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PubMed2000

Matrix metalloproteinase-9 and tissue inhibitor metalloproteinase-1 levels in essential hypertension. Relationship to left ventricular mass and anti-hypertensive therapy.

To test the hypothesis that the activity of enzymes degrading the extracellular matrix in hypertensive patients are abnormal, and that the treatment of hypertension will normalise these abnormalities, we measured the serum levels of metalloproteinase MMP-9, and its inhibitor, tissue metalloproteinase inhibitor (TIMP-1). Thirty-two patients with untreated hypertension (BP 168/96) had significantly lower levels of both MMP-9 and TIMP-1 when compared to 24 matched normotensive controls (BP 123/80) (P<0.001). There was no significant correlation between MMP-9 and TIMP-1 levels (P>0.2). In the patients, there were no significant correlations observed between left ventricular mass, Doppler V(E)/V(A) ratio (an index of diastolic function), blood pressure, left ventricular mass index and either MMP-9 or TIMP-1 levels (all P=NS). Levels of MMP-9 and TIMP-1 were not significantly altered after 2 months of antihypertensive treatment of 29 patients despite mean blood pressure falling from 170/96 to 143/85 mmHg (P<0.001). Correspondingly, there were also no significant alterations in indices of diastolic function and left ventricular mass. Our study suggests that the proteolytic activities of MMP-9 and TIMP-l are depressed in hypertensive patients and were not significantly affected by short-term antihypertensive treatment. The relationship between collagen metabolism in hypertensive subjects, especially in those with cardiac hypertrophy, and the effects of treatment needs to be further explored in larger trials over a longer period of time.

Aged↗
PubMed2004

Comparison of levels of matrix metalloproteinases, tissue inhibitor of metalloproteinases, interleukins, and tissue necrosis factor in carotid endarterectomy specimens from patients on versus not on statins preoperatively.

We performed an observational study on 137 patients undergoing carotid endarterectomy (CEA). Patients on statins were less likely to have had symptoms in the 4 weeks before CEA (p = 0.0049) and were less likely to have spontaneous cerebral embolization detected by transcranial Doppler (p = 0.0459). Carotid plaques retrieved at CEA from patients taking statins revealed significantly lower concentrations of matrix metalloproteinase-1 (p = 0.0176), matrix metalloproteinase-9 (p = 0.0018), and interleukin-6 (p = 0.0005).

Aged↗
PubMed2004

Matrix metalloproteinases, tissue inhibitors of metalloproteinases, aminoterminal propeptide of procollagen type III, and hyaluronan in sera and tissue of patients with capsular contracture after augmentation with Trilucent breast implants.

In various fibrotic diseases, matrix metalloproteinases (MMPs) and their natural inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), play an important role. In our study, serum concentrations of MMP-1, MMP-2, MMP-9, TIMP-1, and TIMP-2 were determined by enzyme-linked immunosorbent assay in 17 female patients with Baker grade II (n =9), III (n =7), and IV (n =1) capsular contracture after bilateral cosmetic mamma augmentation with Trilucent implants (AEI, Inc., Caversham, United Kingdom). Samples of capsular tissue for standard histology and immunohistochemistry were obtained from all patients. Sera from 20 female patients who had plastic surgery for reduction mammaplasty were used as the control group. The aminoterminal propeptide of procollagen type III (PIIINP) and hyaluronan were analyzed as markers for fibrogenesis in both groups, too. Statistical analysis was performed using the Mann-Whitney test and Spearman rank correlation. Patients with capsular contracture presented significantly higher concentrations of TIMP-1 and TIMP-2 in their sera than did the control group (p < 0.05), which correlated with Baker grade (r = 0.7 versus r = 0.65; p < 0.05). The concentration of MMP-2 was significantly higher in the sera of patients with capsule fibrosis, whereas there were no significant differences in MMP-1, MMP-9, and PIIINP serum concentrations. Patients with capsule fibrosis had a significantly lower MMP-to-TIMP ratio (1.1 +/- 0.4, p <0.05) than the control group (1.5 +/- 0.4), which correlated with the Baker classification (r =0.7; p <0.05). The hyaluronan serum concentration of patients with capsular contracture was significantly higher (p < 0.05) and correlated with the Baker grade (r = 0.73; p < 0.05), whereas PIIINP showed no difference. In the histologic evaluation, there was a chronic inflammatory reaction in the capsules around the breast implants and refracting material within the substance. Immunohistochemically, TIMP-1 and TIMP-2 showed an intensive accumulation, and MMP-2 showed a local reaction. PIIINP could be detected, too, whereas there was no staining for MMP-1 and MMP-9. The elevated systemic MMP-2 concentration and the local positive staining in the tissue might be due to the chronic inflammatory reaction. Nevertheless, the balance between MMPs and their natural inhibitors is disturbed in patients with capsule contracture. The elevated systemic concentration of TIMPs might be a pathway in the pathogenesis of severe fibrosis after breast augmentation with alloplastic material. Hyaluronan might be a useful marker for early prediction of capsule fibrosis, whereas PIIINP is not useful as a predictor.

Adult↗
PubMed2003

Expression of matrix metalloproteinase, tissue inhibitors of metalloproteinase and adhesion molecules in silicotic mice with lung tumor metastasis.

The number of metastatic foci in silicotic mice is approximately 1.5-fold that in normal mice and in mice treated with TiO2 as inert particles. Expression of matrix metalloproteinases (MMPs) tissue inhibitors of metalloproteinases (TIMPs) and selectins was investigated in silicotic mice with lung tumor metastasis. Expression of MMP-9 and P-selectin mRNA, but not MMP-2 and E-selectin, increased significantly, showing decreases of the ratio of expression in TIMPs/MMP-9 in tumor-bearing silicotic mice compared with the tumor-bearing normal mice and mice treated with TiO2. Pretreatment with anti-P-selectin antibody inhibited number of metastatic foci significantly in silicotic mice, while pretreatment of animals with anti MMP-9 antibody showed slight decrease of metastatic foci. This evidence indicated that up-regulation of P-selectin expression contributed to enhanced rate of tumor metastasis in lung with silicosis.

Animals↗
PubMed1997

Changes in serum concentrations of matrix metalloproteinases, tissue inhibitors of metalloproteinases and type IV collagen in patients with various types of glomerulonephritis.

One of the major causes of glomerular sclerosis which precedes renal failure is an increase in glomerular extracellular matrices (ECMs). Glomerular ECMs which are composed of mesangial matrix and basement membrane play an important role in physical, mechanical and structural functions of the glomerulus. Matrix metalloproteinases (MMPs) are the enzymes which degrade both the collagenous and noncollagenous components of the ECMs. Tissue inhibitors of metalloproteinases (TIMPs) are inhibitors of MMPs. The regulations by MMPs and TIMPs are considered to contribute to maintain homeostasis in the production and degradation of ECMs in the glomeruli. In the glomeruli of patients with glomerulonephritis, the imbalance between production and degradation of ECMs is supposed to cause the increase in ECMs and glomerular sclerosis. In this study, serum concentrations of MMP-1, -2, and -3, TIMP-1 and 2 and type IV collagen were measured in patients with IgA nephropathy, lupus nephritis and membranous nephropathy. In patients with IgA nephropathy and lupus nephritis which are mesangial proliferative glomerulonephritis, the levels of MMP-3 and TIMP-2 were increased. On the other hand, the levels of type IV collagen, MMP-2 and TIMP-1 were increased in patients with membranous nephropathy in which the thickening of basement membrane is characteristic. These differences may be caused by the difference of the pathogenesis of these diseases. The present results suggest that the imbalance between the metabolism of ECMs occurs in patients with glomerulonephritis and contributes to the progression of glomerulonephritis.

Adult↗
PubMed2001

Messenger-RNA expression of matrix metalloproteinases, tissue inhibitors of metalloproteinases, and transcription factors in rheumatic synovial cells under mechanical stimuli.

In an effort to elucidate the role of mechanical stimuli in rheumatoid arthritis, we determined mRNA levels of matrix metalloproteinase (MMP)-1, MMP-3, MMP-13, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2, and three transcription factors (c-fos, ets-1, and ets-2) under two mechanical shearing conditions as well as simulated unloading. Human synovial cell cultures (MH7A and RA99-01), derived from rheumatoid arthritis patients, were grown for 1 h under mechanical stimuli and the transcript level was assayed by the reverse transcription-polymerase-chain reaction procedure. First, gentle shearing, estimated at approximately 1 dyn/cm(2), induced a consistent decrease in mRNA level of MMP-1, MMP-3, MMP-13, and ets-1 and an increase in the transcript level of TIMP-1, TIMP-2, c-fos, and ets-2. Second, intermediate shearing, estimated at approximately 6 dyn/cm(2), elevated the mRNA level of all MMPs, TIMPs, and the three transcription factors. Third, minimum mRNA level of c-fos, ets-1, and ets-2 was achieved under control conditions at rest, gentle shearing, and simulated unloading, respectively. These in vitro results support a stimulus-dependent transcriptional regulation of MMPs, TIMPs, and transcription factors in cell cultures, suggesting a potential role of shear stress in tissue degradation and prevention in rheumatic joints.

Arthritis, Rheumatoid↗
PubMed2003

Eosinophil inflammation of nasal polyp tissue: relationships with matrix metalloproteinases, tissue inhibitor of metalloproteinase-1, and transforming growth factor-beta1.

Eosinophil and mast cell infiltrations are consistent findings in nasal polyp tissue. Previous studies have shown that matrix metalloproteinases (MMPs) may be involved in eosinophil infiltration in airway mucosa of asthmatic patients, and that transforming growth factor-beta1 (TGF-beta1) induces extracellular matrix deposition in nasal polyp tissue. The aim of this study was to evaluate the role of MMPs and tissue-inhibitor of metalloproteinase-1 (TIMP-1) in association with TGF-beta1, eosinophils and mast cell activation in nasal polyp tissue. Nasal polyp tissues from 20 patients who underwent polypectomies were collected and prepared into tissue homogenate. Eosinophil cationic protein (ECP) and tryptase levels were measured by CAP system (Pharmacia, Sweden). MMP-2, MMP-9, TIMP-1 and TGF-beta1 levels were measured by enzyme-liked immunosorbent assay. MMP-2 was the predominant form of MMPs, followed by MMP-9 and TIMP-1. There were significant correlations between ECP, and MMP-9, MMP-2, TGF-beta1 and tryptase, but not with TIMP-1. Significant correlations were noted between tryptase, and MMP-2, MMP-9, and TGF-beta1, but not with TIMP-1. Close correlations were noted between TGF-beta1, and MMP-9 and MMP-2, but not with TIMP-1. MMP-2, MMP-9, and TGF-beta1 may contribute to eosinophil and mast cell migrations into nasal polyp tissue.

Adult↗
PubMed2003

Effect of adenovirus-mediated overexpression of decorin on metalloproteinases, tissue inhibitors of metalloproteinases and cytokines secretion by human gingival fibroblasts.

Decorin is a small leucine-rich proteoglycan that plays a role in control of cell proliferation, cell migration, collagen fibrillogenesis and modulation of the activity of TGF-beta. In the present study, we investigated the effects of decorin on the production of metalloproteinases (MMP-1, -2, -3, -9 and -13), tissue inhibitors of metalloproteinases (TIMP-1, -2) and cytokines (TGF-beta, IL-1beta, IL-4 and TNF-alpha). Decorin was overexpressed in cultured human gingival fibroblasts using adenovirus-mediated gene transfer. Decorin infection resulted in decreased protein levels of MMP-1 and MMP-3 whereas MMP-2 and TIMP-2 secretion was increased. MMP-9, MMP-13 and TIMP-1 were not affected by decorin infection. Cytokine measurements by ELISA showed that decorin overexpression reduced TGF-beta and IL-1beta. In contrast, IL-4 and TNF-alpha levels were markedly increased in decorin-infected cells. These results suggest that decorin could modulate the expression of certain metalloproteinases and their inhibitors, as well as the production of cytokines. Altogether, our data suggest that decorin might play a pivotal role in tissue remodeling by acting on the balance between extracellular matrix synthesis and degradation.

Adenoviridae↗
PubMed1999

Matrix metalloproteinases, tissue inhibitors of metalloproteinases, and glycosaminoglycans in synovial fluid from patients with rheumatoid arthritis.

OBJECTIVE: To investigate the correlation between synovial fluid (SF) concentrations of metalloproteinase (MMP) -2, -3, and -9, tissue inhibitors of metalloproteinases (TIMP)-1 and -2, chondroitin 4-, 6-sulfate (deltadi-C4S, deltadi-C6S), hyaluronic acid (deltadi-HA), antigenic keratan sulfate (KS), and radiologic grade in patients with rheumatoid arthritis (RA) and to assess the clinical value of these factors as disease markers. METHODS: Enzyme linked immunoassays and high performance liquid chromatography were used. SF samples were collected from 52 patients with RA. Radiographic (Larsen grade) and clinical evaluations were also done. RESULTS: There was no significant correlation between the concentrations of MMP, TIMP, and deltadi-C4S, deltadi-C6S, deltadi-HA, and antigenic KS. No significant correlations were found between the radiologic grade and the concentrations of MMP or TIMP in SF. There was a significant increase in the concentration of antigenic KS and deltadi-C6S/deltadi-C4S ratio in SF from patients with Larsen grade 2 compared to grade 5. A significant correlation between deltadi-C6S and antigenic KS concentrations in SF was observed. CONCLUSION: Although there were large variances between the samples in this study, proteoglycan metabolism in the cartilage matrix of the patients with RA might have been increased in the early phases of tissue destruction and decreased in advanced stages because of scanty cartilage tissue. The concentrations of MMP-2, -3, -9 and TIMP-1, -2 in SF did not seem to be influenced by the amount of residual cartilage.

Aged↗
PubMed1997

Expression of matrix metalloproteinases, tissue inhibitors of metalloproteinases, and extracellular matrix mRNA following exposure to mineral fibers and cigarette smoke in vivo.

To determine the effect of mineral fibers and cigarette smoke on remodeling of lung tissues, we examined matrix metalloproteinase-1 (MMP-1), MMP-2, tissue inhibitors of metalloproteinase-1 (TIMP-1), TIMP-2, and types I and IV collagen mRNA levels from rat lungs exposed to mineral fibers and/or cigarette smoke in vivo. Male Wistar rats (10 weeks of age) were given a single intratracheal instillation of 2 mg of chrysotile or alumina silicate ceramic fibers (RCF). Animals were then exposed to cigarette smoke (side stream) 5 days per week for 4 weeks. Transcriptional levels of mRNA extracted from the lungs were assessed by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). Exposure to cigarette smoke induced increases in MMP-1 and TIMP-1 mRNA levels and decreased TIMP-2 and type I collagen mRNA levels in lung. Chrysotile or RCF stimulated the expression of MMP-1 mRNA in the lung. The mineral fibers and cigarette smoke had more than additive effects on the expression of MMP-2 and TIMP-1 in the lung. These data suggest that the imbalance of the expression of MMPs, TIMPs, and extracellular matrix may be associated with the remodeling of lung tissues induced by mineral fibers and/or cigarette smoke.

Administration, Inhalation↗
PubMed1990

Synovial fluids from infected joints contain metalloproteinase--tissue inhibitor of metalloproteinase (TIMP) complexes.

Samples of synovial fluids aspirated from patients with septic arthritis prior to the commencement of any treatment contained active metalloproteinases but no proteinase inhibitory activity. We therefore assayed these samples for proteinase-inhibitor complexes. Although no biologically active alpha 2-macroglobulin or tissue inhibitor of metalloproteinase (TIMP) was present in the fluids, immunoassay of the samples clearly showed that high molecular weight proteinase-TIMP complexes were present. It is proposed that high levels of active metalloproteinases are released from neutrophils into septic synovial fluids and that these proteinases complex all the available TIMP, forming metalloproteinase-TIMP complexes.

Arthritis, Infectious↗
PubMed2006

High glucose and homocysteine synergistically affect the metalloproteinases-tissue inhibitors of metalloproteinases pattern, but not TGFB expression, in human fibroblasts.

AIMS/HYPOTHESIS: Atherosclerosis is particularly aggressive in patients with diabetes. Hyperhomocysteinaemia causes oxidative stress and cytokine secretion: its atherogenic effect is mediated by an enhanced inflammatory response. Matrix metalloproteinases (MMPs) regulate extracellular matrix degradation and remodelling, and contribute to the vulnerability of the atherosclerotic lesion. Fibroblasts contribute to collagen biosynthesis and participate in plaque remodelling via expression and release of MMP2 and MMP9. To explore the role of hyperhomocysteinaemia in cellular pathways involved in plaque growth and stability in diabetic patients, we studied the effect of hyperhomocysteinaemia in human fibroblasts grown in the presence of normal or high glucose concentrations. MATERIALS AND METHODS: In fibroblasts of five normal subjects, grown at 5.5 or 22 mmol/l glucose and treated with homocysteine, we determined: (1) MMP2, MMP9 and tissue inhibitor of metalloproteinases (TIMP)-1 (an MMP inhibitor) production by western blot analysis; (2) their activity by zymography; (3) TGFB1 expression by real-time PCR; and (4) TGFB, fibronectin and IL6 release by ELISA. RESULTS: Hyperhomocysteinaemia increased the production and enzymatic activity of MMP2 and MMP9, the effect being more pronounced in high glucose. Conversely, TIMP1 production was reduced by hyperhomocysteinaemia in both conditions, especially in high glucose. Hyperhomocysteinaemia also stimulated IL6 release, at least in part through nuclear factor-kappaB activation. TGFB1 expression was not affected by hyperhomocysteinaemia either in normal or in high glucose. CONCLUSIONS/INTERPRETATION: Homocysteine upregulates the MMP-TIMP pathway and IL6 release, the effect being stronger in the presence of high glucose. These actions of homocysteine may contribute to the increased atherogenesis observed in diabetic patients with poor metabolic control.

Drug Synergism↗
PubMed2003

[Expression of matrix metalloproteinase-3 and tissue inhibitor metalloproteinases-1 in regenerated rabbit bone after mandibular osteodistraction].

OBJECTIVE: To observe the expression patterns of matrix metalloproteinase-3 and its inhibitor, tissue inhibitor metalloproteinases (TIMP)-1, in remodeling phase of mandibular distraction osteogenesis. METHODS: Bilateral mandibular osteotomies were performed in 8 mature rabbits. The mandibles were lengthened 6 mm using a custom-made distractor with a rate of 1 mm/d. All animals were killed in 4 weeks after completion of distraction. The distracted calluses were harvested and processed for histology and immunohistochemistry of MMP-3 and TIMP-1. RESULTS: Elevated expression of both MMP-3 and TIMP-1 was found in the distracted calluses resulting from mandibular lengthening. Positive staining for MMP-3 was seen in the osteoblasts and osteocytes, and TIMP-1 was mainly localized in osteoblasts. CONCLUSION: MMP-3 and TIMP-1 appear to play important roles in the remodeling of new bone created by mandibular distraction osteogenesis.

Animals↗
PubMed2002

Expression of matrix metalloproteinases, tissue inhibitors of metalloproteinase, collagens, and Ki67 antigen in pleural malignant mesothelioma: an immunohistochemical and electron microscopic study.

Because matrix metalloproteinases (MMPs) degrade extracellular matrix, including basement membrane, and because tissue inhibitors of MMP (TIMPs) suppress MMP activities, MMPs and TIMPs are considered to play important roles in invasion and metastasis in many malignancies. We examined immunohistochemically the expression of MMPs (MMP-1, -2, -3, -7, and -9), TIMPs (TIMP-1 and -2), and collagens (types I, III, and IV) in 16 patients with pleural malignant mesothelioma (PMM; 8 with the epithelial, 4 with the sarcomatous, and 4 with the biphasic type). Electron microscopy revealed that the tumor cells in all types possessed the characteristics of malignant mesotheliomas, including numerous microvilli and moderate amounts of intermediate filaments. Basement lamina was present only focally. The proliferative Ki67 index was at a high level, compared with values reported in various other malignancies. Positive staining for MMP-1 was observed in most tumor cells in all 16 patients (100%). MMP-2 was expressed in most tumor cells in 2 patients (13%). In contrast, MMP-3, -7, and -9 were not detected in any PMM. TIMP-1 and TIMP-2 were expressed in 3 patients (19%) and 2 patients (13%), respectively. The stromal cells were simultaneously positive for MMPs or TIMPs in the patients whose tumor parenchymal cells were positive for each enzyme. These results indicate that the expression of MMP-1 and MMP-2 may be related to PMM invasion and spread. In particular, as MMP-1 was overexpressed in contrast to the lower expression of TIMP-1, MMP-1 is strongly suggested to play an important role in PMM invasion by degrading the tumor stroma. In spite of general agreement that epithelial-type PMM has a better prognosis than other types, there was no significant difference in the Ki67 index among the histological types of PMM.

Aged↗
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↗
PubMed2005

Longitudinal analysis of metalloproteinases, tissue inhibitors of metalloproteinases and clinical parameters in gingival crevicular fluid from periodontitis-affected patients.

BACKGROUND: The aim of this work was to improve the assessment of the periodontal disease status through measurements of extracellular matrix metalloproteinases (MMPs) and their tissular inhibitors (TIMPs) in the gingival crevicular fluid from patients diagnosed with chronic periodontitis. METHODS: Gingival crevicular fluid samples from patients (n = 13) were taken from 60 sites initially, and from 51 and 41 sites, respectively, 3 and 6 months after scaling and root planing. Gingival crevicular fluid samples were also taken from healthy subjects (n = 11, 24 sites). The presence of MMP-9 and MMP-8 was assessed by zymography and immunowestern blotting, respectively. The actual MMP activity (gelatinase and collagenase) was measured using the fluorogenic substrate assay. TIMP-1 and -2 levels were measured by immunodot blot. RESULTS: The fluorogenic substrate assay determinations showed higher MMP activity in sites with probing depth > or = 4 mm, with significant reduction post-treatment. Gelatinase activity followed by zymography consisted mainly of MMP-9. A different pattern of MMP-8 in control and patient sites was found. Controls only showed species of a partially active form (69 kDa), whereas patient sites showed a high frequency of the active form (56 kDa), and in some cases the latent form (85 kDa) was also observed. The active form reduced its frequency in sites with probing depth > or = 4 mm. TIMP-1 and -2 levels in patients were significantly lower than in controls, and after treatment the recovery of TIMP-1 level similar to control was observed. CONCLUSION: Significant correlations between the severity of the periodontal disease and the actual MMP activity, the active form of MMP-8 and the low level of both TIMP-1 and TIMP-2 were found.

Adult↗
PubMed2005

Expression of matrix metalloproteinases and tissue inhibitor metalloproteinases increases in X-irradiated rat ileum despite the disappearance of CD8a T cells.

AIM: To investigate their expression and activity in the rat ileum after exposure to ionizing radiation along with that of the cellular effectors and molecular mediators involved in the regulation of MMPs. METHODS: Rats were exposed to a single 10-Gy dose of X-rays delivered to the abdomen. A combination of methods, such as zymography, immunohistochemistry and real time reverse transcriptase-polymerase chain reaction, were used to localize and quantify MMPs and the molecules involved in MMP activating and inhibitory pathways (plasmin/plasminogen, TIMPs), CD8+, as well as inflammatory (interleukin (IL)-1beta, IL-8, tumor necrosis factor-alpha, TNF-alpha) and fibrogenic mediators (transforming growth factor-beta1-3) within ileal tissue at 1, 3, and 7 d after irradiation. RESULTS: A marked increase in MMP-2 and -14 mRNA and protein levels associated with an increased activity of MMP-2 was observed in irradiated ileal tissue. MMP-2 and -14 expression was mainly observed in inflammatory, epithelial, and mesenchymal cells, whereas a slight increase in MMP-3 expression was detected in the few infiltrating macrophages at d 1 after irradiation. Conversely, MMP-1, -7, and -9 mRNA levels were not found to be affected by abdominal irradiation. Irradiation was found to induce disappearance of CD8+ cells. Furthermore, we have observed that TNF-alpha and IL-1beta protein levels increased 6 h after irradiation, whereas those of IL-8 only increased after 3 d and was concomitant with neutrophil infiltration. In addition, the expressions of molecules involved in MMP activating and inhibitory pathways (urokinase-type plasminogen activator and tissue-type plasminogen activator; TIMP-1, TIMP-2, and plasminogen activator-inhibitor-1) were found to be increased after abdominal irradiation. CONCLUSION: This study showed that abdominal irradiation induces an acute remodeling of the ileum associated with an increased expression of MMPs and TIMPs that do not involve CD8+ T cells but involve mesenchymal and epithelial cells, although to a lesser extent, and probably even soluble inflammatory and fibrogenic mediators.

Animals↗
PubMed2003

[The effect of estrogen and progestin on the expression of matrix metalloproteinases, tissue inhibitor of metalloproteinase and interleukin-1beta mRNA in synovia of OA rabbit model].

OBJECTIVE: To observe the effect of different dose of estrogen or estrogen plus progestin on the mRNA expression of MMP-1, MMP-3, TIMP-1 and IL-1beta in synovia of female New Zealand White rabbit OA model. METHODS: Sixty-five female New Zealand White rabbits (3 kg +/-, 6 months old) were used in this study. Right knees of all the rabbits were immobilized for 5 weeks to get OA model. Then 5 rabbits were killed by overdose of anesthesia to guarantee the model. Sixty OA rabbits were randomly divided into 6 groups (A, B, C, D, E, F) with 10 each. Group A approximately E were ovariectomized and group F were sham ovariectomized. The rabbits were feed by estradiol valerate (E(2)V) everyday as follows. Group A: E(2)V 1.8 mg/d, group B: E(2)V 3.6 mg/d, group C: E(2)V 7.2 mg/d, group D: E(2)V 3.6 mg/d + MPA 3.6 mg/d, group E was the untreated control group, group F was the untreated sham control group. Five rabbits of each group were killed respectively in 8 and 16 weeks and synovia of the right knee were obtained on all knees. Reverse transcription- polymerase chain reaction were used to detect the mRNA expression of MMP-1, MMP-3, TIMP-1 and IL-1beta in the OA synovia to determine the effect of estrogen and progestin. RESULTS: RT-PCR shows an increase expression of mRNA of MMP-1, MMP-3 and IL-1beta in OA synovia tissue in ovariectomized rabbits. Estrogen supplement could decrease the expression, an enhancement effect could be observed with progestin. Low dose estrogen could decrease the ratio of MMP-1/TIMP-1 and MMP-3/TIMP-1, which could even be decreased by progestin. High dose estrogen could slightly increase the ratio, but still lower than the untreatment control group. CONCLUSION: Our study suggests that certain dose estrogen and perhaps appropriate estrogen and progestin ratio are much important to the normal effect of articular cartilage. Estrogen deficiency or much high estrogen level could both show a damage effect on articular cartilage.

Animals↗