Differential Expression Of Matrix Metalloproteinases Research Articles

Differential expression of matrix metalloproteinases in the fallopian tube of women with Chlamydia trachomatis-associated tubal ectopic pregnancy

Chlamydia trachomatis is an established risk factor for ectopic pregnancy (EP) in fallopian tube (FT). Matrix metalloproteinases (MMPs) have potential role in disease pathogenesis, however, dysregulation of extracellular matrix by MMPs/TIMPs (tissue inhibitors of MMPs) in infection-associated EP remains unknown. The aim was to study the expression of MMP-2, -9, -14/TIMP-1, -2, -3 in C. trachomatis-positive tubal EP patients. The study comprised of 100 tubal EP (Group I) and 100 tubal ligation patients (Group II; controls) enrolled from Department of Obstetrics and Gynaecology, VMMC and Safdarjung hospital, New Delhi (India) for collection of FT. Detection of C. trachomatis MOMP was done by PCR while quantitative expression of MMPs/TIMPs was studied by real-time PCR. Data was statistically evaluated by Graphpad prism. Overall, C. trachomatis was found in 18/100 tubal EP patients. After ruling out Neisseria gonnorhoeae and Mycoplasma genitalium, Group I was divided into Group Ia (C. trachomatis DNA-positive) and Group Ib (C. trachomatis DNA-negative; internal controls). Significant upregulation of MMP-2, -9, -14 and downregulated TIMP-1, -2, -3 were found in Group Ia versus controls (Groups Ib/II) (p < 0.05). Fold-change in MMP was significantly higher in Group Ia versus controls (‘p’ < 0.05). Maximum 5.5-fold upregulation was found in MMP-2. It is apparent by molecular analysis that differential expression of MMPs/TIMPs, particularly enhanced MMP-2 leads to tubal EP in C. trachomatis DNA-positive women.

Identification of potential diagnostic biomarkers in MMPs for pancreatic carcinoma.

Pancreatic cancer (PC) is a malignant tumor which ranks fourth in cancer-related death. However, the specificity and sensitivity of traditional biomarkers such as carbohydrate antigen 19-9 no longer meet the clinical requirements.Tools as ONCOMINE and Gene Expression Profiling Interactive Analysis (GEPIA) were used to analyze the differential expression of matrix metalloproteinases (MMPs) in PC and adjacent tissues. For further analysis, we adopted database for annotation, visualization and integrated discovery (DAVID 6.8), transcriptional regulatory relationships unraveled by sentence-based text (TRRUST) and other tools. We also identified drugs targeted the selected MMPs.Eight MMPs (MMP1, MMP2, MMP7, MMP9, MMP11, MMP12, MMP14, and MMP28) were differentially expressed in PC and adjacent tissue. MMP1 (P = .0189), MMP7 (P = .000216), MMP11 (P = .0209), MMP14 (P = .00611) were correlated with the pathological stages of PC. Patients with higher expression of MMP1 (P = .0011), MMP2 (P = .011), MMP7 (P = .0081), MMP9 (P = .046), MMP11 (P = .0019), MMP12 (P = .0011), MMP14 (P = .0011), and MMP28 (P = 6.3e-06) showed poor prognosis. Ten transcription factors were associated with the up-regulation of selected MMPs. Marimastat (DB00786) was found to target selected MMPs.Our research revealed that selected MMPs played an important role in the early diagnosis and prognosis of PC.

Differential expression of matrix metalloproteinases and miRNAs in the metastasis of oral squamous cell carcinoma

BackgroundOur study aimed to reveal the regulatory mechanisms of miRNAs and matrix metalloproteinases (MMPs) in oral squamous cell carcinoma (OSCC).MethodsThe mRNA and miRNA expression profiles of six metastatic tumour samples, six nonmetastatic tumour samples, and six normal tissue samples were used for microarray analysis. Moreover, the important genes and miRNAs were validated by published profiles in Oncomine and by qRT-PCR.ResultsMMP7, MMP13, and MMP10 were upregulated, and MMP12 and MMP9 were downregulated in metastatic tumours compared with nonmetastatic tumours. MMP7 was regulated by miR-4697-5p and miR-7109-5p. MMP7 and MMP13 were upregulated in OSCC samples compared with normal samples in Oncomine. Moreover, qRT-PCR revealed that the expression of miR-7109-5p and miR-34b was decreased in metastatic tumours compared with nonmetastatic tumours.ConclusionsOur study suggested that miR-7109-5p and miR-34b might play important roles in the metastasis of OSCC by regulating MMP7 and MMP13 expression, respectively.

An integrated bioinformatics analysis of potential therapeutic targets among matrix metalloproteinases in breast cancer.

Breast cancer (BC) is one of the most aggressive malignancies worldwide among females. Matrix metalloproteinases (MMPs), as the most abundant class of non-serine proteases present in invasive and metastatic tumors, can regulate a variety of alterations in the microenvironment during tumor progression. However, the differential expression of MMPs and its prognostic values in BC is yet to be elucidated. In this research, using the ONCOMINE dataset, The Cancer Genome Atlas, Breast Cancer Gene-Expression Miner v4.1 (Bc-GenExMiner), Kaplan-Meier Plotter and cBioPortal, the transcriptional MMPs and survival outcome data of patients with BC was compared. It was indicated that mRNA levels of MMP1/3/9/10/11/12/13 were increased compared with non-tumor tissues, whereas mRNA expression of MMP2/16/19/23B/28 was lower in BC tissues. Kaplan-Meier plots showed that high mRNA levels of MMP2/10/16/19/20/23B/27 in patients with BC were associated with better recurrence-free survival. In contrast, high MMP1/8/9/11/12 conferred worse RFS rate. Meanwhile, high transcription levels of MMP1/3/11/12/13 predicted shorter distant metastasis-free survival, while high levels of MMP1/12 demonstrated worse overall survival in patients with BC. From Bc-GenExMiner, it was indicated that high expression of MMP16/20 was correlated with better prognosis, while MMP1/9/11/12/13/14/15 exerted a negative effect on patient prognosis. The integrative bioinformatics analysis performed in the present study suggests that MMP1/9/12/16, compared with other MMPs, are potentially appropriate targets for targeted therapy in patients with BC.

Differential Expression of Matrix Metalloproteinases 2, 9 and Cytokines by Neutrophils and Monocytes in the Clinical Forms of Chagas Disease.

Dilated cardiomyopathy, the most severe manifestation in chronic phase of Chagas disease, affects about 30% of patients and is characterized by myocardial dysfunction and interstitial fibrosis due to extracellular matrix (ECM) remodeling. ECM remodeling is regulated by proteolytic enzymes such as matrix metalloproteinases (MMPs) and cytokines produced by immune cells, including phagocytes. We evaluated by flow cytometry the expression of MMP-2, MMP-9, IL-1β, TNF-α, TGF-β and IL-10 by neutrophils and monocytes from patients with indeterminate (IND) and cardiac (CARD) clinical forms of Chagas disease and non-infected individuals (NI), before and after in vitro stimulation with Trypanosoma cruzi antigens. Our results showed an important contribution of neutrophils for MMPs production, while monocytes seemed to be involved in cytokine production. The results showed that neutrophils and monocytes from IND and CARD patients had higher intracellular levels of MMP-2 and MMP-9 than NI individuals. On the other hand, T. cruzi derived-antigens promote a differential expression of MMP-2 and MMP-9 in patients with Chagas disease and may regulate MMPs expression in neutrophils and monocytes, mainly when a cardiac alteration is not present. Our data also showed that in the presence of T. cruzi derived-antigens the production of cytokines by neutrophils and monocytes, but mainly by monocytes, may be intensified. Correlation analysis demonstrated that MMP-2 had a positive correlation with IL-10 and a negative correlation with IL-1β, whereas MMP-9 showed a negative correlation with IL-10. We also observed that IND patients presented a greater percentage of high producer cells of regulatory molecules when compared to CARD patients, indicating a different pattern in the immune response. Our data suggest that MMPs and cytokines produced by neutrophils and monocytes are important contributors for cardiac remodeling and may be an interesting target for new biomarker research.

MicroRNAs Associated with Shoulder Tendon Matrisome Disorganization in Glenohumeral Arthritis.

The extracellular matrix (ECM) provides core support which is essential for the cell and tissue architectural development. The role of ECM in many pathological conditions has been well established and ECM-related abnormalities leading to serious consequences have been identified. Though much has been explored in regards to the role of ECM in soft tissue associated pathologies, very little is known about its role in inflammatory disorders in tendon. In this study, we performed microRNA (miRNA) expression analysis in the long head of the human shoulder biceps tendon to identify key genes whose expression was altered during inflammation in patients with glenohumeral arthritis. We identified differential regulation of matrix metalloproteinases (MMPs) that could be critical in collagen type replacement during tendinopathy. The miRNA profiling showed consistent results between the groups and revealed significant changes in the expression of seven different miRNAs in the inflamed tendons. Interestingly, all of these seven miRNAs were previously reported to have either a direct or indirect role in regulating the ECM organization in other pathological disorders. In addition, these miRNAs were also found to alter the expression levels of MMPs, which are the key matrix degrading enzymes associated with ECM-related abnormalities and pathologies. To our knowledge, this is the first report which identifies specific miRNAs associated with inflammation and the matrix reorganization in the tendons. Furthermore, the findings also support the potential role of these miRNAs in altering the collagen type ratio in the tendons during inflammation which is accompanied with differential expression of MMPs.

Imbalance between matrix metalloproteinases and their tissue inhibitors in preeclampsia and gestational trophoblastic diseases.

The invasion cascade exhibited by placental trophoblasts and cancerous cells bears many similarities, and it is attributed to extracellular matrix degradation mediated by matrix metalloproteinases (MMPs). Although proper and controlled invasion by trophoblasts into the maternal uterus is an essential requirement for maintenance of normal pregnancy, any abnormality in this phenomenon results in the development of invasion-related disorders such as gestational trophoblastic diseases (GTDs) and preeclampsia. We studied the epigenetic basis of differential expression of two placental MMPs (MMP2 and MMP9) and tissue inhibitors of metalloproteinases (TIMP2 and TIMP1) during normal gestation and invasion-related disorders, i.e., preeclampsia and GTDs. Our study suggests the association of H3K9/27me3 with differential expression of these MMPs and their inhibitors, which regulate the placental invasion during normal pregnancy, whereas no role of CpG methylation was observed in the differential expression of MMPs/TIMPs. Further, development of GTDs was associated with abnormally higher expression of these MMPs and lower levels of their inhibitors, whereas the reverse trends were observed for MMPs and their TIMPs in case of preeclampsia, in association with abnormal changes in H3K9/27me3. These results suggest the involvement of higher levels of MMPs in an aggressive invasive behavior depicted by GTDs, whereas lower levels of these MMPs in shallow and poor invasive phenotype associated with preeclampsia. Thus, our study shows the significance of a proper balance regulated by histone trimethylation between differential expression of MMPs and their TIMPs for maintaining normal pregnancy and its deregulation as a contributing factor for pathogenesis of invasive disorders during pregnancy.

Bimatoprost, latanoprost, and tafluprost induce differential expression of matrix metalloproteinases and tissue inhibitor of metalloproteinases.

BackgroundDifferences in the increase in matrix metalloproteinase (MMP) and decrease in tissue inhibitor of metalloproteinase (TIMP) activity may contribute to the different characteristics observed clinically on decreased intraocular pressure in patients with glaucoma or ocular hypertension. The purpose of this study was to investigate differences in the expression profiles of MMPs and TIMPs induced by the prostaglandin analogs bimatoprost, latanoprost, and tafluprost in human non-pigmented ciliary epithelial cells (HNPCECs).MethodsHNPCECs were cultured for 24 h with 0, 10, 100, or 1000 μM of the free acid forms of bimatoprost, latanoprost, and tafluprost. We measured the expression levels of MMPs and TIMPs using real-time polymerase chain reaction, and compared the results. Enzyme activities of MMP-2 and −9 in conditioned media were measured by gelatin zymography.ResultsAll prostaglandin analogs we examined dose-dependently increased expression levels of MMP-1, −2, −3, −9, and −17, whereas expression levels of TIMP-1 and −2 decreased with increasing concentrations of each analog. Each prostaglandin analog induced different levels of increases in MMPs and decreases in TIMPs.ConclusionsUnique expression profiles of MMPs and TIMPs induced by bimatoprost, latanoprost, and tafluprost, as shown in HNPCECs, may contribute to clinically different effects on intraocular pressure decreases in patients with glaucoma or ocular hypertension.

Acute exacerbations of COPD are associated with significant activation of matrix metalloproteinase 9 irrespectively of airway obstruction, emphysema and infection.

BackgroundAcute exacerbations of chronic obstructive pulmonary disease (AE-COPD) are associated with accelerated aggravation of clinical symptoms and deterioration of pulmonary function. The mechanisms by which exacerbations may contribute to airway remodeling and declined lung function are poorly understood. In this study, we investigated if AE-COPD are associated with differential expression of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in bronchoalveolar lavage (BAL).MethodsCOPD patients undergoing diagnostic bronchoscopy, with either stable disease (n = 53) or AE-COPD (n = 44), matched for their demographics and lung function parameters were included in this study. Protein levels of MMP-2,–9,–12 and of TIMP-1 and -2 in BAL were measured by ELISA. Enzymatic activity of MMP-2 and -9 was assessed by gelatin zymography.ResultsWe observed that MMP-9, TIMP-1 and TIMP-2 were significantly increased in BAL during AE-COPD. Furthermore, there was a significant negative correlation of MMP-9, TIMP-1 and TIMP-2 with FEV1% predicted and a significant positive correlation of TIMP-1 and TIMP-2 with RV% predicted in AE-COPD. None of MMPs and TIMPs correlated with DLCO% predicted, indicating that they are associated with airway remodeling leading to obstruction rather than emphysema. In AE-COPD the gelatinolytic activity of MMP-2 was increased and furthermore, MMP-9 activation was significantly up-regulated irrespective of lung function, bacterial or viral infections and smoking.ConclusionsThe results of this study indicate that during AE-COPD increased expression of TIMP-1, TIMP-2, and MMP-9 and activation of MMP-9 may be persistent aggravating factors associated with airway remodeling and obstruction, suggesting a pathway connecting frequent exacerbations to lung function decline.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-015-0240-4) contains supplementary material, which is available to authorized users.

Circulating matrix metalloproteinase patterns in association with aortic dilatation in bicuspid aortic valve patients with isolated severe aortic stenosis.

Bicuspid aortic valve (BAV) exhibits a clinical incline toward aortopathy, in which aberrant tensile and shear stress generated by BAV can induce differential expression of matrix metalloproteinases (MMPs) and their endogenous tissue inhibitors (TIMPs). Whether stenotic BAV, which exhibits additional eccentric high-velocity flow jet upon ascending aorta and further worsens circumferential systolic wall shear stress than BAV with echocardiographically normal aortic valve, can lead to unique plasma MMP/TIMP patterns is still unknown. According to their valvulopathy and aortic dilatation status, 93 BAV patients were included in the present study. Group A (n = 37) and B (n = 28) comprised severely stenotic patients with or without ascending aorta dilatation; Group C (n = 12) and D (n = 16) comprised echocardiographically normal BAV patients with or without ascending aorta dilatation. Plasma MMP/TIMP levels (MMP-1, -2, -3, -8, -9, -10, -13 and TIMP-1, -2, -4) were determined via a multiplex ELISA detection system in a single procedure. Among patients with isolated severe aortic stenosis, plasma levels of MMP-2 and -9 were significantly elevated when ascending aortic dilatation was present (p = 0.001 and p = 0.002, respectively). MMP-2, however, remained as the single elevated plasma component among echocardiographically normal BAV patients with dilated ascending aorta (p = 0.027). Multivariate analysis revealed that MMP-2 and MMP-9 could both serve as independent risk factor for aortic dilatation in the case of isolated severe stenosis (p = 0.003 and p = 0.001, respectively), and MMP-2 in echocardiographically normal patients (p = 0.002). In conclusion, BAV patients with isolated severe aortic stenosis demonstrated a distinct plasma MMP/TIMP pattern, which might be utilized as circulating biomarkers for early detection of aortic dilatation.

CCR9/CCL25 expression in non-small cell lung cancer correlates with aggressive disease and mediates key steps of metastasis.

Poor clinical outcome of lung cancer (LuCa) is primarily due to lack of knowledge about specific molecules involved in its progression and metastasis. In this study, we for the first time show the clinical and biological significance of CC chemokine receptor-9 (CCR9) in non-small cell lung cancer (NSCLC). Expression of CCR9 and CCL25, the only natural ligand of CCR9, was significantly higher (p<0.0001) in NSCLC tissues and serum respectively, compared to their respective controls. Interestingly, expression of both CCR9 and CCL25 was significantly higher in adenocarcinomas (ACs) compared to squamous cell carcinomas (SCCs) (p = 0.04, and p< 0.0001). Similar to tissues, AC and SCC cell lines were positive for CCR9 expression. Despite of marginal difference in CCR9 expression, AC cells showed higher migratory and invasive potential in response to CCL25, compared to SCC cells. This differential biological response of AC cells was primarily due to differential expression of matrix metalloproteinases and tissue inhibitor of metalloproteinases under the influence of CCL25. Our results suggest CCR9 as a potential target for developing new treatment modality for NSCLC. Additionally, differential serum CCL25 level in ACs and SCCs, two NSCLC subtypes, suggest its potential as a non-invasive diagnostic/prognostic biomarker.

Pressure therapy upregulates matrix metalloproteinase expression and downregulates collagen expression in hypertrophic scar tissue

Background Pressure therapy improves hypertrophic scar healing, but the mechanisms for this process are not well understood. We sought to investigate the differential expression of matrix metalloproteinases (Mmps) and collagen in post-traumatic hypertrophic scar tissue with mechanical pressure and delineate the molecular mechanisms of pressure therapy for hypertrophic scars. Methods Fibroblast lines of normal skin and scar tissue were established and a mechanical pressure system was devised to simulate pressure therapy. Reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting assays were used to compare differences in the mRNA and protein expression of Mmps and collagen in scar fibroblasts before and after pressure therapy. Results The expression differed between the hypertrophic scar cell line and the normal cell line. RT-PCR assays showed that Collagen I, highly expressed in the hypertrophic scar cell line, decreased significantly after pressure therapy. Mmp2, Mmp9, and Mmp12 expression in the hypertrophic scar tissue increased significantly after pressure therapy (P &lt;0.05). Western blotting assays further revealed that Mmp9 and Mmp12 expression increased significantly in the hypertrophic scar tissue after pressure therapy (P &lt;0.05) but not Mmp2 expression (P &gt;0.05). Conclusion Mechanical pressure induces degradation of Collagen I in hypertrophic scar tissue by affecting the expression of Mmp9 and Mmp12.

Implications of time‐series gene expression profiles of replicative senescence

Although senescence has long been implicated in aging-associated pathologies, it is not clearly understood how senescent cells are linked to these diseases. To address this knowledge gap, we profiled cellular senescence phenotypes and mRNA expression patterns during replicative senescence in human diploid fibroblasts. We identified a sequential order of gain-of-senescence phenotypes: low levels of reactive oxygen species, cell mass/size increases with delayed cell growth, high levels of reactive oxygen species with increases in senescence-associated β-galactosidase activity (SA-β-gal), and high levels of SA-β-gal activity. Gene expression profiling revealed four distinct modules in which genes were prominently expressed at certain stages of senescence, allowing us to divide the process into four stages: early, middle, advanced, and very advanced. Interestingly, the gene expression modules governing each stage supported the development of the associated senescence phenotypes. Senescence-associated secretory phenotype-related genes also displayed a stage-specific expression pattern with three unique features during senescence: differential expression of interleukin isoforms, differential expression of interleukins and their receptors, and differential expression of matrix metalloproteinases and their inhibitory proteins. We validated these phenomena at the protein level using human diploid fibroblasts and aging Sprague-Dawley rat skin tissues. Finally, disease-association analysis of the modular genes also revealed stage-specific patterns. Taken together, our results reflect a detailed process of cellular senescence and provide diverse genome-wide information of cellular backgrounds for senescence.

Differential Expression of Matrix Metalloproteinases (MMPs) in Lung Cancer Metastasis

Metastasis accounts for most cancer related deaths. The common metastasis models utilize intravenous injection of tumor cells, bypassing the egression of malignant cells. We developed a unique metastasis model by in vivo passaging the Lewis lung carcinoma (3LL) cells and maintaining them in vivo with 7–11 days of intermittent culture. When injected subcutaneously, parental 3LL cells have minimal metastasis, while in vivo passaged 3LL cells (p‐ 3LL) show robust metastasis. To determine the differences between metastatic p‐3LL versus non‐metastatic 3LL, we compared the gene expression profiles by microarray analysis of RNA from these cells as well as the primary tumors from each. The array analysis revealed alteration in the expression of numerous genes previously known to be associated with tumor metastasis. The data also revealed several novel markers associated with increased metastasis including enhanced expression of two matrix metalloproteinases (MMPs), MMP‐9 and MMP‐12, and the decreased expression of MMP‐2. Given the role of MMPs in the remodeling of the extracellular matrix and cell motility, we further investigated the altered RNA and protein expression of MMPs in p‐3LLs and their tumors by real time PCR and Western blot analysis. Together, these suggest that these three MMPs may play an important role in lung cancer metastasis.

Expression of matrix metalloproteinases and their inhibitors at the feto-maternal interface in unruptured ectopic tubal pregnancy

To investigate expression of matrix metalloproteinases (MMPs) and the tissue inhibitors of MMPs (TIMPs) at the feto-maternal interface and non-implantation sites in unruptured tubal pregnancies. Prospective study. Setting. University teaching hospital. Eighteen patients with unruptured tubal pregnancy undergoing salpingectomy. Immunohistochemistry was used to detect MMP-2, -9 and -14, and TIMP-1, -2 and -3 at the feto-maternal interface and non-implantation regions of the Fallopian tube. Serum levels of human chorionic gonadotropin (β-hCG) were determined, and trophoblastic invasion was histologiclly classified as stage I when limited to the tubal mucosa and stage II when extending to the muscular layer. The relation between serum β-hCG concentration with the depth of trophoblastic invasion into the tubal wall and differential expression of MMPs and TIMPs. A significant difference in the β-hCG concentrations was seen between stage I and II invasion. Immunoreactivity for MMP-2, -9 and -14, and TIMP-1, -2 and -3 was primarily localized to cytotrophoblasts. At the implantation sites, the intensity of MMPs increased along the invasive pathway towards the maternal interstitium. The expression of MMP-2, MMP-14 and TIMP-3 was localized to the epithelium and smooth muscle cells of the Fallopian tube, while expression of MMP-9, TIMP-1 and TIMP-2 was weak or absent. Human chorionic gonadotropin correlated positively with invasion stage of trophoblasts. At ectopic implantation sites, the expression of MMPs gradually increased with increasing invasion depth of trophoblasts. TIMP-1 and TIMP-2 were only weakly expressed. The imbalance between expression of MMPs and TIMPs at the ectopic implantation sites may lead to the extensive destructive degradation of the extracellular matrix.

Variations on brain microglial gene expression of MMPs, RECK, and TIMPs in inflammatory and non-inflammatory diseases in dogs

Matrix metalloproteinases (MMPs), MMP inhibitors (TIMPs, tissue inhibitors of matrix metalloproteinases), and the membrane-anchored glycoprotein RECK (reversion-inducing cysteine-rich protein with Kazal motifs) contribute to the pathogenesis of many CNS diseases. To assess the potential pathogenetic roles of microglial MMP, TIMP, and RECK generation in extracellular matrix breakdown, opening of the blood brain barrier (BBB) and subsequent recruitment of leukocytes in the CNS, twenty-four dogs suffering from spontaneously occurring different intracranial and extracranial (control group) diseases were examined. Microglia cells were isolated ex vivo by density gradient centrifugation and their expressions of MMP-2, MMP-9, MMP-12, MMP-13, MMP-14, TIMP-1, TIMP-2, and RECK were examined via quantitative real-time polymerase chain reaction (qPCR). Zymography on CNS tissues in selected cases was performed to assess differences at the protein level. Dogs were grouped in different disease categories according to histopathological examinations, in groups with or without inflammatory reactions, and in groups with/without contrast enhancement in advanced diagnostic imaging as a function of BBB breakdown. The results showed a significant up-regulation of MMP-9 in dogs with inflammation in the nervous system compared to dogs with non-inflammatory diseases. An increased expression of MMP-9 might lead to a facilitated invasion of white blood cells. Furthermore, down-regulation of MMP-13 was found in dogs with contrast enhancement. Zymographical data reflected MMP-2 qPCR data. In conclusion, differential expression of MMPs and their inhibitors, but not of RECK, which might crucially influence the pathogenesis of a given disease, could be demonstrated in canine microglia. This reflects a further pathway in the microglial repertoire to respond to various disease conditions in the CNS, a characteristic that might be of particular relevance as a target for specific treatments.

Allelic variation of the matrix metalloproteinase-9 gene is associated with collagenous colitis

Collagenous colitis is a chronic inflammatory bowel disease of unknown origin characterized by a thickened subepithelial collagen layer. Differential expression of matrix-metalloproteinases (MMPs) have been implicated in the pathogenesis of collagenous colitis. The aim was to assess genetic polymorphisms of MMP-1, -7, and -9 in a case-control setting for susceptibility to collagenous colitis. Seventy-five patients with symptomatic collagenous colitis and 334 healthy blood donors were genotyped for single nucleotide polymorphisms (SNPs) in MMP-1-1607, MMP-7-153, MMP-7-181, and MMP-9 exon 6 using TaqMan technology. Susceptibility to collagenous colitis was tested by comparison of the carrier status of the rare allele. The carrier frequency of the allele GG of the coding SNP MMP-9 in exon 6 was 24% in patients with collagenous colitis and 14.3% in healthy blood donors (P = 0.039). The carriage of the allele GG significantly increased the risk for collagenous colitis with an odds ratio of 1.9 (95% confidence interval: 1.0-3.5). None of the other SNPs of MMP-1, MMP-7-153, and MMP-7-181 were associated with collagenous colitis. Allelic variation in the MMP-9 gene may be part of a complex genetic risk profile for collagenous colitis. Further studies are needed to confirm this observation and to explore the functional role of this gene polymorphism in collagenous colitis.

Differential expression of matrix metalloproteinases and proteoglycans in Juvenile Hyaline Fibromatosis

Juvenile Hyaline Fibromatosis (JHF) is a rare autosomal recessive disorder, histologically characterized by the production and deposition of an unidentified hyaline material in the skin and other organs. Extracellular matrix molecules are implicated in the development of skin lesion which is debilitating and recurrent and, so far, no treatment is satisfactory. To investigate the expression of matrix metalloproteinases (MMPs), their tissue inhibitors (TIMPs) and proteoglycans in lesional as compared to site-matched lesion-free skin tissue specimens of a JHF patient, aiming to elucidate the aetiopathological mechanisms involved in the development of JHF skin lesions. Gelatinase activity of MMP-2 and MMP-9 was investigated by gelatine zymography. Protein levels of MMP-2, MMP-9, TIMP-1 and TIMP-2 in skin tissue extracts were measured by ELISA. Gene expression of MMPs, TIMPs and proteoglycans was examined by quantitative RT-PCR. JHF lesions exhibited significantly higher activity as well as elevated protein and gene expression of MMP-2 and MMP-9, as compared to lesion-free skin tissue specimens. Decorin was downregulated and aggrecan was upregulated in lesional skin, as compared to normal skin. The results presented in this study indicate that MMPs and proteoglycans may be involved in the pathogenesis of JHF and therefore these molecules may offer alternative targets for pharmacological intervention to achieve more radical and effective treatment.

Inhibition of matrix metalloproteinases in Siberian hamsters impedes photostimulated recrudescence of ovaries

Exposure of Siberian hamsters to short photoperiod for 14 weeks induces ovarian regression. Subsequent transfer to long photoperiod restores ovarian function, and 2 weeks of photostimulation increases plasma estradiol (E(2)), antral follicles, and corpora lutea (CL). Because tissue remodeling involved with photostimulated ovarian recrudescence is associated with differential expression of matrix metalloproteinases (MMPs), we hypothesized that inhibiting MMP activity using a broad-spectrum in vivo MMP inhibitor, GM6001, would curtail recrudescence. One group of hamsters was placed in long days (LD; 16 h light:8 h darkness) for 16 weeks. Another group was placed in inhibitory short days (SD; 8 h light:16 h darkness) for 14 weeks. A third group was placed in SD for 14 weeks and transferred to LD for 2 weeks to stimulate recrudescence. During weeks 14-16, animals were either not treated or treated daily with i.p. injections of GM6001 (20 mg/kg) or vehicle (DMSO). GM6001 reduced gelatinase activity and decreased immunohistochemical staining for MMP1, MMP2, and MMP3 compared with vehicle. No differences between controls, vehicle, or GM6001 treatment were observed among LD animals, despite a trend toward reduction in CL and E(2) with GM6001. Although SD reduced ovarian function, photostimulation of transferred controls increased uterine mass, plasma E(2), appearance of antral follicles, and CL. With GM6001 treatment, photostimulation failed to increase uterine mass, plasma E(2), antral follicles, or CL. These data show, for the first time, that in vivo GM6001 administration inhibits MMP activity in hamster ovaries during photostimulation, and indicate that this inhibition may impede photostimulated recrudescence of ovaries. This study suggests an intriguing link between MMP activity and return to ovarian function during photostimulated recrudescence.

Matrix metalloproteinases are elevated in the urine of patients with endometriosis

In a prospective, blinded, longitudinal study MMP-2, MMP-9, and MMP-9/neutrophil gelatinase-associated lipocalin were significantly more likely to be detected in the urine of patients with endometriosis than in controls.