerebral ischemia and intracerebral hemorrhage cause extensive damage to neurons, disrupt the extracellular matrix, and increase capillary permeability. Multiple substrates participate in the cellular damage, including free radicals and proteases. Matrix metalloproteinases and serine proteases are two classes of proteases that are normally present in brain in latent forms, but once activated, contribute to the injury process. These enzymes have a unique role in the remodeling of the extracellular matrix and in the modulation of the capillary permeability. Intracerebral injection of the matrix metalloproteinase, type IV collagenase, attacks the basal lamina around the capillary and opens the blood-brain barrier. Extracellular matrix-degrading proteases are induced by immediate early genes and cytokines, and regulated by growth factors. Activity of the matrix metalloproteinases is tightly controlled by activation mechanisms and tissue inhibitors of metalloproteinases. During ischemia and hemorrhage, multiple matrix metalloproteinases and serine proteases are produced along with their inhibitors. These proteolytic enzymes are involved in the delayed injury that accompanies the neuroinflammatory response. Synthetic inhibitors to metalloproteinases reduce proteolytic tissue damage, and may limit secondary neuroinflammation.

Animals↗
PubMed2005

Production of matrix metalloproteinases by cultured bovine theca and granulosa cells.

Matrix metalloproteinases (MMPs) degrade the proteinaceous components of the extracellular matrix and are presumably essential for follicular growth culminating in ovulation or atresia. The objectives of this study were to characterize the gelatinolytic and caseinolytic MMPs secreted by cultured bovine thecal and granulosal cells and to determine the effect of luteinizing hormone (LH) on MMP secretion. Thecal and granulosal cells were collected from small bovine follicles (<5 mm) on day 2 or 5 of the estrous cycle (day 0=estrus). A serum-free culture system was utilized in which bovine thecal and granulosal cells do not spontaneously luteinize, but produce androstenedione and estradiol in response to physiological concentrations of LH and follicle-stimulating hormone (FSH) respectively. The effect of LH (0, 1 or 100 ng/ml) on MMP production was determined in conditioned media collected every 48 h for 144 h. MMPs were detected by gelatin and casein zymography and MMP activity was quantified by image analysis. Thecal and granulosal cell conditioned media contained MMPs that had a relative molecular size (Mr) ranging from 53,000 to 200,000 and addition of 1,10 phenanthroline (MMP inhibitor) blocked gelatinolytic and caseinolytic activity. Patterns of gelatinolytic activity in thecal and granulosal cell conditioned media differed over time with the Mr 62,000 and 83,000 MMPs being increased (P <0.05) and the Mr 53,000 MMP being decreased (P <0.05) at 96 h of culture. LH (1 or 100 ng/ml) increased (P <0.05) gelatinolytic activity of the Mr 53,000 and 62,000 gelatinases within thecal cell conditioned media but not granulosal cell conditioned media. The Mr 62,000 and 83,000 gelatinolytic activities corresponded to the active forms of gelatinase A (Mr 62,000) and B (Mr, 83,000) and gelatinase A was detected in thecal cell conditioned media by Western blot analysis. Caseinolytic activity (Mr 83,000) was detected in both thecal and granulosal cell conditioned media and increased from 48 to 96 h. In summary, thecal and granulosal cells secrete gelatinolytic and caseinolytic MMPs and thecal cell production of gelatinase A was stimulated by LH.

Animals↗
PubMed2001

Inhibition of transcription factor NF-kappaB reduces matrix metalloproteinase-1, -3 and -9 production by vascular smooth muscle cells.

OBJECTIVE: Matrix metalloproteinases (MMPs) contribute to the destruction of the extracellular matrix at the shoulder regions of atherosclerotic plaques that leads to plaque destabilisation and triggers clinical cardiovascular disease. There is therefore considerable interest in establishing the mechanisms responsible for increased MMP production. MMPs-1, -3 and -9 are upregulated by inflammatory cytokines and growth factors that are produced by plaque resident macrophages and smooth muscle cells. Our present studies focused on NF-kappaB, which regulates numerous inflammatory genes, and is activated in plaque smooth muscle cells. Moreover, an NF-kappaB binding site is present in the promoter of the MMP-9 gene and an NF-kappaB-like element in the promoter of the MMP-1 gene. METHODS: We used adenovirus mediated overexpression of its inhibitor, I kappaBalpha to investigate the role of NF-kappaB in regulation of MMP-1, -3 and -9 by isolated, cytokine stimulated rabbit aortic and human saphenous vein VSMC. RESULTS: IL-1alpha potently activated NF-kappa B in VSMCs and acted synergistically with growth factors to upregulate expression of MMP-1, -3 and -9. Overexpression of I kappaBalpha, almost completely inhibited expression of MMP-1, -3 and -9 in response to IL-1alpha alone or in combination with bFGF and PDGF. CONCLUSION: NF-kappaB is required for cytokine upregulation of MMP-1, -3 and -9 in VSMCs, which suggests that NF-kappaB inhibition may promote plaque stabilisation.

Animals↗
PubMed2004

Aberrant, persistent inclusion into lipid rafts limits the tumorigenic function of membrane type-1 matrix metalloproteinase in malignant cells.

Membrane type-1 matrix metalloproteinase (MT1-MMP) is a key enzyme in cell locomotion and tissue remodeling. Trafficking to the plasma membrane and internalization into the transient storage compartment both regulate the cell surface presentation of MT1-MMP. Our data indicate that mutant MT1-MMP lacking the cytoplasmic tail is recruited to the caveolae-enriched lipid raft membrane microdomains in breast carcinoma MCF7 cells. In contrast, the wild-type protease is not permanently associated with lipid rafts. Trafficking to lipid rafts correlated with poor internalization and the persistent presentation of MT1-MMP at the cell surface. The tail mutant efficiently functioned in inducing the activation of the latent proMMP-2 zymogen, matrix remodeling, and contraction of three-dimensional collagen lattices. Recruitment of the tail mutant to lipid raft antagonized, however, the cleavage of the plasma membrane-associated E-cadherin. These events limited the contribution of the tail mutant to cell locomotion and malignant growth. It is conceivable that the tail peptide sequence plays a crucial role in the translocations of MT1-MMP across the cell and contributes to coordinated cellular functions. It is tempting to hypothesize that the mechanisms involved in trafficking of MT1-MMP to caveolin-enriched lipid rafts may be targeted in a clinically advantageous manner.

Amino Acid Substitution↗
PubMed1995

The distribution of matrix metalloproteinases and tissue inhibitor of metalloproteinases in colorectal cancer.

Studies suggest that the interplay between matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitor of metalloproteinases (TIMPs), is an important mediator of tumour invasion and metastasis. Using immunohistochemistry, 40 specimens of colorectal cancer were examined for the presence of TIMP-1 and the MMPs, stromelysin, gelatinases A and B and interstitial collagenase. Neither enzyme nor TIMP-1 was detected in histologically normal mucosa. Within malignant tissue, stromelysin and gelatinase A were conspicuously absent in tumour cells but were immunolocalized to the extracellular matrix and for gelatinase A also to peritumoural fibroblast-like cells. Gelatinase B was confined to polymorphonuclear leucocytes. Interstitial collagenase was not identified. TIMP-1 was present in only three of the 40 tumours within the malignant stroma. These observations suggest that the mesenchymal elements of colorectal carcinomas, by acting as a source of MMPs and TIMPs, may modulate tumour invasion.

Collagenases↗
PubMed1999

Biochemical characterization of the catalytic domain of membrane-type 4 matrix metalloproteinase.

A C-terminal truncated form of membrane-type 4 matrix metalloproteinase (MT4-MMP; MMP 17), lacking the hemopexin-like and transmembrane domain, was expressed in Escherichia coli. The catalytic domain was produced by tryptic activation of the recombinant proenzyme and proved to be catalytically active towards the fluorogenic substrate for matrix metalloproteinases (7-methoxycoumarin-4-yl) acetyl-Pro-Leu-Gly-Leu(3-(2,4-dinitrophenyl)-L-2,3-diaminopro-p ionyl)-Ala-Arg-NH2. In contrast to the other three MT-MMPs (MT1-, MT2-, and MT3-MMP), the catalytic domain of MT4-MMP does not activate progelatinase A, nor does it hydrolyze one of the offered extracellular matrix (ECM) proteins, such as collagen types I, II, III, IV, and V, gelatin, fibronectin, laminin or decorin. TIMP-1, a poor inhibitor of MT1-, MT2- and MT3-MMP, suppresses MT4-MMP activity effectively. The progelatinase A/TIMP-2 complex that usually reacts like TIMP-2 also inhibits MT4-MMP. TIMP-2, a strong inhibitor of other MT-MMPS, inhibits MT4-MMP at low concentrations. With increasing TIMP-2 concentration, however, activity passes through a minimum and then increases until at high TIMP-2 concentration the activity is the same as in the absence of TIMP-2. TIMP-1 or the progelatinase A/TIMP-2 complex do not prevent reactivation of MT4-MMP catalytic domain at high TIMP-2 concentrations.

Amino Acid Sequence↗
PubMed2004

Persistent increase of matrix metalloproteinases in cerebrospinal fluid of tuberculous meningitis.

Matrix metalloproteinase (MMP)-2 and MMP-9 were analyzed by gelatin zymography and an enzyme-linked immunosorbent assay (ELISA) in a cerebrospinal fluid (CSF) from patients with tuberculous meningitis (n=24), acute aseptic meningitis (n=23) and the control (n=10). The MMP-2 and MMP-9 levels were significantly higher in the samples from the tuberculous meningitis patients than those from either the aseptic meningitis patients or the controls. In tuberculous meningitis, the patients with late neurologic complications had higher MMP-2 and MMP-9 levels than those without. The persistent increase in the MMP-2 and MMP-9 levels was associated with the development of complications following tuberculous meningitis. Inhibiting the MMPs may be an effective strategy for preventing or reducing the complications in tuberculous meningitis.

Electrophoresis, Polyacrylamide Gel↗
PubMed1995

Expression pattern of matrix metalloproteinases in human liver.

Antibodies were raised against seven major matrix metalloproteinases: stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), stromelysin-3 (MMP-11), interstitial collagenase (MMP-1), M(r) 72,000 type IV collagenase (72 kDa type IV collagenase, MMP-2), M(r) 92,000 type IV collagenase (92 kDa type IV collagenase, MMP-9) and matrilysin (PUMP, MMP-7) as well as against prolyl 4-hydroxylase, to study the expression of these collagenolytic enzymes in normal liver in relation to the activity of collagen synthesis. Tissue samples of four normal human livers, three hepatocellular carcinomas and one cholangiocellular carcinoma were analysed. In normal liver we found expression of stromelysin-1, stromelysin-3, interstitial collagenase, M(r) 72,000 and M(r) 92,000 type IV collagenases and varying expression of prolyl 4-hydroxylase. Stromelysin-2 was inconsistently detectable; matrilysin was not found. In hepatocellular carcinoma the expression pattern of matrix metalloproteinases showed only minor changes compared with the normal tissue; stronger signals than in normal tissue were seen for stromelysin-1, and stromelysin-2 was also strongly positive. M(r) 72,000 and M(r) 92,000 type IV collagenases and interstitial collagenase were less strongly expressed; stromelysin-3 was unchanged. Expression of prolyl 4-hydroxylase was also increased compared with normal liver. Matrilysin was only seen in cholangiocellular carcinoma, which showed a completely different pattern of matrix metalloproteinase expression. Our results show that metalloproteinases are expressed in human liver with much greater abundance than previously described. Their expression pattern is not changed fundamentally in hepatocellular carcinoma but is completely different from that of other tumour tissues such as cholangiocellular carcinoma.

Antibody Specificity↗
PubMed1995

Levels of circulating collagenase, stromelysin-1, and tissue inhibitor of matrix metalloproteinases 1 in patients with rheumatoid arthritis. Relationship to serum levels of antigenic keratan sulfate and systemic parameters of inflammation.

OBJECTIVE: To measure serum levels of matrix metalloproteinase-1 (MMP-1), matrix metalloproteinase-3 (MMP-3), and tissue inhibitor of MMP-1 (TIMP-1) in patients with rheumatoid arthritis (RA) and in age-matched control subjects, and to determine how these correlate with serum levels of antigenic keratan sulfate (KS) and other biochemical and clinical indicators of disease activity. METHODS: Immunoassays were used to measure levels of MMP-1, MMP-3, TIMP-1, and antigenic KS. Radiologic and functional joint scores were based upon Steinbrocker's criteria. Erythrocyte sedimentation rates (ESR) and levels of C-reactive proteins (CRP) were measured. RESULTS: In RA patients, levels of MMP-3 and TIMP-1 were significantly increased, and strongly correlated with the ESR and CRP levels but not with radiologic or functional joint scores. Levels of antigenic KS were significantly lower in RA patients and correlated negatively with systemic parameters of inflammation and serum levels of TIMP-1. CONCLUSIONS: The increase in serum levels of MMP-3 and TIMP-1 appears to reflect systemic inflammation in RA. The inverse correlation between serum levels of TIMP-1 and antigenic KS suggests that an upregulation of TIMP-1 synthesis might be responsible for the apparent suppression of cartilage aggrecan catabolism in patients with severe inflammatory changes.

Adult↗
PubMed2006

Inhibitory effect of chitooligosaccharides on matrix metalloproteinase-9 in human fibrosarcoma cells (HT1080).

Matrix metalloproteinase-9 (MMP-9) has gelatinase activity and plays an important role in cancer invasion and metastasis. Therefore, inhibition of specific types of MMPs including MMP-9 has become an attractive target for therapeutic intervention. The aim of this study was to investigate the effect of chitooligosaccharides (COS) on activity and expression of MMP-9 in HT1080 cells. The inhibitory effect of COS with different molecular masses was examined by gelatin zymography, reverse transcriptase-polymerase chain reaction (RT-PCR), gene reporter assay, and Western blot analysis. MMP-9 inhibition in the presence of COS was clearly observed in gelatin zymography. Specifically, 1- to 3-kDa COS (COS-I) exhibited the highest inhibitory effect on MMP-9 activity in HT1080 cells among tested molecular mass fractions. It was also found that COS-I was capable of inhibiting both gene and protein expression of MMP-9 (P<0.01). These results suggest that low molecular mass COS can be considered as a potent inhibitor of MMP-9.

Cell Line, Tumor↗