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Fakhari S, Moradzad M, Ahmadi A, Hekmatnia M, Jalili A, Nikkhoo B, Rahmani MR, Sheikhesmaeili F. Downregulation of MT2-MMP and MT5-MMP in ulcerative colitis serves a diagnostic predictor and potential therapeutic targets. Mol Biol Rep 2025; 52:359. [PMID: 40178713 DOI: 10.1007/s11033-025-10449-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Accepted: 03/17/2025] [Indexed: 04/05/2025]
Abstract
BACKGROUND Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) characterized by persistent inflammation and tissue remodeling. Matrix metalloproteinases (MMPs) play a key role in extracellular matrix degradation, and their dysregulation is implicated in IBD. However, the specific role of membrane-type MMPs (MT-MMPs) in UC remains underexplored. This study investigates the expression of MT-MMPs in UC patients, including new cases and treatment-resistant patients, and evaluates their expression patterns compared to healthy people. METHODS AND RESULTS Colon biopsy samples were collected from three groups: healthy controls (n = 20), newly diagnosed UC patients (n = 20), and UC patients resistant to standard treatments (n = 20). The mRNA expression levels of MT-MMPs were assessed using quantitative real-time PCR. Receiver operating characteristic (ROC) curve analysis was performed to determine the diagnostic utility of these MT-MMPs. Correlation analysis was also conducted to explore the relationship between MT-MMPs and inflammatory markers (CRP, ESR) and vitamin D levels. Out of 6 members of MT-MMPs, MT2-MMP, and MT5-MMP were significantly downregulated in new cases and resistant UC patients compared to controls (P < 0.0001). ROC analysis demonstrated high sensitivity and specificity for MT2-MMP and MT5-MMP in differentiating UC patients from healthy individuals. Additionally, MT2,5-MMP expression was negatively correlated with CRP, ESR, and vitamin D levels, indicating their possible modulation of systematic inflammation. CONCLUSION MT2-MMP and MT5-MMP are downregulated in UC and may serve as diagnostic biomarkers for disease severity. The findings highlight the need for further investigation into their therapeutic potential in modulating inflammation and tissue remodeling in UC.
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Affiliation(s)
- Shohreh Fakhari
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Mohammad Moradzad
- Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.
| | - Amjad Ahmadi
- Department of Microbiology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Melika Hekmatnia
- Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Ali Jalili
- Cancer & Immunology Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Bahram Nikkhoo
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
- Cancer & Immunology Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Mohammad Reza Rahmani
- Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Farshad Sheikhesmaeili
- Liver& Digestive Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
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Dong S, Zhang Y, Ye L, Cao Q. Identification of a Novel Activated NK-Associated Gene Score Associated with Diagnosis and Biological Therapy Response in Ulcerative Colitis. Digestion 2024; 106:1-22. [PMID: 39182484 PMCID: PMC11825133 DOI: 10.1159/000540939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 08/08/2024] [Indexed: 08/27/2024]
Abstract
INTRODUCTION Natural killer (NK) cells are associated with the pathogenesis of ulcerative colitis (UC); however, their precise contributions remain unclear. The present study aimed to investigate the diagnostic value of the activated NK-associated gene (ANAG) score in UC and evaluate its predictive value in response to biological therapy. METHODS Bulk RNA-seq and scRNA-seq datasets were obtained from the Gene Expression Omnibus (GEO) and Single Cell Portal (SCP) databases. In the bulk RNA-seq, differentially expressed genes (DEGs) were screened by the "Batch correction" and "Robust rank aggregation" (RRA) methods. The immune infiltration landscape was estimated using single-sample gene set enrichment analysis (ssGSEA) and CIBERSORT. DEGs that correlated with activated NK cells were identified as activated NK-associated genes (ANAGs). Protein-protein interaction (PPI) analysis and least absolute shrinkage and selection operator (LASSO) regression were used to screen key ANAGs and establish an ANAG score. The expression levels of the four key ANAGs were validated in human samples by real-time quantitative polymerase chain reaction (RT-qPCR) and immunofluorescence. The potential therapeutic drugs for UC were identified using the DSigDB database. Through scRNA-seq data analysis, the cell scores based on the ANAGs were calculated by "AddModuleScore" and "AUCell." RESULTS Immune infiltration analysis revealed a higher abundance of activated NK cells in noninflamed UC tissues (ssGSEA, p < 0.001; CIBERSORT, p < 0.01). Fifty-four DEGs correlated with activated NK cells were identified as ANAGs. The ANAG score was established using four key ANAGs (SELP, TIMP1, MMP7, and ABCG2). The ANAG scores were significantly higher in inflamed tissues (p < 0.001) and in biological therapy nonresponders (NR) tissues before treatment (golimumab, p < 0.05; ustekinumab, p < 0.001). The ANAG score demonstrated an excellent diagnostic value (AUC = 0.979). Patients with higher ANAG scores before treatment were more likely to experience a lack of response to golimumab or ustekinumab (golimumab, p < 0.05; ustekinumab, p < 0.001). CONCLUSION This study established a novel ANAG score with the ability to precisely diagnose UC and distinguish the efficacy of biological treatment. INTRODUCTION Natural killer (NK) cells are associated with the pathogenesis of ulcerative colitis (UC); however, their precise contributions remain unclear. The present study aimed to investigate the diagnostic value of the activated NK-associated gene (ANAG) score in UC and evaluate its predictive value in response to biological therapy. METHODS Bulk RNA-seq and scRNA-seq datasets were obtained from the Gene Expression Omnibus (GEO) and Single Cell Portal (SCP) databases. In the bulk RNA-seq, differentially expressed genes (DEGs) were screened by the "Batch correction" and "Robust rank aggregation" (RRA) methods. The immune infiltration landscape was estimated using single-sample gene set enrichment analysis (ssGSEA) and CIBERSORT. DEGs that correlated with activated NK cells were identified as activated NK-associated genes (ANAGs). Protein-protein interaction (PPI) analysis and least absolute shrinkage and selection operator (LASSO) regression were used to screen key ANAGs and establish an ANAG score. The expression levels of the four key ANAGs were validated in human samples by real-time quantitative polymerase chain reaction (RT-qPCR) and immunofluorescence. The potential therapeutic drugs for UC were identified using the DSigDB database. Through scRNA-seq data analysis, the cell scores based on the ANAGs were calculated by "AddModuleScore" and "AUCell." RESULTS Immune infiltration analysis revealed a higher abundance of activated NK cells in noninflamed UC tissues (ssGSEA, p < 0.001; CIBERSORT, p < 0.01). Fifty-four DEGs correlated with activated NK cells were identified as ANAGs. The ANAG score was established using four key ANAGs (SELP, TIMP1, MMP7, and ABCG2). The ANAG scores were significantly higher in inflamed tissues (p < 0.001) and in biological therapy nonresponders (NR) tissues before treatment (golimumab, p < 0.05; ustekinumab, p < 0.001). The ANAG score demonstrated an excellent diagnostic value (AUC = 0.979). Patients with higher ANAG scores before treatment were more likely to experience a lack of response to golimumab or ustekinumab (golimumab, p < 0.05; ustekinumab, p < 0.001). CONCLUSION This study established a novel ANAG score with the ability to precisely diagnose UC and distinguish the efficacy of biological treatment.
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Affiliation(s)
- Siyuan Dong
- Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine Zhejiang University, Hangzhou, China
- Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, College of Medicine Zhejiang University, Hangzhou, China
- Institute of Gastroenterology, Zhejiang University, Hangzhou, China
| | - Yu Zhang
- Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine Zhejiang University, Hangzhou, China
- Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, College of Medicine Zhejiang University, Hangzhou, China
- Institute of Gastroenterology, Zhejiang University, Hangzhou, China
| | - Lingna Ye
- Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine Zhejiang University, Hangzhou, China
- Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, College of Medicine Zhejiang University, Hangzhou, China
- Institute of Gastroenterology, Zhejiang University, Hangzhou, China
| | - Qian Cao
- Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine Zhejiang University, Hangzhou, China
- Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, College of Medicine Zhejiang University, Hangzhou, China
- Institute of Gastroenterology, Zhejiang University, Hangzhou, China
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Chen SY, Fang CY, Su BH, Chen HM, Huang SC, Wu PT, Shiau AL, Wu CL. Early Growth Response Protein 1 Exacerbates Murine Inflammatory Bowel Disease by Transcriptional Activation of Matrix Metalloproteinase 12. Biomedicines 2024; 12:780. [PMID: 38672136 PMCID: PMC11047900 DOI: 10.3390/biomedicines12040780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 03/19/2024] [Accepted: 03/26/2024] [Indexed: 04/28/2024] Open
Abstract
Inflammatory bowel disease (IBD) is an inflammatory condition affecting the colon and small intestine, with Crohn's disease and ulcerative colitis being the major types. Individuals with long-term IBD are at an increased risk of developing colorectal cancer. Early growth response protein 1 (Egr1) is a nuclear protein that functions as a transcriptional regulator. Egr1 is known to control the expression of numerous genes and play a role in cell growth, proliferation, and differentiation. While IBD has been associated with severe inflammation, the precise mechanisms underlying its pathogenesis remain unclear. This study aimed to investigate the role of Egr1 in the development of IBD. High levels of Egr1 expression were observed in a mouse model of colitis induced by dextran sulfate sodium (DSS), as determined by immunohistochemical (IHC) staining. Chronic DSS treatment showed that Egr1 knockout (KO) mice exhibited resistance to the development of IBD, as determined by changes in their body weight and disease scores. Additionally, enzyme-linked immunosorbent assay (ELISA) and IHC staining demonstrated decreased expression levels of proinflammatory cytokines such as IL-1β, IL-6, and TNF-α, as well as matrix metalloproteinase 12 (MMP12). Putative Egr1 binding sites were identified within the MMP12 promoter region. Through reporter assays and chromatin immunoprecipitation (ChIP) analysis, it was shown that Egr1 binds to the MMP12 promoter and regulates MMP12 expression. In conclusion, we found that Egr1 plays a role in the inflammation process of IBD through transcriptionally activating MMP12.
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Affiliation(s)
- Shih-Yao Chen
- Department of Nursing, College of Nursing, Chung Hwa University of Medical Technology, Tainan 717302, Taiwan;
| | - Chuan-Yin Fang
- Division of Colon and Rectal Surgery, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi 600566, Taiwan
| | - Bing-Hwa Su
- School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei 110301, Taiwan
| | - Hao-Ming Chen
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan
| | - Shih-Chi Huang
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan
| | - Po-Ting Wu
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan
- Department of Orthopedics, College of Medicine, National Cheng Kung University, 1 University Road, Tainan 701401, Taiwan
- Department of Orthopaedics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan
- Medical Device Innovation Center, National Cheng Kung University, Tainan 701401, Taiwan
- Department of Biomedical Engineering, National Cheng Kung University, Tainan 701401, Taiwan
| | - Ai-Li Shiau
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan
| | - Chao-Liang Wu
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan
- Department of Medical Research, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi 600566, Taiwan
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Cameron O, Neves JF, Gentleman E. Listen to Your Gut: Key Concepts for Bioengineering Advanced Models of the Intestine. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2302165. [PMID: 38009508 PMCID: PMC10837392 DOI: 10.1002/advs.202302165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 10/12/2023] [Indexed: 11/29/2023]
Abstract
The intestine performs functions central to human health by breaking down food and absorbing nutrients while maintaining a selective barrier against the intestinal microbiome. Key to this barrier function are the combined efforts of lumen-lining specialized intestinal epithelial cells, and the supportive underlying immune cell-rich stromal tissue. The discovery that the intestinal epithelium can be reproduced in vitro as intestinal organoids introduced a new way to understand intestinal development, homeostasis, and disease. However, organoids reflect the intestinal epithelium in isolation whereas the underlying tissue also contains myriad cell types and impressive chemical and structural complexity. This review dissects the cellular and matrix components of the intestine and discusses strategies to replicate them in vitro using principles drawing from bottom-up biological self-organization and top-down bioengineering. It also covers the cellular, biochemical and biophysical features of the intestinal microenvironment and how these can be replicated in vitro by combining strategies from organoid biology with materials science. Particularly accessible chemistries that mimic the native extracellular matrix are discussed, and bioengineering approaches that aim to overcome limitations in modelling the intestine are critically evaluated. Finally, the review considers how further advances may extend the applications of intestinal models and their suitability for clinical therapies.
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Affiliation(s)
- Oliver Cameron
- Centre for Craniofacial and Regenerative BiologyKing's College LondonLondonSE1 9RTUK
| | - Joana F. Neves
- Centre for Host‐Microbiome InteractionsKing's College LondonLondonSE1 9RTUK
| | - Eileen Gentleman
- Centre for Craniofacial and Regenerative BiologyKing's College LondonLondonSE1 9RTUK
- Department of Biomedical SciencesUniversity of LausanneLausanne1005Switzerland
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Sosna B, Aebisher D, Myśliwiec A, Dynarowicz K, Bartusik-Aebisher D, Oleś P, Cieślar G, Kawczyk-Krupka A. Selected Cytokines and Metalloproteinases in Inflammatory Bowel Disease. Int J Mol Sci 2023; 25:202. [PMID: 38203373 PMCID: PMC10779120 DOI: 10.3390/ijms25010202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 12/19/2023] [Accepted: 12/20/2023] [Indexed: 01/12/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a collective term for two diseases: ulcerative colitis (UC) and Crohn's disease (CD). There are many factors, e.g., genetic, environmental and immunological, that increase the likelihood of these diseases. Indicators of IBDs include extracellular matrix metalloproteinases (MMPs). The aim of this review is to present data on the role of selected cytokines and metalloproteinases in IBD. In recent years, more and more transcriptomic studies are emerging. These studies are improving the characterization of the cytokine microenvironment inside inflamed tissue. It is observed that the levels of several cytokines are consistently increased in inflamed tissue in IBD, both in UC and CD. This review shows that MMPs play a major role in the pathology of inflammatory processes, cancer, and IBD. IBD-associated inflammation is associated with increased expression of MMPs and reduced ability of tissue inhibitors of metalloproteinases (TIMPs) to inhibit their action. In IBD patients in tissues that are inflamed, MMPs are produced in excess and TIMP activity is not sufficient to block MMPs. This review is based on our personal selection of the literature that was retrieved by a selective search in PubMed using the terms "Inflammatory bowel disease" and "pathogenesis of Inflammatory bowel diseases" that includes systematic reviews, meta-analyses, and clinical trials. The involvement of the immune system in the pathophysiology of IBD is reviewed in terms of the role of the cytokines and metalloproteinases involved.
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Affiliation(s)
- Barbara Sosna
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (P.O.); (G.C.)
| | - David Aebisher
- Department of Photomedicine and Physical Chemistry, Medical College, University of Rzeszów, 35-959 Rzeszów, Poland;
| | - Angelika Myśliwiec
- Center for Innovative Research in Medical and Natural Sciences, Medical College, University of Rzeszów, 35-310 Rzeszów, Poland; (A.M.); (K.D.)
| | - Klaudia Dynarowicz
- Center for Innovative Research in Medical and Natural Sciences, Medical College, University of Rzeszów, 35-310 Rzeszów, Poland; (A.M.); (K.D.)
| | - Dorota Bartusik-Aebisher
- Department of Biochemistry and General Chemistry, Medical College, University of Rzeszów, 35-959 Rzeszów, Poland;
| | - Piotr Oleś
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (P.O.); (G.C.)
| | - Grzegorz Cieślar
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (P.O.); (G.C.)
| | - Aleksandra Kawczyk-Krupka
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (P.O.); (G.C.)
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Chrzanowski G, Pasternak G, Aebisher D, Dynarowicz K, Myśliwiec A, Bartusik-Aebisher D, Sosna B, Cieślar G, Kawczyk-Krupka A, Filip R. An Analysis of the Content of Metalloproteinases in the Intestinal Wall of Patients with Crohn's Disease. Life (Basel) 2023; 13:2013. [PMID: 37895400 PMCID: PMC10608236 DOI: 10.3390/life13102013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 09/27/2023] [Accepted: 10/03/2023] [Indexed: 10/29/2023] Open
Abstract
One of the inflammatory bowel diseases is Crohn's disease. Although this term has been used in the medical community since 1932, a significant increase in the number of publications occurs at the end of the 20th century and the beginning of the 21st century. Crohn's disease is a disease that cannot be fully cured. In many cases, it is chronic, i.e., recurrent. All preventive and therapeutic measures taken by doctors are aimed at inhibiting the development of the disease and minimizing the occurrence of any potential "side effects" resulting from the developing disease. One of the diagnostic methods is the qualitative and quantitative determination of metalloproteinases in inflammatory tissues and in the blood. The aim of the study was the quantitative and qualitative determination of metalloproteinases in inflammatory bowel tissues in patients diagnosed with Crohn's disease. The in vitro study was performed on surgical tissues from patients diagnosed with Crohn's disease. The results show that in inflammatory tissues the concentration of metalloproteinases -3, -7, -8, -9 was higher compared to tissues taken from the resection margin without signs of inflammation, defined as healthy. The experiment confirmed that the biochemical test, which is the determination of metalloproteinases in tissues, is a useful diagnostic tool to differentiate inflammatory from non-inflammatory tissues.
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Affiliation(s)
- Grzegorz Chrzanowski
- Department of Biology, College of Natural Sciences, University of Rzeszów, 35-310 Rzeszów, Poland;
| | - Grzegorz Pasternak
- Department of General Surgery, Provincial Clinical Hospital No. 2 in Rzeszów, 35-301 Rzeszów, Poland;
| | - David Aebisher
- Department of Photomedicine and Physical Chemistry, Medical College of University of Rzeszów, University of Rzeszów, 35-310 Rzeszów, Poland
| | - Klaudia Dynarowicz
- Center for Innovative Research in Medical and Natural Sciences, Medical College of the University of Rzeszów, 35-310 Rzeszów, Poland; (K.D.); (A.M.)
| | - Angelika Myśliwiec
- Center for Innovative Research in Medical and Natural Sciences, Medical College of the University of Rzeszów, 35-310 Rzeszów, Poland; (K.D.); (A.M.)
| | - Dorota Bartusik-Aebisher
- Department of Biochemistry and General Chemistry, Medical College of University of Rzeszów, University of Rzeszów, 35-310 Rzeszów, Poland;
| | - Barbara Sosna
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (G.C.); (A.K.-K.)
| | - Grzegorz Cieślar
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (G.C.); (A.K.-K.)
| | - Aleksandra Kawczyk-Krupka
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (G.C.); (A.K.-K.)
| | - Rafał Filip
- Department of Internal Medicine, Medical College of University of Rzeszów, University of Rzeszów, 35-310 Rzeszów, Poland;
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Xiao Y, Powell DW, Liu X, Li Q. Cardiovascular manifestations of inflammatory bowel diseases and the underlying pathogenic mechanisms. Am J Physiol Regul Integr Comp Physiol 2023; 325:R193-R211. [PMID: 37335014 PMCID: PMC10979804 DOI: 10.1152/ajpregu.00300.2022] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 06/01/2023] [Accepted: 06/01/2023] [Indexed: 06/21/2023]
Abstract
Inflammatory bowel disease (IBD), consisting of ulcerative colitis and Crohn's disease, mainly affects the gastrointestinal tract but is also known to have extraintestinal manifestations because of long-standing systemic inflammation. Several national cohort studies have found that IBD is an independent risk factor for the development of cardiovascular disorders. However, the molecular mechanisms by which IBD impairs the cardiovascular system are not fully understood. Although the gut-heart axis is attracting more attention in recent years, our knowledge of the organ-to-organ communication between the gut and the heart remains limited. In patients with IBD, upregulated inflammatory factors, altered microRNAs and lipid profiles, as well as dysbiotic gut microbiota, may induce adverse cardiac remodeling. In addition, patients with IBD have a three- to four times higher risk of developing thrombosis than people without IBD, and it is believed that the increased risk of thrombosis is largely due to increased procoagulant factors, platelet count/activity, and fibrinogen concentration, in addition to decreased anticoagulant factors. The predisposing factors for atherosclerosis are present in IBD and the possible mechanisms may involve oxidative stress system, overexpression of matrix metalloproteinases, and changes in vascular smooth muscle phenotype. This review focuses mainly on 1) the prevalence of cardiovascular diseases associated with IBD, 2) the potential pathogenic mechanisms of cardiovascular diseases in patients with IBD, and 3) adverse effects of IBD drugs on the cardiovascular system. Also, we introduce here a new paradigm for the gut-heart axis that includes exosomal microRNA and the gut microbiota as a cause for cardiac remodeling and fibrosis.
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Affiliation(s)
- Ying Xiao
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, China
- Division of Gastroenterology, Department of Internal Medicine, University of Texas Medical Branch at Galveston, Galveston, Texas, United States
| | - Don W Powell
- Division of Gastroenterology, Department of Internal Medicine, University of Texas Medical Branch at Galveston, Galveston, Texas, United States
| | - Xiaowei Liu
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, China
| | - Qingjie Li
- Division of Gastroenterology, Department of Internal Medicine, University of Texas Medical Branch at Galveston, Galveston, Texas, United States
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Deng J, Zhao N, Lv LP, Ma P, Zhang YY, Xu JB, Zhou XP, Chen ZA, Zhang YY. Integrated analysis of multiple microarray studies to establish differential diagnostic models of Crohn's disease and ulcerative colitis based on a metalloproteinase-associated module. Front Immunol 2022; 13:1022850. [PMID: 36479126 PMCID: PMC9720321 DOI: 10.3389/fimmu.2022.1022850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 10/25/2022] [Indexed: 11/22/2022] Open
Abstract
Background The ulcerative colitis (UC) and Crohn's disease (CD) subtypes of inflammatory bowel disease (IBD) are autoimmune diseases influenced by multiple complex factors. The clinical treatment strategies for UC and CD often differ, indicating the importance of improving their discrimination. Methods Two methods, robust rank aggregation (RRA) analysis and merging and intersection, were applied to integrate data from multiple IBD cohorts, and the identified differentially expressed genes (DEGs) were used to establish a protein-protein interaction (PPI) network. Molecular complex detection (MCODE) was used to identify important gene sets. Two differential diagnostic models to distinguish CD and UC were established via a least absolute shrinkage and selection operator (LASSO) logistic regression, and model evaluation was performed in both the training and testing groups, including receiver operating characteristic (ROC) curves, calibration plots and decision curve analysis (DCA). The potential value of MMP-associated genes was further verified using different IBD cohorts and clinical samples. Results Four datasets (GSE75214, GSE10616, GSE36807, and GSE9686) were included in the analysis. Both data integration methods indicated that the activation of the MMP-associated module was significantly elevated in UC. Two LASSO models based on continuous variable (Model_1) and binary variable (Model_2) MMP-associated genes were established to discriminate CD and UC. The results showed that Model_1 exhibited good discrimination in the training and testing groups. The calibration analysis and DCA showed that Model_1 exhibited good performance in the training group but failed in the testing group. Model_2 exhibited good discrimination, calibration and DCA results in the training and testing groups and exhibited greater diagnostic value. The effects of Model_1 and Model_2 were further verified in a new IBD cohort of GSE179285. The MMP genes exhibited high value as biomarkers for the discrimination of IBD patients using published cohort and immunohistochemistry (IHC) staining data. The MMP-associated gene levels were statistically significantly positively correlated with the levels of the differentially expressed cell types, indicating their potential value in differential diagnosis. The single-cell analysis confirmed that the expression of ANXA1 in UC was higher than that in CD. Conclusion MMP-associated modules are the main differential gene sets between CD and UC. The established Model_2 overcomes batch differences and has good clinical applicability. Subsequent in-depth research investigating how MMPs are involved in the development of different IBD subtypes is necessary.
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Affiliation(s)
- Jiang Deng
- Institute of Health Service and Transfusion Medicine, Beijing, China,Beijing Key Laboratory of Blood Safety and Supply Technologies, Beijing, China
| | - Ning Zhao
- Institute of Health Service and Transfusion Medicine, Beijing, China,Beijing Key Laboratory of Blood Safety and Supply Technologies, Beijing, China
| | - Li-ping Lv
- Institute of Health Service and Transfusion Medicine, Beijing, China,Beijing Key Laboratory of Blood Safety and Supply Technologies, Beijing, China
| | - Ping Ma
- Institute of Health Service and Transfusion Medicine, Beijing, China,Beijing Key Laboratory of Blood Safety and Supply Technologies, Beijing, China
| | - Yang-yang Zhang
- Institute of Health Service and Transfusion Medicine, Beijing, China,Beijing Key Laboratory of Blood Safety and Supply Technologies, Beijing, China
| | - Jin-bo Xu
- Institute of Health Service and Transfusion Medicine, Beijing, China,Beijing Key Laboratory of Blood Safety and Supply Technologies, Beijing, China
| | - Xi-peng Zhou
- Institute of Health Service and Transfusion Medicine, Beijing, China,Beijing Key Laboratory of Blood Safety and Supply Technologies, Beijing, China
| | - Zi-an Chen
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China,Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Disease, Shijiazhuang, Hebei, China,*Correspondence: Zi-an Chen, ; Yan-yu Zhang,
| | - Yan-yu Zhang
- Institute of Health Service and Transfusion Medicine, Beijing, China,Beijing Key Laboratory of Blood Safety and Supply Technologies, Beijing, China,*Correspondence: Zi-an Chen, ; Yan-yu Zhang,
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Czajkowska A, Guzinska-Ustymowicz K, Pryczynicz A, Lebensztejn D, Daniluk U. Are Matrix Metalloproteinase-9 and Tissue Inhibitor of Metalloproteinase-1 Useful as Markers in Diagnostic Management of Children with Newly Diagnosed Ulcerative Colitis? J Clin Med 2022; 11:jcm11092655. [PMID: 35566780 PMCID: PMC9103541 DOI: 10.3390/jcm11092655] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 04/28/2022] [Accepted: 05/06/2022] [Indexed: 02/06/2023] Open
Abstract
Matrix Metaloproteinase-9 (MMP-9) and Tissue Inhibitor of Metaloproteinase-1 (TIMP-1), enzymes involved in tissue remodelling, have been previously reported to be overexpressed in the colonic mucosa of patients with Ulcerative colitis (UC). The aim of this study was to determine the relation of MMP-9 and TIMP-1 with UC phenotypes, the disease activity index and routinely tested inflammatory markers in newly diagnosed paediatric patients. The study group comprised 35 children diagnosed with UC and 20 control groups. Serum and faecal concentrations of MMP-9 and TIMP-1 were estimated using enzyme-like immunosorbent assay kits and correlated to the disease activity index (Paediatric Ulcerative Colitis Activity Index, PUCAI), UC phenotype (Paris Classification), inflammatory markers and endoscopic score (Mayo score). Children with UC presented with significantly higher serum and faecal concentrations of studied markers compared to the control group. Both serums, MMP-9 and TIMP-1, were higher in children with more extended and severe lesions in the colon. Furthermore, serum MMP-9 correlated with the Mayo score, Paris classification and C-reactive protein (CRP) levels. Serum TIMP-1 showed correlation with PUCAI, Paris Classification, CRP levels and the erythrocyte sedimentation rate. Serum and faecal levels of MMP-9 and TIMP-1 are useful in discriminating UC patients and non-invasive assessments of disease phenotypes. It seemed that simultaneous measurement of these proteins in combination with other common markers of inflammation could be applied in clinical practice.
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Affiliation(s)
- Aleksandra Czajkowska
- Department of Pediatrics, Gastroenterology, Hepatology, Nutrition and Allergology, Medical University of Bialystok, 17 Waszyngtona Street, 15-274 Bialystok, Poland; (D.L.); (U.D.)
- Correspondence: or
| | | | - Anna Pryczynicz
- Department of General Pathomorphology, Medical University of Bialystok, 15-089 Bialystok, Poland; (K.G.-U.); (A.P.)
| | - Dariusz Lebensztejn
- Department of Pediatrics, Gastroenterology, Hepatology, Nutrition and Allergology, Medical University of Bialystok, 17 Waszyngtona Street, 15-274 Bialystok, Poland; (D.L.); (U.D.)
| | - Urszula Daniluk
- Department of Pediatrics, Gastroenterology, Hepatology, Nutrition and Allergology, Medical University of Bialystok, 17 Waszyngtona Street, 15-274 Bialystok, Poland; (D.L.); (U.D.)
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10
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Marônek M, Marafini I, Gardlík R, Link R, Troncone E, Monteleone G. Metalloproteinases in Inflammatory Bowel Diseases. J Inflamm Res 2021; 14:1029-1041. [PMID: 33790618 PMCID: PMC8001665 DOI: 10.2147/jir.s288280] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 03/09/2021] [Indexed: 12/13/2022] Open
Abstract
Inflammatory bowel diseases (IBD) are chronic inflammatory diseases of the gastrointestinal tract, encompassing two main disorders: Crohn's disease (CD) and ulcerative colitis (UC). In both these pathologies, excessive and local immune response against luminal antigens promotes a pathological process leading to various degrees of gut damage. Matrix metalloproteinases (MMPs) are a family of neutral proteases with the ability to degrade all components of extracellular matrix. In physiological conditions, MMPs are produced at very low level and generally in the latent form and are involved in the normal tissue turnover. Their function is inhibited by tissue inhibitors of metalloproteinases (TIMPs). However, in inflamed tissue of IBD patients, MMPs are produced in excess and/or the activity of TIMPs is not sufficient to block MMPs, thereby making a major contribution to the IBD-related mucosal degradation. In this review, we summarize the available evidence on the expression and role of MMPs in IBD.
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Affiliation(s)
- Martin Marônek
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University in Bratislava, Bratislava, 81108, Slovakia
| | - Irene Marafini
- Department of Systems Medicine, University of Rome "Tor Vergata", Rome, 00133, Italy
| | - Roman Gardlík
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University in Bratislava, Bratislava, 81108, Slovakia
| | - René Link
- Institute of Experimental Medicine, Faculty of Medicine, University of Pavol Jozef Šafárik, Košice, 040 11, Slovakia
| | - Edoardo Troncone
- Department of Systems Medicine, University of Rome "Tor Vergata", Rome, 00133, Italy
| | - Giovanni Monteleone
- Department of Systems Medicine, University of Rome "Tor Vergata", Rome, 00133, Italy
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11
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The Citrullinated and MMP-degraded Vimentin Biomarker (VICM) Predicts Early Response to Anti-TNFα Treatment in Crohn's Disease. J Clin Gastroenterol 2021; 55:59-66. [PMID: 32301833 DOI: 10.1097/mcg.0000000000001341] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND In Crohn's disease (CD), 10% to 40% of patients do not respond to anti-tumor necrosis factor-α (TNFα) treatment. Currently, there are no biomarkers with adequate sensitivity to separate responders from nonresponders at an early stage. AIM The aim of this study was to investigated whether early changes in the VICM (citrullinated and matrix metalloproteinase-degraded vimentin) biomarker were associated with response to anti-TNFα treatment in patients with CD. METHODS Serum VICM levels were measured by ELISA in 2 independent cohorts of CD patients (n=42) treated with anti-TNFα (infliximab or adalimumab). Response was determined by achieving clinical remission (Harvey Bradshaw Index<5). RESULTS Compared with baseline, VICM serum levels were reduced by anti-TNFα in the infliximab cohort (week 6 and 14) and in the adalimumab cohort (week 8). VICM was lower in the responders compared with the nonresponders [infliximab: week 6, P<0.05; area under the curve (AUC)=0.90; adalimumab: week 1, P<0.01 (AUC=0.91), and week 8, P<0.05 (AUC=0.86)], and were able to predict response to treatment after 1 week of treatment with an odds ratio of 42.5. CONCLUSIONS The VICM biomarker was time dependently reduced in CD patients responding to anti-TNFα treatment. We suggest that VICM may be used as a marker for monitoring early response to anti-TNFα in patients with CD.
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12
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Onfroy-Roy L, Hamel D, Foncy J, Malaquin L, Ferrand A. Extracellular Matrix Mechanical Properties and Regulation of the Intestinal Stem Cells: When Mechanics Control Fate. Cells 2020; 9:cells9122629. [PMID: 33297478 PMCID: PMC7762382 DOI: 10.3390/cells9122629] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 12/01/2020] [Accepted: 12/04/2020] [Indexed: 02/07/2023] Open
Abstract
Intestinal stem cells (ISC) are crucial players in colon epithelium physiology. The accurate control of their auto-renewal, proliferation and differentiation capacities provides a constant flow of regeneration, maintaining the epithelial intestinal barrier integrity. Under stress conditions, colon epithelium homeostasis in disrupted, evolving towards pathologies such as inflammatory bowel diseases or colorectal cancer. A specific environment, namely the ISC niche constituted by the surrounding mesenchymal stem cells, the factors they secrete and the extracellular matrix (ECM), tightly controls ISC homeostasis. Colon ECM exerts physical constraint on the enclosed stem cells through peculiar topography, stiffness and deformability. However, little is known on the molecular and cellular events involved in ECM regulation of the ISC phenotype and fate. To address this question, combining accurately reproduced colon ECM mechanical parameters to primary ISC cultures such as organoids is an appropriated approach. Here, we review colon ECM physical properties at physiological and pathological states and their bioengineered in vitro reproduction applications to ISC studies.
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Affiliation(s)
- Lauriane Onfroy-Roy
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, 31024 Toulouse, France;
- Correspondence: (L.O.-R.); (A.F.); Tel.: +33-5-62-744-522 (A.F.)
| | - Dimitri Hamel
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, 31024 Toulouse, France;
- LAAS-CNRS, Université de Toulouse, CNRS, 31400 Toulouse, France; (J.F.); (L.M.)
| | - Julie Foncy
- LAAS-CNRS, Université de Toulouse, CNRS, 31400 Toulouse, France; (J.F.); (L.M.)
| | - Laurent Malaquin
- LAAS-CNRS, Université de Toulouse, CNRS, 31400 Toulouse, France; (J.F.); (L.M.)
| | - Audrey Ferrand
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, 31024 Toulouse, France;
- Correspondence: (L.O.-R.); (A.F.); Tel.: +33-5-62-744-522 (A.F.)
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13
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Solà-Tapias N, Vergnolle N, Denadai-Souza A, Barreau F. The Interplay Between Genetic Risk Factors and Proteolytic Dysregulation in the Pathophysiology of Inflammatory Bowel Disease. J Crohns Colitis 2020; 14:1149-1161. [PMID: 32090263 DOI: 10.1093/ecco-jcc/jjaa033] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Crohn's disease [CD] and ulcerative colitis [UC] are the two main forms of inflammatory bowel disease [IBD]. Previous studies reported increased levels of proteolytic activity in stool and tissue samples from IBD patients, whereas the re-establishment of the proteolytic balance abrogates the development of experimental colitis. Furthermore, recent data suggest that IBD occurs in genetically predisposed individuals who develop an abnormal immune response to intestinal microbes once exposed to environmental triggers. In this review, we highlight the role of proteases in IBD pathophysiology, and we showcase how the main cellular pathways associated with IBD influence proteolytic unbalance and how functional proteomics are allowing the unambiguous identification of dysregulated proteases in IBD, paving the way to the development of new protease inhibitors as a new potential treatment.
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Affiliation(s)
- Núria Solà-Tapias
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France
| | - Nathalie Vergnolle
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France.,Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada
| | - Alexandre Denadai-Souza
- Department of Chronic Diseases, Metabolism and Ageing, University of Leuven, Leuven, Belgium
| | - Frédérick Barreau
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France
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14
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Aguirre JE, Beswick EJ, Grim C, Uribe G, Tafoya M, Chacon Palma G, Samedi V, McKee R, Villeger R, Fofanov Y, Cong Y, Yochum G, Koltun W, Powell D, Pinchuk IV. Matrix metalloproteinases cleave membrane-bound PD-L1 on CD90+ (myo-)fibroblasts in Crohn's disease and regulate Th1/Th17 cell responses. Int Immunol 2020; 32:57-68. [PMID: 31633754 DOI: 10.1093/intimm/dxz060] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 09/30/2019] [Indexed: 01/01/2023] Open
Abstract
Increased T helper (Th)1/Th17 immune responses are a hallmark of Crohn's disease (CD) immunopathogenesis. CD90+ (myo-)fibroblasts (MFs) are abundant cells in the normal (N) intestinal mucosa contributing to mucosal tolerance via suppression of Th1 cell activity through cell surface membrane-bound PD-L1 (mPD-L1). CD-MFs have a decreased level of mPD-L1. Consequently, mPD-L1-mediated suppression of Th1 cells by CD-MFs is decreased, yet the mechanism responsible for the reduction in mPDL-1 is unknown. Increased expression of matrix metalloproteinases (MMPs) has been reported in CD. Herein we observed that when compared to N- and ulcerative colitis (UC)-MFs, CD-MFs increase in LPS-inducible levels of MMP-7 and -9 with a significant increase in both basal and inducible MMP-10. A similar pattern of MMP expression was observed in the CD-inflamed mucosa. Treatment of N-MFs with a combination of recombinant human MMP-7, -9 and -10 significantly decreased mPD-L1. In contrast, inhibition of MMP activity with MMP inhibitors or anti-MMP-10 neutralizing antibodies restores mPD-L1 on CD-MFs. CD-MFs demonstrated reduced capacity to suppress Th1 and Th17 responses from activated CD4+ T cells. By contrast, supplementation of the CD-MF:T-cell co-cultures with MMP inhibitors or anti-MMP neutralizing antibodies restored the CD-MF-mediated suppression. Our data suggest that (i) increased MMP-10 expression by CD-MFs and concomitant cleavage of PD-L1 from the surface of CD-MFs are likely to be one of the factors contributing to the decrease of mPD-L1-mediated suppression of Th1/Th17 cells in CD; and (ii) MMPs are likely to have a significant role in the intestinal mucosal immune responses.
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Affiliation(s)
- Jose E Aguirre
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, USA.,Institute of Translational Science, University of Texas Medical Branch, Galveston, TX, USA
| | - Ellen J Beswick
- Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Carl Grim
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, USA
| | - Gabriela Uribe
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, USA.,Department of Medicine at PennState Health Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Marissa Tafoya
- Department of Pathology, University of New Mexico, Albuquerque, NM, USA
| | | | - Von Samedi
- School of Medicine, University of New Mexico, Albuquerque, NM, USA
| | - Rohini McKee
- Department of Surgery at the University of New Mexico, Albuquerque, NM, USA
| | - Romain Villeger
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, USA
| | - Yuriy Fofanov
- Department of Pharmacology & Toxicology, University of Texas Medical Branch, Galveston, TX, USA
| | - Yingzi Cong
- Microbiology and Immunology at the University of Texas Medical Branch, Galveston, TX, USA
| | - Gregory Yochum
- Department of Biochemistry and Molecular Biology, PennState Health Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Walter Koltun
- Department of Colorectal Surgery at PennState Health Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Don Powell
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, USA.,Institute of Translational Science, University of Texas Medical Branch, Galveston, TX, USA
| | - Irina V Pinchuk
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, USA.,Institute of Translational Science, University of Texas Medical Branch, Galveston, TX, USA.,Department of Medicine at PennState Health Milton S. Hershey Medical Center, Hershey, PA, USA.,Microbiology and Immunology at the University of Texas Medical Branch, Galveston, TX, USA
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15
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Wang N, Zhou S, Fang XC, Gao P, Qiao Q, Wu T, He XL. MMP-2, -3 and TIMP-2, -3 polymorphisms in colorectal cancer in a Chinese Han population: A case-control study. Gene 2020; 730:144320. [DOI: 10.1016/j.gene.2019.144320] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 12/21/2019] [Accepted: 12/21/2019] [Indexed: 12/11/2022]
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16
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Mortensen JH, Lindholm M, Langholm LL, Kjeldsen J, Bay-Jensen AC, Karsdal MA, Manon-Jensen T. The intestinal tissue homeostasis - the role of extracellular matrix remodeling in inflammatory bowel disease. Expert Rev Gastroenterol Hepatol 2019; 13:977-993. [PMID: 31587588 DOI: 10.1080/17474124.2019.1673729] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Introduction: Extracellular matrix (ECM) remodeling of the intestinal tissue is important in inflammatory bowel disease (IBD) due to the extensive mucosal remodeling. There are still gaps in our knowledge as to how ECM remodeling is related to intestinal epithelium homeostasis and healing of the intestinal mucosa.Areas covered: The aim of this review is to highlight the importance of the ECM in relation to the pathogenesis of IBD, while addressing basement membrane and interstitial matrix remodeling, and the processes of wound healing of the intestinal tissue in IBD.Expert opinion: In IBD, basement membrane remodeling may reflect the integrity of the intestinal epithelial-cell homeostasis. The interstitial matrix remodeling is associated with deep inflammation such as the transmural inflammation as seen in fistulas and intestinal fibrosis leading to fibrostenotic strictures, in patients with CD. The interplay between wound healing processes and ECM remodeling also affects the tissue homeostasis in IBD. The interstitial matrix, produced by fibroblasts, holds a very different biology as compared to the epithelial basement membrane in IBD. In combination with integration of wound healing, quantifying the interplay between damage and repair to these sub compartments may provide essential information in IBD patient profiling, mucosal healing and disease management.
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Affiliation(s)
- J H Mortensen
- Nordic Bioscience A/S, Biomarkers & Research, Herlev, Denmark
| | - M Lindholm
- Nordic Bioscience A/S, Biomarkers & Research, Herlev, Denmark.,Department of Medical Gastroenterology, Odense University hospital, Odense, Denmark
| | - L L Langholm
- Nordic Bioscience A/S, Biomarkers & Research, Herlev, Denmark
| | - J Kjeldsen
- Department of Medical Gastroenterology, Odense University hospital, Odense, Denmark
| | - A C Bay-Jensen
- Nordic Bioscience A/S, Biomarkers & Research, Herlev, Denmark
| | - M A Karsdal
- Nordic Bioscience A/S, Biomarkers & Research, Herlev, Denmark
| | - T Manon-Jensen
- Nordic Bioscience A/S, Biomarkers & Research, Herlev, Denmark
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17
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Drankowska J, Kos M, Kościuk A, Marzęda P, Boguszewska-Czubara A, Tylus M, Święch-Zubilewicz A. MMP targeting in the battle for vision: Recent developments and future prospects in the treatment of diabetic retinopathy. Life Sci 2019; 229:149-156. [PMID: 31100326 DOI: 10.1016/j.lfs.2019.05.038] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Revised: 05/08/2019] [Accepted: 05/13/2019] [Indexed: 12/15/2022]
Abstract
Matrix metalloproteinases (MMPs) are enzymes capable of degrading nearly all types of extracellular matrix. They perform a wide range of roles in physiological processes, which is the reason for their strict regulation by numerous mechanisms including natural tissue inhibitors of metalloproteinases (TIMP). Research only started to shed light on more troublesome aspects of MMPs function, like cancer progression, Alzheimer's disease, atherosclerosis, ageing. Moreover, their profound role in diabetes is being carefully investigated including one of its most debilitating complications - diabetic retinopathy (DR), the leading cause of acquired blindness worldwide. Traditional treatment of this condition seems to be only mildly satisfactory, which elicited substantial interest in the field of new therapeutic methods including MMP targeting. So far, significant roles of MMP-2 and MMP-9 in the development of retinopathy have been established, with special attention given to the process of blood-retinal barrier impairment. Further exploration revealed MMP-10 and MMP-14 involvement as well as changes in MMP/TIMP ratio. In this review, we provide insight into MMPs role in diabetic retinopathy with a clarification of various mechanisms regulating MMP activity in the light of the recent studies. We conclude with an overview of novel DR therapies targeting MMPs and point to the need of further examination of their usefulness in clinical setting, with an eye towards future research.
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Affiliation(s)
- Justyna Drankowska
- Department of Medical Chemistry, Medical University of Lublin, Chodźki 4a, PL 20-093 Lublin, Poland.
| | - Michał Kos
- Department of Medical Chemistry, Medical University of Lublin, Chodźki 4a, PL 20-093 Lublin, Poland.
| | - Andrzej Kościuk
- Department of Medical Chemistry, Medical University of Lublin, Chodźki 4a, PL 20-093 Lublin, Poland
| | - Paweł Marzęda
- Department of Medical Chemistry, Medical University of Lublin, Chodźki 4a, PL 20-093 Lublin, Poland
| | - Anna Boguszewska-Czubara
- Department of Medical Chemistry, Medical University of Lublin, Chodźki 4a, PL 20-093 Lublin, Poland
| | - Magdalena Tylus
- Department of Retinal and Vitreal Surgery, Medical University of Lublin, Chmielna 1, PL 20-079 Lublin, Poland
| | - Anna Święch-Zubilewicz
- Department of Retinal and Vitreal Surgery, Medical University of Lublin, Chmielna 1, PL 20-079 Lublin, Poland
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18
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Strong association of tissue inhibitor of metalloproteinase (TIMP)-2 and -3 promoter single nucleotide polymorphisms with risk of colorectal cancer in ethnic Kashmiri population - a case control study. Biosci Rep 2019; 39:BSR20190478. [PMID: 30988064 PMCID: PMC6509169 DOI: 10.1042/bsr20190478] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 04/02/2019] [Accepted: 04/08/2019] [Indexed: 12/28/2022] Open
Abstract
Background: The tissue inhibitors of metalloproteinases (TIMPs) including TIMP2 and TIMP3 are the key physiological inhibitors of matrix metalloproteinases (MMPs) and along with MMPs, TIMPs play a vital role in the coordinated proteolytic breakdown and remodeling of the extracellular matrix (ECM) and the basement membrane that represent the barriers to any malignant tumor invasion and progression. These enzymes are vital for tumor invasion and metastasis and also play a critical role in several other stages of tumor development and progression. The studies on the association of various polymorphisms in human TIMP2 and TIMP3 genes including TIMP2-418G/C and TIMP3-1296T/C single nucleotide polymorphisms (SNPs) and CRC risk are limited, mixed, and inconclusive.Materials and methods: The aim of the present study was to analyze the association of TIMP2-418G/C and TIMP3-1296T/C promoter SNPs with colorectal cancer (CRC) susceptibility and development risk and also to evaluate the modifying effects of possible TIMP2-418G/C and TIMP3-1296T/C SNPs' genotypes on different risk factors of CRC or the reciprocal effect in ethnic population of Kashmir, India through a case-control setup. The genotype frequencies of TIMP2-418G/C and TIMP3-1296T/C promoter SNPs were compared between 142 CRC patients and 184 individually matched healthy controls by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The associations between the TIMP2-418G/C and TIMP3-1296T/C SNPs and CRC risk were examined through conditional logistic regression models adjusted for multiple possible confounding (third) variables. The possible effect measure modification of the association between the relevant SNP genotypes and CRC risk by various CRC risk factors including age, gender, and smoking status was also analyzed. Further, the associations between these SNPs and various clinico-pathological parameters, demographic variables, and environmental factors within the case group subjects with regard to CRC risk were also evaluated.Results: The overall association between the TIMP2-418G/C and TIMP3-1296T/C SNPs and the modulation of CRC risk was found to be highly significant (P=0.019 and P=0.000 for TIMP2 and TIMP3 SNPs, respectively). The heterozygous genotype (GC) of TIMP2-418G/C was significantly associated with an increased risk of colorectal cancer [OR, 1.87 (95%CI, 1.07-3.27); P=0.027] whereas the heterozygous genotype (TC) of TIMP3-1296T/C SNP was significantly associated with a decreased risk of colorectal cancer [OR, 0.53 (95%CI, 0.32-0.86); P=0.011]. The variant genotype (CC) of TIMP3-1296T/C SNP was also significantly associated with a decreased risk of colorectal cancer [OR, 0.18 (95%CI, 0.05-0.65); P=0.009].Conclusion: The present study demonstrates that there is a strong and highly significant association between the TIMP2-418G/C and TIMP3-1296T/C promoter SNPs and the risk of developing CRC in ethnic Kashmiri population. However, in order to substantiate our findings, the present study needs to be replicated with bigger sample size and should involve other ethnically defined populations with high CRC risk.
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19
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Differential Intestinal Mucosa Transcriptomic Biomarkers for Crohn's Disease and Ulcerative Colitis. J Immunol Res 2018; 2018:9208274. [PMID: 30417021 PMCID: PMC6207860 DOI: 10.1155/2018/9208274] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Accepted: 09/04/2018] [Indexed: 02/07/2023] Open
Abstract
Genetic research has shaped the inflammatory bowel disease (IBD) landscape identifying nearly two hundred risk loci. Nonetheless, the identified variants rendered only a partial success in providing criteria for the differential diagnosis between ulcerative colitis (UC) and Crohn's disease (CD). Transcript levels from affected intestinal mucosa may serve as tentative biomarkers for improving classification and diagnosis of IBD. The aim of our study was to identify gene expression profiles specific for UC and CD, in endoscopically affected and normal intestinal colonic mucosa from IBD patients. We evaluated a panel of 84 genes related to the IBD-inflammatory pathway on 21 UC and 22 CD paired inflamed and not inflamed mucosa and on age-matched normal mucosa from 21 non-IBD controls. Two genes in UC (CCL11 and MMP10) and two in CD (C4BPB and IL1RN) showed an upregulation trend in both noninflamed and inflamed mucosa compared to controls. Our results suggest that the transcript levels of CCL11, MMP10, C4BPB, and IL1RN are candidate biomarkers that could help in clinical practice for the differential diagnosis between UC and CD and could guide new research on future therapeutic targets.
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20
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Carbone F, Bodini G, Brunacci M, Bonaventura A, Vecchiè A, Liberale L, Crespi M, Baldissarro I, Dallegri F, Savarino V, Montecucco F, Giannini EG. Reduction in TIMP-2 serum levels predicts remission of inflammatory bowel diseases. Eur J Clin Invest 2018; 48:e13002. [PMID: 30011062 DOI: 10.1111/eci.13002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Accepted: 07/15/2018] [Indexed: 12/22/2022]
Abstract
BACKGROUND Growing evidence indicates tissue inhibitors of matrix metalloproteinases (TIMPs) as potential players in inflammatory bowel disease (IBD), but, no prospective data are available in IBD remission/relapse. MATERIAL & METHODS In this prospective pilot study, a cohort of IBD patients (n = 32) was enrolled and treated with monoclonal anti-TNF-α antibodies. Patients were clinically followed up for a median period of 54 weeks. Serum circulating levels of C-reactive protein (CRP), TIMP-1 and -2, matrix metalloproteinase (MMP)-9 and -8, myeloperoxidase (MPO) and neutrophil elastase (NE) were assessed by ELISA at enrolment and at the end of the treatment. RESULTS The percentage (%) TIMP-2 reduction from baseline to end of treatment was independently associated with IBD remission at the end of treatment and follow-up as well. ROC curve analysis further confirmed the good prognostic accuracy of % TIMP-2 reduction over the treatment period. Conversely, no other change in inflammatory molecule concentrations was able to predict short- or long-term IBD remission. CONCLUSIONS This study indicates TIMP-2 reduction during IBD treatment with monoclonal anti-TNF-α antibodies as a potential prognostic parameter of short and long term remission. To understand if TIMP-2 is an innocent biomarker or an active pathophysiological factor in IBD remains to be clarified.
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Affiliation(s)
- Federico Carbone
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
| | - Giorgia Bodini
- Division of Gastroenterology Department of Internal Medicine, University of Genoa, Genoa, Italy
| | - Matteo Brunacci
- Division of Gastroenterology Department of Internal Medicine, University of Genoa, Genoa, Italy
| | - Aldo Bonaventura
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
| | - Alessandra Vecchiè
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
| | - Luca Liberale
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
- Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland
| | - Mattia Crespi
- Division of Gastroenterology Department of Internal Medicine, University of Genoa, Genoa, Italy
| | - Isabella Baldissarro
- Division of Gastroenterology Department of Internal Medicine, University of Genoa, Genoa, Italy
| | - Franco Dallegri
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
- Ospedale Policlinico San Martino, Genoa, Italy
| | - Vincenzo Savarino
- Division of Gastroenterology Department of Internal Medicine, University of Genoa, Genoa, Italy
- Ospedale Policlinico San Martino, Genoa, Italy
| | - Fabrizio Montecucco
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
- Ospedale Policlinico San Martino, Genoa, Italy
- Centre of Excellence for Biomedical Research (CEBR), University of Genoa, Genoa, Italy
| | - Edoardo G Giannini
- Division of Gastroenterology Department of Internal Medicine, University of Genoa, Genoa, Italy
- Ospedale Policlinico San Martino, Genoa, Italy
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21
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Hanifeh M, Rajamäki MM, Syrjä P, Mäkitalo L, Kilpinen S, Spillmann T. Identification of matrix metalloproteinase-2 and -9 activities within the intestinal mucosa of dogs with chronic enteropathies. Acta Vet Scand 2018. [PMID: 29530095 PMCID: PMC5848456 DOI: 10.1186/s13028-018-0371-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Matrix metalloproteinases (MMPs) 2 and 9 are zinc- and calcium-dependent endopeptidases involved in the breakdown and reconstitution of extracellular matrix under both physiological and pathological conditions. Mucosal MMP-2 and -9 activities have been reported to be upregulated in the intestine of humans with inflammatory bowel disease (IBD), and in animal models of IBD. However, their involvement in the pathogenesis of canine chronic enteropathies (CE) is unknown. This study investigated mucosal pro- and active MMP-2 and -9 activities in dogs with CE and healthy dogs using gelatin zymography, and also to determine the association of their activities in dogs with CE with the canine IBD activity index (CIBDAI), histopathologic findings, the clinical outcome, and hypoalbuminemia. Intestinal mucosal samples from duodenum, ileum, colon, and cecum were collected from 40 dogs with CE and 18 healthy Beagle dogs. RESULTS In dogs with CE, the number of samples positive for mucosal pro- and active MMP-2 was significantly higher in the duodenum (P < 0.0001 and P = 0.011, respectively), ileum (P = 0.002 and P = 0.018, respectively), and colon (P < 0.0001 and P = 0.002, respectively), compared with healthy controls. Mucosal pro-MMP-9-positive samples in the duodenum and colon were significantly more frequent in dogs with CE than in healthy dogs (P = 0.0004 and P = 0.001, respectively). Despite the presence of mucosal samples positive for active MMP-9 in the intestinal segments of dogs with CE, the difference compared to healthy controls did not reach statistical significance. None of the intestinal mucosal samples in healthy dogs showed gelatinolytic activity corresponding to the control bands of active MMP-2 and -9. Mucosal active MMP-9 activities displayed a significant positive association with the severity of neutrophil infiltration in the duodenum (P = 00.040), eosinophils in the cecum (P = 00.037), and the CIBDAI score for ileum samples (P = 0.023). There was no significant association of pro- and active MMP-2 and -9 levels with the clinical outcome or hypoalbuminemia. CONCLUSIONS This study is the first to demonstrate upregulation of mucosal pro- and active MMP-2 and pro-MMP-9 in the intestine of dogs with CE compared to healthy dogs. The results provide supporting evidence for the possible involvement of MMP-2 and -9 in the pathogenesis of canine CE.
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22
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Van Spaendonk H, Ceuleers H, Witters L, Patteet E, Joossens J, Augustyns K, Lambeir AM, De Meester I, De Man JG, De Winter BY. Regulation of intestinal permeability: The role of proteases. World J Gastroenterol 2017; 23:2106-2123. [PMID: 28405139 PMCID: PMC5374123 DOI: 10.3748/wjg.v23.i12.2106] [Citation(s) in RCA: 130] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Revised: 01/20/2017] [Accepted: 03/02/2017] [Indexed: 02/06/2023] Open
Abstract
The gastrointestinal barrier is - with approximately 400 m2 - the human body's largest surface separating the external environment from the internal milieu. This barrier serves a dual function: permitting the absorption of nutrients, water and electrolytes on the one hand, while limiting host contact with noxious luminal antigens on the other hand. To maintain this selective barrier, junction protein complexes seal the intercellular space between adjacent epithelial cells and regulate the paracellular transport. Increased intestinal permeability is associated with and suggested as a player in the pathophysiology of various gastrointestinal and extra-intestinal diseases such as inflammatory bowel disease, celiac disease and type 1 diabetes. The gastrointestinal tract is exposed to high levels of endogenous and exogenous proteases, both in the lumen and in the mucosa. There is increasing evidence to suggest that a dysregulation of the protease/antiprotease balance in the gut contributes to epithelial damage and increased permeability. Excessive proteolysis leads to direct cleavage of intercellular junction proteins, or to opening of the junction proteins via activation of protease activated receptors. In addition, proteases regulate the activity and availability of cytokines and growth factors, which are also known modulators of intestinal permeability. This review aims at outlining the mechanisms by which proteases alter the intestinal permeability. More knowledge on the role of proteases in mucosal homeostasis and gastrointestinal barrier function will definitely contribute to the identification of new therapeutic targets for permeability-related diseases.
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23
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Breynaert C, de Bruyn M, Arijs I, Cremer J, Martens E, Van Lommel L, Geboes K, De Hertogh G, Schuit F, Ferrante M, Vermeire S, Ceuppens J, Opdenakker G, Van Assche G. Genetic Deletion of Tissue Inhibitor of Metalloproteinase-1/TIMP-1 Alters Inflammation and Attenuates Fibrosis in Dextran Sodium Sulphate-induced Murine Models of Colitis. J Crohns Colitis 2016; 10:1336-1350. [PMID: 27194531 DOI: 10.1093/ecco-jcc/jjw101] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2015] [Accepted: 04/28/2016] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Increased levels of tissue inhibitor of metalloproteinase-1 [TIMP-1] have been detected in both inflammatory and fibrotic lesions in Crohn's disease. In a murine model of chronic inflammation, fibrosis was associated with an increase in TIMP-1 and inhibition of matrix metalloproteinase [MMP]-mediated degradation. We investigated the effect of TIMP-1 deficiency in acute and chronic murine models of colitis. METHODS Colitis was induced via oral administration of dextran sodium sulphate [DSS] to B6.129S4-Timp1tm1Pds/J knock-out [KO] and C57BL/6J wild-type [WT] mice. Levels of inflammation and fibrosis were assessed and gelatin zymographies and gene expression microarrays were performed. RESULTS Compared with WT mice, TIMP-1 KO mice had higher inflammatory parameters after acute DSS administration and developed less fibrosis after chronic DSS administration. MMP-2 levels were increased in WT versus TIMP-1 KO mice with acute colitis, whereas a trend for higher proMMP-9 levels was observed in WT versus TIMP-1 KO mice with chronic colitis. In control conditions, several immune-related genes [e.g Ido1, Cldn8] were differentially expressed between young TIMP-1 KO and WT mice, but to a lesser extent between older TIMP-1 KO and WT mice. In response to DSS, the gene expression pattern was significantly different between young TIMP-1 KO and WT mice, whereas it was similar in older TIMP-1 KO and WT mice. CONCLUSIONS TIMP-1 deficiency leads to differential expression of immune-related genes and to attenuated development of fibrosis. Unravelling the role of TIMP-1 in intestinal remodelling is necessary to develop more effective and more targeted therapeutic strategies for intestinal fibrosis.
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Affiliation(s)
- Christine Breynaert
- Translational Research Center for Gastrointestinal Disorders [TARGID], Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.,Laboratory of Clinical Immunology, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium
| | - Magali de Bruyn
- Translational Research Center for Gastrointestinal Disorders [TARGID], Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.,Laboratory of Immunobiology, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
| | - Ingrid Arijs
- Translational Research Center for Gastrointestinal Disorders [TARGID], Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.,Faculty of Medicine and Life Sciences, Hasselt University, Hasselt, Belgium
| | - Jonathan Cremer
- Translational Research Center for Gastrointestinal Disorders [TARGID], Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.,Laboratory of Clinical Immunology, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium
| | - Erik Martens
- Laboratory of Immunobiology, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
| | - Leentje Van Lommel
- Gene Expression Unit, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
| | - Karel Geboes
- Translational Cell and Tissue Research, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium
| | - Gert De Hertogh
- Translational Cell and Tissue Research, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium
| | - Frans Schuit
- Gene Expression Unit, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
| | - Marc Ferrante
- Translational Research Center for Gastrointestinal Disorders [TARGID], Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.,University Hospitals Leuven, Department of Gastroenterology and Hepatology, KU Leuven, Leuven, Belgium
| | - Séverine Vermeire
- Translational Research Center for Gastrointestinal Disorders [TARGID], Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.,University Hospitals Leuven, Department of Gastroenterology and Hepatology, KU Leuven, Leuven, Belgium
| | - Jan Ceuppens
- Laboratory of Clinical Immunology, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium
| | - Ghislain Opdenakker
- Laboratory of Immunobiology, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
| | - Gert Van Assche
- Translational Research Center for Gastrointestinal Disorders [TARGID], Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium .,University Hospitals Leuven, Department of Gastroenterology and Hepatology, KU Leuven, Leuven, Belgium
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Abstract
To date, we encounter more and more pediatric patients with ulcerative colitis (UC). For yet unclear reasons, UC in pediatric patients seems to be a more aggressive and extensive disease than in their adult counterparts. In the majority of pediatric patients, the disease presents as pancolitis. The severity of the disease is reflected in the high use of corticosteroids and immunosuppressants and a high rate of surgery for medically refractory patients. The means by which to assess disease activity or to accurately predict its course are far from optimal. This review summarizes the current knowledge on the means for assessing UC activity in children. Research for developing new tools by which to monitor and forecast disease activity, are needed in all areas including invasive endoscopy, clinical evaluation, and treatment follow-up.
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Affiliation(s)
- Kaija-Leena Kolho
- a Children's Hospital , Helsinki University Central Hospital, University of Helsinki , Helsinki , Finland
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25
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de Bruyn M, Vandooren J, Ugarte-Berzal E, Arijs I, Vermeire S, Opdenakker G. The molecular biology of matrix metalloproteinases and tissue inhibitors of metalloproteinases in inflammatory bowel diseases. Crit Rev Biochem Mol Biol 2016; 51:295-358. [PMID: 27362691 DOI: 10.1080/10409238.2016.1199535] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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26
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Expressions of Matrix Metalloproteinases (MMP-2, MMP-7, and MMP-9) and Their Inhibitors (TIMP-1, TIMP-2) in Inflammatory Bowel Diseases. Gastroenterol Res Pract 2016; 2016:2456179. [PMID: 27034654 PMCID: PMC4789560 DOI: 10.1155/2016/2456179] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2015] [Revised: 12/21/2015] [Accepted: 01/27/2016] [Indexed: 12/30/2022] Open
Abstract
Crohn's disease (CD) and ulcerative colitis (UC) belong to a group of inflammatory bowel diseases (IBD). The aim of our study was to evaluate the expression of MMP-2, MMP-7, MMP-9, TIMP-1, and TIMP-2 in ulcerative colitis and Crohn's disease. The study group comprised 34 patients with UC and 10 patients with CD. Evaluation of MMP-2, MMP-7, MMP-9, TIMP-1, and TIMP-2 expression in tissue samples was performed using immunohistochemistry. The overexpression of MMP-9 and TIMP-1 was dominant in both the glandular epithelium and inflammatory infiltration in UC patients. In contrast, in CD subjects the positive expression of MMP-2 and TIMP-1 was in glandular tubes while mainly MMP-7 and TIMP-2 expression was in inflammatory infiltration. Metalloproteinases' expression was associated with the presence of erosions, architectural tissue changes, and inflammatory infiltration in the lamina propria of UC patients. The expression of metalloproteinase inhibitors correlated with the presence of eosinophils and neutrophils in UC and granulomas in CD patients. Our studies indicate that the overexpression of metalloproteinases and weaker expression of their inhibitors may determine the development of IBD. It appears that MMP-2, MMP-7, and MMP-9 may be a potential therapeutic target and the use of their inhibitors may significantly reduce UC progression.
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27
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Kawamura Y, Gotoh K, Takeuchi N, Miura H, Nishimura N, Ozaki T, Yoshikawa T. Role of matrix metalloproteinases in the pathogenesis of childhood gastroenteritis. J Med Virol 2016; 88:1341-6. [PMID: 26765397 DOI: 10.1002/jmv.24473] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/10/2016] [Indexed: 11/11/2022]
Abstract
Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) have been implicated in the pathogenesis of gastrointestinal diseases, such as rotavirus gastroenteritis (GE). Kinetics of these biomarkers were examined in paired serum samples collected from bacterial enteritis patients with Campylobacter (n = 2) and Salmonella (n = 4) and viral GE patients with rotavirus (n = 27), norovirus (n = 25), and adenovirus (n = 11). At the time of hospital admission, all viral GE patients demonstrated increased MMP-9 and decreased MMP-2 and TIMP-2 serum levels. In contrast to viral GE patients, serum MMP-9 levels were not elevated at the time of hospital admission but elevated at the time of discharge; serum MMP-2 and TIMP-2 levels were decreased both at the time of admission and discharge in bacterial enteritis patients. Interestingly, the kinetics of serum MMP-2, MMP-9, and TIMP-2 levels were similar among the viral GE patients but distinct from bacterial enteritis patients. Thus, the involvement of MMPs and TIMPs in the pathophysiology of gastrointestinal symptoms likely varies depending on the etiological agent. Further studies are required to verify whether the extent of the bacterial enteritis or age of the patients influences these serum biomarkers. J. Med. Virol. 88:1341-1346, 2016. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Yoshiki Kawamura
- Department of Pediatrics, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
| | - Kensei Gotoh
- Department of Pediatrics, Konan Kosei Hospital, Konan, Aichi, Japan
| | - Nao Takeuchi
- Department of Pediatrics, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
| | - Hiroki Miura
- Department of Pediatrics, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
| | - Naoko Nishimura
- Department of Pediatrics, Konan Kosei Hospital, Konan, Aichi, Japan
| | - Takao Ozaki
- Department of Pediatrics, Konan Kosei Hospital, Konan, Aichi, Japan
| | - Tetsushi Yoshikawa
- Department of Pediatrics, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
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28
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Quetglas EG, Mujagic Z, Wigge S, Keszthelyi D, Wachten S, Masclee A, Reinisch W. Update on pathogenesis and predictors of response of therapeutic strategies used in inflammatory bowel disease. World J Gastroenterol 2015; 21:12519-12543. [PMID: 26640330 PMCID: PMC4658608 DOI: 10.3748/wjg.v21.i44.12519] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Accepted: 09/14/2015] [Indexed: 02/06/2023] Open
Abstract
The search for biomarkers that characterize specific aspects of inflammatory bowel disease (IBD), has received substantial interest in the past years and is moving forward rapidly with the help of modern technologies. Nevertheless, there is a direct demand to identify adequate biomarkers for predicting and evaluating therapeutic response to different therapies. In this subset, pharmacogenetics deserves more attention as part of the endeavor to provide personalized medicine. The ultimate goal in this area is the adjustment of medication for a patient’s specific genetic background and thereby to improve drug efficacy and safety rates. The aim of the following review is to utilize the latest knowledge on immunopathogenesis of IBD and update the findings on the field of Immunology and Genetics, to evaluate the response to the different therapies. In the present article, more than 400 publications were reviewed but finally 287 included based on design, reproducibility (or expectancy to be reproducible and translationable into humans) or already measured in humans. A few tests have shown clinical applicability. Other, i.e., genetic associations for the different therapies in IBD have not yet shown consistent or robust results. In the close future it is anticipated that this, cellular and genetic material, as well as the determination of biomarkers will be implemented in an integrated molecular diagnostic and prognostic approach to manage IBD patients.
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29
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Matrix metalloproteinases in inflammatory bowel disease: an update. Mediators Inflamm 2015; 2015:964131. [PMID: 25948887 PMCID: PMC4408746 DOI: 10.1155/2015/964131] [Citation(s) in RCA: 98] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2014] [Accepted: 09/07/2014] [Indexed: 02/07/2023] Open
Abstract
Matrix metalloproteinases (MMPs) are known to be upregulated in inflammatory bowel disease (IBD) and other inflammatory conditions, but while their involvement is clear, their role in many settings has yet to be determined. Studies of the involvement of MMPs in IBD since 2006 have revealed an array of immune and stromal cells which release the proteases in response to inflammatory cytokines and growth factors. Through digestion of the extracellular matrix and cleavage of bioactive proteins, a huge diversity of roles have been revealed for the MMPs in IBD, where they have been shown to regulate epithelial barrier function, immune response, angiogenesis, fibrosis, and wound healing. For this reason, MMPs have been recognised as potential biomarkers for disease activity in IBD and inhibition remains a huge area of interest. This review describes new roles of MMPs in the pathophysiology of IBD and suggests future directions for the development of treatment strategies in this condition.
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30
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Role of MMP-2 and MMP-9 and their natural inhibitors in liver fibrosis, chronic pancreatitis and non-specific inflammatory bowel diseases. Hepatobiliary Pancreat Dis Int 2014; 13:570-9. [PMID: 25475858 DOI: 10.1016/s1499-3872(14)60261-7] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND There is a growing evidence that matrix metalloproteinase (MMP)-2 and MMP-9 (gelatinases) play an important role in the pathogenesis of numerous disorders, especially with inflammatory etiology and extracellular matrix (ECM) remodeling. Despite the fact that gelatinases involve in liver cirrhosis is provided in the literature, their role in the pathogenesis of chronic pancreatitis and non-specific inflammatory bowel diseases is still under investigation. DATA SOURCES We carried out a PubMed search of English-language articles relevant to the involvement of gelatinases in the pathogenesis of liver fibrosis, pancreatitis, and non-specific inflammatory bowel diseases. RESULTS The decreased activity of gelatinases, especially MMP-2, is related to the development of liver fibrosis, probably due to the decrease of capability for ECM remodeling. Similar situation can be found in chronic pancreatitis; however, reports on this matter are rare. The presence of non-specific inflammatory bowel diseases results in MMP-9 activity elevation. CONCLUSION The fluctuation of gelatinases activity during liver fibrosis, chronic pancreatitis and non-specific inflammatory bowel diseases is observed, but the exact role of these enzymes demands further studies.
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31
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Gene expression profiling of Lucilia sericata larvae extraction/secretion-treated skin wounds. Gene 2014; 550:223-9. [DOI: 10.1016/j.gene.2014.08.033] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2014] [Revised: 08/05/2014] [Accepted: 08/17/2014] [Indexed: 12/13/2022]
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32
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HANIFEH M, RAJAMÄKI MM, MÄKITALO L, SYRJÄ P, SANKARI S, KILPINEN S, SPILLMANN T. Identification of matrix metalloproteinase-2 and -9 activities within intestinal mucosa of clinically healthy beagle dogs. J Vet Med Sci 2014; 76:1079-85. [PMID: 24748420 PMCID: PMC4155186 DOI: 10.1292/jvms.13-0578] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2013] [Accepted: 04/01/2014] [Indexed: 01/20/2023] Open
Abstract
Matrix metalloproteinases (MMPs) 2 and 9 are zinc-dependent endopeptidases that contribute to the control of breakdown and reconstitution of extracellular matrix under both normal and pathological conditions. The main objective of this study was to identify the presence of MMP-2 and -9 in the mucosa of the small and large intestines of clinically healthy beagle dogs using gelatin zymography technique. Intestinal mucosa samples from four different parts of the intestine (duodenum, jejunum, ileum and colon) were taken from 12 healthy laboratory beagle dogs and examined histologically. Based on WSAVA histology standards, recorded findings of all samples were considered insignificant. Pro-MMP-2 and -9 activities were found in 17/48 (35%) and 25/48 (52%) of the samples, respectively. Among four different parts of the intestine of 12 dogs, the ileum had the highest positivity rates of 7/12 (58.3%) and 8/12 (66.7%) for pro-MMP-2 and -9 activities, respectively. However, statistical analysis showed no significant difference of pro-MMP-2 and -9 activities between the separate parts of the intestine (P>0.05). None of the intestinal samples showed gelatinolytic activity corresponding to the control bands of active MMP-2 and MMP-9. This study showed that pro-MMP-2 and -9 could be detected in the intestinal mucosa of healthy dogs using zymography, which seems to be a useful tool to evaluate the role of MMP-2 and -9 in the pathogenesis of canine chronic enteropathies, including inflammatory bowel diseases.
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Affiliation(s)
- Mohsen HANIFEH
- Department of Equine and Small Animal Medicine, Faculty of
Veterinary Medicine, University of Helsinki, P.O. Box 57 (Viikintie 49), 00014 Helsinki,
Finland
- Department of Clinical Sciences, Faculty of Veterinary
Medicine, University of Tabriz, Postal Code 5166616471, Tabriz, Iran
| | - Minna M RAJAMÄKI
- Department of Equine and Small Animal Medicine, Faculty of
Veterinary Medicine, University of Helsinki, P.O. Box 57 (Viikintie 49), 00014 Helsinki,
Finland
| | - Laura MÄKITALO
- Children’s Hospital, Helsinki University Central Hospital
and University of Helsinki, P.O. Box 63 (Haartmaninkatu 8), 00014 Helsinki, Finland
| | - Pernilla SYRJÄ
- Department of Veterinary Biosciences, Faculty of Veterinary
Medicine, University of Helsinki, P.O. Box 66 (Agnes Sjöbergin katu 2), 00014 Helsinki,
Finland
| | - Satu SANKARI
- Department of Equine and Small Animal Medicine, Faculty of
Veterinary Medicine, University of Helsinki, P.O. Box 57 (Viikintie 49), 00014 Helsinki,
Finland
| | - Susanne KILPINEN
- Department of Equine and Small Animal Medicine, Faculty of
Veterinary Medicine, University of Helsinki, P.O. Box 57 (Viikintie 49), 00014 Helsinki,
Finland
| | - Thomas SPILLMANN
- Department of Equine and Small Animal Medicine, Faculty of
Veterinary Medicine, University of Helsinki, P.O. Box 57 (Viikintie 49), 00014 Helsinki,
Finland
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33
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Koelink PJ, Overbeek SA, Braber S, Morgan ME, Henricks PAJ, Roda MA, Verspaget HW, Wolfkamp SC, te Velde AA, Jones CW, Jackson PL, Blalock JE, Sparidans RW, Kruijtzer JAW, Garssen J, Folkerts G, Kraneveld AD. Collagen degradation and neutrophilic infiltration: a vicious circle in inflammatory bowel disease. Gut 2014; 63:578-87. [PMID: 23525573 PMCID: PMC3963538 DOI: 10.1136/gutjnl-2012-303252] [Citation(s) in RCA: 117] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Proline-glycine-proline (PGP) has been shown to have chemotactic effects on neutrophils via CXCR2 in several lung diseases. PGP is derived from collagen by the combined action of matrix metalloproteinase (MMP) 8 and/or MMP9 and prolyl endopeptidase (PE). We investigated the role of PGP in inflammatory bowel disease (IBD). DESIGN In intestinal tissue from patients with IBD and mice with dextran sodium sulfate (DSS)-induced colitis, MMP8, MMP9 and PE were evaluated by ELISA, immunoblot and immunohistochemistry. Peripheral blood polymorphonuclear cell (PMN) supernatants were also analysed accordingly and incubated with collagen to assess PGP generation ex vivo. PGP levels were measured by mass spectrometry, and PGP neutralisation was achieved with a PGP antagonist and PGP antibodies. RESULTS In the intestine of patients with IBD, MMP8 and MMP9 levels were elevated, while PE was expressed at similar levels to control tissue. PGP levels were increased in intestinal tissue of patients with IBD. Similar results were obtained in intestine from DSS-treated mice. PMN supernatants from patients with IBD were far more capable of generating PGP from collagen ex vivo than healthy controls. Furthermore, PGP neutralisation during DSS-induced colitis led to a significant reduction in neutrophil infiltration in the intestine. CONCLUSIONS The proteolytic cascade that generates PGP from collagen, as well as the tripeptide itself, is present in the intestine of patients with IBD and mice with DSS-induced colitis. PGP neutralisation in DSS-treated mice showed the importance of PGP-guided neutrophilic infiltration in the intestine and indicates a vicious circle in neutrophilic inflammation in IBD.
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Affiliation(s)
- Pim J Koelink
- Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Saskia A Overbeek
- Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Saskia Braber
- Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Mary E Morgan
- Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Paul A J Henricks
- Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Mojtaba Abdul Roda
- Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Hein W Verspaget
- Department of Gastroenterology-Hepatology, Leiden University Medical Centre, Leiden, The Netherlands
| | - Simone C Wolfkamp
- Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Anje A te Velde
- Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Caleb W Jones
- Department of Chemistry, University of Alabama at Birmingham, Birmingham, Alabama,USA
| | - Patricia L Jackson
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine and the Lung Health Center, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - J Edwin Blalock
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine and the Lung Health Center, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Rolf W Sparidans
- Division of Pharmacoepidemiology & Clinical Pharmacology, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - John A W Kruijtzer
- Medicinal Chemistry and Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Johan Garssen
- Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Gert Folkerts
- Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Aletta D Kraneveld
- Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
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Comparison of multiple enzyme activatable near-infrared fluorescent molecular probes for detection and quantification of inflammation in murine colitis models. Inflamm Bowel Dis 2014; 20:363-77. [PMID: 24374874 PMCID: PMC4618379 DOI: 10.1097/01.mib.0000440612.98950.79] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Activatable near-infrared fluorescent (NIRF) probes have been used for ex vivo and in vivo detection of intestinal tumors in animal models. We hypothesized that NIRF probes activatable by cathepsins or metalloproteinases will detect and quantify dextran sulphate sodium (DSS)-induced acute colonic inflammation in wild type mice or chronic colitis in interleukin-10 (IL-10)-null mice ex vivo or in vivo. METHODS Wild type mice given DSS, water controls, and IL-10-null mice with chronic colitis were administered probes by retro-orbital injection. FMT2500 LX system imaged fresh and fixed intestine ex vivo and mice in vivo. Inflammation detected by probes was verified by histology and colitis scoring. NIRF signal intensity was quantified using 2-dimensional region of interest ex vivo or 3-dimensional region of interest analysis in vivo. RESULTS Ex vivo, 7 probes tested yielded significant higher NIRF signals in colon of DSS-treated mice versus controls. A subset of probes was tested in IL-10-null mice and yielded strong ex vivo signals. Ex vivo fluorescence signal with 680 series probes was preserved after formalin fixation. In DSS and IL-10-null models, ex vivo NIRF signal strongly and significantly correlated with colitis scores. In vivo, ProSense680, CatK680FAST, and MMPsense680 yielded significantly higher NIRF signals in DSS-treated mice than controls, but background was high in controls. CONCLUSIONS Both cathepsin or metalloproteinase-activated NIRF probes can detect and quantify colonic inflammation ex vivo. ProSense680 yielded the strongest signals in DSS colitis ex vivo and in vivo, but background remains a problem for in vivo quantification of colitis.
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Infliximab restores the dysfunctional matrix remodeling protein and growth factor gene expression in patients with inflammatory bowel disease. Inflamm Bowel Dis 2014; 20:339-52. [PMID: 24378596 DOI: 10.1097/01.mib.0000438430.15553.90] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
BACKGROUND Matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), a disintegrin and metalloprotease with thrombospondin motifs [ADAM(TS)s] and growth factors are involved in inflammation and tissue damage and repair, all occurring in inflammatory bowel disease (IBD). We studied the impact of anti-inflammatory therapy with infliximab on mucosal expression of these tissue remodeling genes in patients with IBD. METHODS Mucosal gene expression of 23 MMPs, 4 TIMPs, 50 ADAM(TS)s, and 158 growth factors was investigated in 61 patients with IBD before and after the first infliximab therapy and in 12 controls, with microarrays and quantitative RT-PCR. Protein localization, mucosal gelatinase levels, and net gelatinolytic activity were investigated by immunohistochemistry, zymography analysis, and gelatin degradation assay, respectively. RESULTS In patients with active IBD before infliximab versus controls, gene expression of many MMPs, TIMPs, ADAM(TS)s, and growth factors was upregulated, whereas colonic expression of MMP28 and TGFA and ileal expression of ADAMDEC1 and AGT were downregulated. After controlling inflammation with infliximab, most gene dysregulations observed at baseline were restored in responders. Increased ratio of MMP1/TIMP1 expression at baseline in active IBD was restored in responders with colonic mucosal healing. With immunohistochemistry, protein localization differences of MMP1, MMP3, REG1A, and TIMP1 were shown between active IBD and control mucosa. With zymography analysis and gelatin degradation assay, higher gelatinase levels and net gelatinolytic activity were measured before infliximab and levels normalized after infliximab. CONCLUSIONS Our data suggest that suppression of inflammation results in the arrest of epithelial damage and subsequent mucosal healing. Therefore, the therapeutic potential of agents targeting MMPs or growth factors as primary therapy seems rather complex.
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Fecal calprotectin, MMP-9, and human beta-defensin-2 levels in pediatric inflammatory bowel disease. Int J Colorectal Dis 2014; 29:43-50. [PMID: 24077667 DOI: 10.1007/s00384-013-1775-9] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/17/2013] [Indexed: 02/04/2023]
Abstract
PURPOSE Fecal MMP-9 and human beta-defensin-2 (HBD-2)levels, potential markers of intestinal inflammation, are in sufficiently explored in pediatric inflammatory bowel disease(IBD). The aim was to study fecal MMP-9 and HBD-2 in pediatric IBD to compare their performance to calprotectin and to study whether they would provide additional value in categorizing patients according to their disease subtype. METHODS Fecal calprotectin, MMP-9, and HBD-2 levels were measured with ELISA in 110 pediatric patients with IBD(Crohn’s disease, n = 68; ulcerative colitis (UC), n = 27; unclassified, n = 15; median age, 14). To compare the performance of the fecal markers, the area under the receiver operating characteristics curve (±95 % CI) was used. In addition,the best cut-off values of each measure to differentiate IBD patients and controls (n = 27 presenting with diarrhea, abdominal pain, and/or anemia) were derived by maximizing sensitivity and specificity. RESULTS Of the fecal markers studied, calprotectin performed best for separation of IBD and non-IBD patients with the are a under curve (AUC) of 0.944 (95 % CI, 0.907 to 0.981). For MMP-9, AUC was 0.837 (95% CI, 0.766 to 0.909), the levels being significantly higher in active IBD and in UC compared with Crohn’s disease (p = 0.0013), but categorization of these patient groups did not take place. HBD-2 did not categorize any of the studied groups. CONCLUSIONS Calprotectin was the best fecal marker in pediatric IBD, but MMP-9 showed almost comparable performance in UC, suggesting applicability as a surrogate marker of inflammation. Fecal HBD-2 did not bring information to the disease characteristics of pediatric IBD patients.
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Krarup PM, Eld M, Heinemeier K, Jorgensen LN, Hansen MB, Ågren MS. Expression and inhibition of matrix metalloproteinase (MMP)-8, MMP-9 and MMP-12 in early colonic anastomotic repair. Int J Colorectal Dis 2013; 28:1151-9. [PMID: 23619615 DOI: 10.1007/s00384-013-1697-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/27/2013] [Indexed: 02/04/2023]
Abstract
PURPOSE Submucosal collagen is paramount for colonic anastomotic integrity. Matrix metalloproteinases (MMPs) mediate collagen degradation that increases the risk of wound dehiscence. Although broad-spectrum MMP inhibitors are beneficial for anastomotic strength, they can cause adverse reactions. Knowledge of specific MMPs responsible for the weakening of anastomoses can be used to optimise MMP inhibition therapy. We aimed to quantify transcript and protein levels of multiple MMPs in colonic anastomoses and evaluate the effect of inhibiting the MMPs that displayed the highest expression levels on anastomotic repair. METHODS Left-sided colonic anastomoses were made in male Sprague-Dawley rats. After 3 days when biomechanical strength is lowest, MMP mRNA and protein levels were measured by quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assays and gelatin zymography. The effects of the MMP-8, MMP-9 and MMP-12 synthetic inhibitor AZD3342 was also studied. RESULTS MMP-8, MMP-9 and MMP-12 gene and protein expression increased profoundly (p < 0.01), and MMP-13 mRNA and MMP-2 mRNA and protein modestly (p < 0.001) in the anastomoses. MMP-3 mRNA levels were not up-regulated significantly compared with adjacent uninjured colon. Increased anastomotic MMP-12 levels paralleled macrophage infiltration by immunohistochemical analyses. AZD3342 (50 mg/kg) treatment increased the anastomotic breaking strength by 29% (p = 0.015) day 3 compared with vehicle. Improved anastomotic strength was not accompanied with alterations of type I or type III procollagen mRNA but was possibly due to inhibition of the concerted digestive action on the existent submucosal collagens by the targeted MMPs. CONCLUSION The present findings justify the concept of selective MMP inhibition to enhance anastomotic strength in colon.
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Affiliation(s)
- Peter-Martin Krarup
- Department of Surgery K, Bispebjerg Hospital, Bispebjerg Bakke 23, DK 2400 Copenhagen NV, Denmark.
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Piekkala M, Hagström J, Tanskanen M, Rintala R, Haglund C, Kolho KL. Low trypsinogen-1 expression in pediatric ulcerative colitis patients who undergo surgery. World J Gastroenterol 2013; 19:3272-3280. [PMID: 23745029 PMCID: PMC3671079 DOI: 10.3748/wjg.v19.i21.3272] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2012] [Revised: 01/22/2013] [Accepted: 04/19/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate whether matrix metalloproteinases-9 (MMP-9) or trypsinogens could serve as histological markers for an aggressive disease course in pediatric ulcerative colitis (UC).
METHODS: We identified 24 patients with pediatric onset (≤ 16 years) UC who had undergone surgery during childhood/adolescence a median of 2.1 years (range 0.1-7.4 years) after the diagnosis (between 1990 and 2008) in Children’s Hospital, Helsinki, Finland. We also identified 27 conservatively treated UC patients and matched them based on their age at the time of diagnosis and follow-up at a median of 6 years (range 3-11 years) to serve as disease controls. Twenty children for whom inflammatory bowel disease (IBD) had been excluded as a result of endoscopy served as non-IBD controls. Colon biopsies taken by diagnostic endoscopy before the onset of therapy were stained using immunohistochemistry to study the expression of MMP-9, trypsinogen-1 (Tryp-1), Tryp-2, and a trypsin inhibitor (TATI). The profiles of these proteases and inhibitor at diagnosis were compared between the surgery group, the conservatively treated UC patients and the non-IBD controls.
RESULTS: The proportions of Tryp-1 and Tryp-2 positive samples in the colon epithelium and in the inflammatory cells of the colon stroma were comparable between the studied groups at diagnosis. Interestingly, the immunopositivity of Tryp-1 (median 1; range 0-3) was significantly lower in the epithelium of the colon in the pediatric UC patients undergoing surgery when compared to that of the conservatively treated UC patients (median 2; range 0-3; P = 0.03) and non-IBD controls (median 2; range 0-3; P = 0.04). For Tryp-2, there was no such difference. In the inflammatory cells of the colon stroma, the immunopositivities of Tryp-1 and Tryp-2 were comparable between the studied groups at diagnosis. Also, the proportion of samples positive for TATI, as well as the immunopositivity, was comparable between the studied groups in the colon epithelium. In the stromal inflammatory cells of the colon, TATI was not detected. In UC patients, there were significantly more MMP-9 positive samples and a higher immunopositivity in the stromal inflammatory cells of the colon when compared to the samples from the non-IBD patients (P = 0.006 and P = 0.002, respectively); the immunopositivity correlated with the histological grade of inflammation (95%CI: 0.22-0.62; P = 0.0002), but not with the other markers of active disease. There were no differences in the immunopositivity or in the proportions of MMP-9 positive samples when examined by epithelial staining. The staining profiles in the ileal biopsies were comparable between the studied groups for all of the studied markers.
CONCLUSION: For pediatric UC patients who require surgery, the immunopositivity of Tryp-1 at diagnosis is lower when compared to that of patients with a more benign disease course.
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Liu H, Patel NR, Walter L, Ingersoll S, Sitaraman SV, Garg P. Constitutive expression of MMP9 in intestinal epithelium worsens murine acute colitis and is associated with increased levels of proinflammatory cytokine Kc. Am J Physiol Gastrointest Liver Physiol 2013; 304:G793-803. [PMID: 23471340 DOI: 10.1152/ajpgi.00249.2012] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn's disease, is a chronic inflammatory disease associated with an increased risk for colon cancer. Matrix metalloproteinases (MMPs) are the predominant proteinases expressed in the gut mucosa during active IBD. Our laboratory has previously demonstrated that epithelial-derived MMP9 is absent in normal colonic tissue but is upregulated during IBD. In this study MMP9 transgenic mice (Tg-villin-MMP9) are generated specifically to overexpress MMP9 in intestinal epithelium to examine the role and underlying mechanism by which it modulates the pathogenesis of acute colitis. Dextran sodium sulfate (3% DSS)- and Salmonella typhimurium (S.T.)-induced colitis models were used to study gut inflammation in Tg-villin-MMP9 and wild-type littermates (WT). Colonic tissue was analyzed via Western blot, histology, myeloperoxidase (MPO) assay, and quantitative PCR. Tg-villin-MMP9 mice expressed significantly increased MMP9 mRNA and protein expression at basal level. There was a significant decrease in the goblet cells, but a significant increase in proliferation and apoptosis were observed among Tg-villin-MMP9 mice compared with WT mice. There was also a significant increase in the proinflammatory chemokine Kc among Tg-villin-MMP9 compared with WT mice. Tg-villin-MMP9 exhibited a severe inflammatory response than WT mice in both DSS- and S.T.-induced colitis models as evident by greater weight loss and higher clinical score, histological score, and MPO activity, which correlated with relative levels of Kc mRNA. MMP9 expressed by intestinal epithelial cells mediates inflammation in colitis with simultaneous increase in proinflammatory cytokine Kc.
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Affiliation(s)
- Hongchun Liu
- Center for Diagnostics and Therapeutics, Department of Biology, Georgia State University, Atlanta, GA 30303, USA
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Mao JW, He XM, Tang HY, Wang YD. Protective role of metalloproteinase inhibitor (AE-941) on ulcerative colitis in rats. World J Gastroenterol 2012; 18:7063-9. [PMID: 23323009 PMCID: PMC3531695 DOI: 10.3748/wjg.v18.i47.7063] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2012] [Revised: 06/12/2012] [Accepted: 07/09/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the protective role of AE-941, a matrix metalloproteinase (MMP) inhibitor, on ulcerative colitis (UC) in rats.
METHODS: Sprague Dawley (SD) rats were randomly divided into three groups: a control group, an AE-941 treatment group, and an UC model group. Rats were sacrificed on days 7, 21, or 56 following administration of treatment by enema and the disease activity index (DAI), colonic mucosa damage index (CMDI) and colonic expression of MMP-2 and MMP-9 were assessed.
RESULTS: DAI and CDMI scores in the UC model group increased significantly compared to the control group at all timepoints (P < 0.001), and also increased significantly at the 21- and 56-d timepoints compared to the AE-941-treated group (DAI: 21- and 56-d = 2.09 ± 0.25, 1.52 ± 0.30 vs 1.55 ± 0.28, 0.59 ± 0.19, respectively, P = 0.040 and 0.007, CMDI: 21- and 56-d = 3.03 ± 0.42, 1.60 ± 0.35 vs 2.08 ± 0.46, 0.86 ± 0.37, respectively, P = 0.040 and 0.005). Furthermore, the colonic expression of MMP-2 and MMP-9 in the UC model group increased significantly compared to the control group (P < 0.001), and also increased compared to the AE-941-treated group on the 21- and 56-d timepoints (MMP-2: 21- and 56-d = 0.6048 ± 0.0522, 0.4163 ± 0.0330 vs 0.3983 ± 0.0218, 0.1093 ± 0.0072, respectively, P = 0.010; MMP-9: 21- and 56-d = 0.6873 ± 0.0472, 0.4328 ± 0.0257 vs 0.5179 ± 0.0305, 0.2673 ± 0.0210, respectively, P = 0.010 and 0.040).
CONCLUSION: Expression of MMP-2 and MMP-9 increased significantly in rats with UC. AE-941 can reduce colonic mucosal damage by downregulating the expression of MMP-2 and MMP-9.
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Symeonidis C, Papakonstantinou E, Galli A, Tsinopoulos I, Mataftsi A, Batzios S, Dimitrakos SA. Matrix metalloproteinase (MMP-2, -9) and tissue inhibitor (TIMP-1, -2) activity in tear samples of pediatric type 1 diabetic patients. Graefes Arch Clin Exp Ophthalmol 2012; 251:741-9. [DOI: 10.1007/s00417-012-2221-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2012] [Revised: 11/06/2012] [Accepted: 11/20/2012] [Indexed: 01/04/2023] Open
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Monteleone I, Federici M, Sarra M, Franzè E, Casagrande V, Zorzi F, Cavalera M, Rizzo A, Lauro R, Pallone F, MacDonald TT, Monteleone G. Tissue inhibitor of metalloproteinase-3 regulates inflammation in human and mouse intestine. Gastroenterology 2012; 143:1277-1287.e4. [PMID: 22819866 DOI: 10.1053/j.gastro.2012.07.016] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2011] [Revised: 06/28/2012] [Accepted: 07/10/2012] [Indexed: 12/22/2022]
Abstract
BACKGROUND & AIMS Tissue inhibitor of metalloproteinases (TIMP)-3 is an inhibitor of matrix metalloproteinases, which regulates tissue inflammation, damage, and repair. We investigated the role of TIMP-3 in intestinal inflammation in human beings and mice. METHODS We used real-time polymerase chain reaction and flow cytometry to measure levels of TIMP-3 in intestine samples from patients with Crohn's disease (CD) and those without (controls). We also analyzed TIMP-3 levels in lamina propria mononuclear cells (LPMCs) collected from biopsy samples of individuals with or without CD (controls) and then stimulated with transforming growth factor (TGF)-β1, as well as in biopsy samples collected from patients with CD and then incubated with a Smad7 anti-sense oligonucleotide (knock down). LPMCs and biopsy samples from patients with CD were cultured with exogenous TIMP-3 and levels of inflammatory cytokines were measured. We evaluated the susceptibility of wild-type, TIMP-3-knockout (TIMP-3-KO), and transgenic (TIMP-3-Tg) mice to induction of colitis with 2, 4, 6-trinitrobenzene-sulfonic-acid (TNBS), and the course of colitis in recombinase-activating gene-1-null mice after transfer of wild-type or TIMP-3-KO T cells. RESULTS Levels of TIMP-3 were reduced in intestine samples from patients with CD compared with controls. Incubation of control LPMCs with TGF-β1 up-regulated TIMP-3; knockdown of Smad7, an inhibitor of TGF-β1, in biopsy samples from patients with CD increased levels of TIMP-3. Exogenous TIMP-3 reduced levels of inflammatory cytokines in CD LPMCs and biopsy samples. TIMP-3-KO mice developed severe colitis after administration of TNBS, whereas TIMP-3-Tg mice were resistant to TNBS-induced colitis. Reconstitution of recombinase-activating gene-1-null mice with T cells from TIMP-3-KO mice increased the severity of colitis, compared with reconstitution with wild-type T cells. CONCLUSIONS TIMP-3 is down-regulated in inflamed intestine of patients with CD. Its expression is regulated by TGF-β1, and knock-down of Smad7 in intestinal tissues from patient with CD up-regulates TIMP-3. Loss or reduction of TIMP-3 in mice promotes development of colitis.
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Affiliation(s)
- Ivan Monteleone
- Dipartimento di Medicina dei Sistemi, Università Tor Vergata, Rome, Italy
| | - Massimo Federici
- Dipartimento di Medicina dei Sistemi, Università Tor Vergata, Rome, Italy
| | - Massimiliano Sarra
- Dipartimento di Medicina dei Sistemi, Università Tor Vergata, Rome, Italy
| | - Eleonora Franzè
- Dipartimento di Medicina dei Sistemi, Università Tor Vergata, Rome, Italy
| | - Viviana Casagrande
- Dipartimento di Medicina dei Sistemi, Università Tor Vergata, Rome, Italy
| | - Francesca Zorzi
- Dipartimento di Medicina dei Sistemi, Università Tor Vergata, Rome, Italy
| | - Michele Cavalera
- Dipartimento di Medicina dei Sistemi, Università Tor Vergata, Rome, Italy
| | - Angelamaria Rizzo
- Dipartimento di Medicina dei Sistemi, Università Tor Vergata, Rome, Italy
| | - Renato Lauro
- Dipartimento di Medicina dei Sistemi, Università Tor Vergata, Rome, Italy
| | - Francesco Pallone
- Dipartimento di Medicina dei Sistemi, Università Tor Vergata, Rome, Italy
| | - Thomas T MacDonald
- Centre for Immunology and Infectious Disease, Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, London, United Kingdom
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Herszényi L, Hritz I, Lakatos G, Varga MZ, Tulassay Z. The behavior of matrix metalloproteinases and their inhibitors in colorectal cancer. Int J Mol Sci 2012; 13:13240-13263. [PMID: 23202950 PMCID: PMC3497324 DOI: 10.3390/ijms131013240] [Citation(s) in RCA: 117] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2012] [Revised: 10/08/2012] [Accepted: 10/10/2012] [Indexed: 02/06/2023] Open
Abstract
Matrix metalloproteinases (MMPs) play an important role in the degradation of extracellular matrix components crucial for tumor growth, invasion and metastasis. MMPs are controlled by natural inhibitors called tissue inhibitors of metalloproteinases (TIMPs). We and others have demonstrated that MMPs and TIMPs are especially important in the process of tumor invasion, progression and the metastasis of colorectal cancer (CRC). It has been proposed that MMPs and TIMPs might play a part not only in tumor invasion and initiation of metastasis but also in carcinogenesis from colorectal adenomas. Several recent studies demonstrated that high preoperative serum or plasma MMP-2, MMP-9 and TIMP-1 antigen levels are strong predictive factors for poor prognosis in patients with CRC and their determination might be useful for identification of patients with higher risk for cancer recurrence. MMP-9 and TIMP-1 have significant potential tumor marker impact in CRC. Their diagnostic sensitivity is consistently higher than those of conventional biomarkers. The pharmacological targeting of CRC by the development of a new generation of selective inhibitors of MMPs, that is highly specific for certain MMPs, is a promising and challenging area for the future.
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Affiliation(s)
- László Herszényi
- Second Department of Medicine, Semmelweis University, H-1088 Budapest, Szentkirályi str. 46, H-1088, Hungary; E-Mails: (I.H.); (G.L.); (M.Z.V.); (Z.T.)
| | - István Hritz
- Second Department of Medicine, Semmelweis University, H-1088 Budapest, Szentkirályi str. 46, H-1088, Hungary; E-Mails: (I.H.); (G.L.); (M.Z.V.); (Z.T.)
- First Department of Medicine, Fejér County Szent György Hospital, Székesfehérvár, H-8000, Hungary
| | - Gábor Lakatos
- Second Department of Medicine, Semmelweis University, H-1088 Budapest, Szentkirályi str. 46, H-1088, Hungary; E-Mails: (I.H.); (G.L.); (M.Z.V.); (Z.T.)
- Department of Oncology, Szent László Hospital, Budapest, H-1097, Hungary
| | - Mária Zsófia Varga
- Second Department of Medicine, Semmelweis University, H-1088 Budapest, Szentkirályi str. 46, H-1088, Hungary; E-Mails: (I.H.); (G.L.); (M.Z.V.); (Z.T.)
| | - Zsolt Tulassay
- Second Department of Medicine, Semmelweis University, H-1088 Budapest, Szentkirályi str. 46, H-1088, Hungary; E-Mails: (I.H.); (G.L.); (M.Z.V.); (Z.T.)
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Al-Azri AR, Gibson RJ, Keefe DMK, Logan RM. Matrix metalloproteinases: do they play a role in mucosal pathology of the oral cavity? Oral Dis 2012; 19:347-59. [DOI: 10.1111/odi.12023] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2012] [Revised: 08/16/2012] [Accepted: 09/04/2012] [Indexed: 12/19/2022]
Affiliation(s)
| | - RJ Gibson
- School of Medical Sciences; University of Adelaide; Adelaide; SA; Australia
| | - DMK Keefe
- Department of Medical Oncology, Royal Adelaide Hospital Cancer Centre; Adelaide; SA; Australia
| | - RM Logan
- School of Dentistry; University of Adelaide; Adelaide; SA; Australia
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Mäkitalo L, Piekkala M, Ashorn M, Pakarinen M, Koivusalo A, Karikoski R, Natunen J, Saarialho-Kere U, Rintala R, Kolho KL. Matrix metalloproteinases in the restorative proctocolectomy pouch of pediatric ulcerative colitis. World J Gastroenterol 2012; 18:4028-36. [PMID: 22912554 PMCID: PMC3420000 DOI: 10.3748/wjg.v18.i30.4028] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2012] [Revised: 05/09/2012] [Accepted: 05/13/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in pouch mucosa of pediatric onset ulcerative colitis (UC).
METHODS: In this cross-sectional study, 28 patients with pediatric onset UC underwent ileal pouch biopsy 13 years (median) after proctocolectomy. Expression of MMPs-3, -7, -8, -9, -12 and -26 and TIMPs-1, -2 and -3 in samples was examined using immunohistochemichal methods, and another biopsy was used to evaluate the grade of histological inflammation. Two investigators independently graded the immunohistochemical specimens in a semiquantitative fashion, using a scale marking staining intensity as follows: 0 = less than 20 positive cells; 1 = 20-50 positive cells; 2 = 50-200 positive cells; 3 = over 20 positive cells. Fecal calprotectin and blood inflammatory markers [serum C-reactive protein (CRP) and erythrocyte sedimentation rate] were determined during a follow-up visit to examine correlations between these markers and the expression of MMPs and TIMPs.
RESULTS: Of the 28 patients with pediatric onset UC, nine had not experienced pouchitis, whereas thirteen reported a single episode, and six had recurrent pouchitis (≥ 4 episodes). At the time of the study, six patients required metronidazole. In all of the others, the most recent episode of pouchitis had occurred over one month earlier, and none were on antibiotics. Only four samples depicted no sign of inflammation, and these were all from patients who had not had pouchitis. Two samples were too small to determine the grade of inflammation, but both had suffered pouchitis, the other recurrent. No sample depicted signs of colonic metaplasia. Most pouch samples showed expression of epithelial (e) and stromal (s) MMP-3 (e, n = 22; s, n = 20), MMP-7 (e, n = 28; s, n = 27), MMP-12 (e, n = 20; s, n =24), TIMP-2 (e, n = 23; s, n = 23) and MMP-3 (e, n = 23; s, n = 28) but MMP-8 (e, n = 0; s, n = 1), MMP-9 (e, n = 0; s, n = 9) and MMP-26 (e, n = 0; s, n = 3) and TIMP-1 (n = 0, both) were lacking. In samples with low grade of inflammatory activity, the epithelial MMP-3 and MMP-7 expression was increased (r = -0.614 and r = -0.472, respectively, P < 0.05 in both). MMPs and TIMPs did not correlate with the markers of inflammation, fecal calprotectin, erythrocyte sedimentation rate, or CRP, with the exception of patients with low fecal calprotectin (< 100 μg/g) in whom a higher expression of epithelial MMP-7 was found no differences in MMP- or TIMP-profiles were seen in patients with a history of pouchitis compared to ones with no such episodes. Anastomosis with either straight ileoanal anastomosis or ileoanal anastomosis with J-pouch did depict differences in MMP- or TIMP-expression.
CONCLUSION: The expression of MMPs pediatric UC pouch in the long-term shares characteristics with inflammatory bowel disease, but inflammation cannot be classified as a reactivation of the disease.
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Mäkitalo L, Rintamäki H, Tervahartiala T, Sorsa T, Kolho KL. Serum MMPs 7-9 and their inhibitors during glucocorticoid and anti-TNF-α therapy in pediatric inflammatory bowel disease. Scand J Gastroenterol 2012; 47:785-94. [PMID: 22519363 DOI: 10.3109/00365521.2012.677954] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVES In inflammatory bowel diseases (IBD), matrix metalloproteinases (MMPs) participate in intestinal tissue damage and regenerative processes. MMP activity is inhibited by tissue inhibitors of MMPs (TIMPs) and plasma inhibitor, α₂-macroglobulin (α2M). We evaluated serum MMPs, their inhibitors and markers of neutrophil activity, myeloperoxidase (MPO) and human neutrophil elastase (HNE), during glucocorticoid (GC) and anti-TNF-α therapies in pediatric IBD, in aim to find new tools for assessment of therapeutic response. METHODS Serum samples were collected before and within a month after the start of therapy with oral GC (n = 19) or anti-TNF-α agent (n = 16), and from 32 pediatric control patients. Serum levels of MMP-7, MMP-9, TIMP-1, TIMP-2, α2M, MPO, and HNE were analyzed with enzyme-linked immunoabsorbent assays (ELISA) and MMP-8 by immunofluorometric assay (IFMA). Disease activity was monitored with erythrocyte sedimentation rate (ESR), CRP, fecal calprotectin (FC), and physician's global assessment of clinical disease activity (PGA). RESULTS In IBD, pretreatment serum MMP-7, MMP-8, MMP-9, α2M, MPO, and HNE were elevated compared with controls. During GC therapy, MMP-7, TIMP-1, and MMP-7/TIMP-2 decreased (all p < 0.05). During anti-TNF-α therapy, MMP-7 decreased (p = 0.063), but remained higher than that after GC therapy (p < 0.05). α2M (p < 0.05) and HNE (p < 0.05) increased, the former higher than that in GC-treated patients. The levels of MMPs and their inhibitors did not markedly associate with inflammatory markers in blood or feces. CONCLUSIONS In pediatric IBD, serum MMP-7 mirrors disease activity, and together with TIMP-1, reflects GC therapy response. α₂-Macroglobulin expression parallels the anti-TNF-α response.
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Affiliation(s)
- Laura Mäkitalo
- Children's Hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.
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Kawamura Y, Sugata K, Nakai H, Asano Y, Ohashi M, Kato T, Nishimura N, Ozaki T, Yui A, Taniguchi K, Yoshikawa T. Correlation between serum matrix metalloproteinase and antigenemia levels in patients infected with rotavirus. J Med Virol 2012; 84:986-91. [DOI: 10.1002/jmv.23296] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
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Bene L, Falus A, Baffy N, Fulop AK. Cellular and molecular mechanisms in the two major forms of inflammatory bowel disease. Pathol Oncol Res 2011; 17:463-72. [PMID: 21681604 DOI: 10.1007/s12253-011-9397-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2010] [Accepted: 03/25/2011] [Indexed: 02/08/2023]
Abstract
The factors involved in the pathogenesis of Crohn's disease and ulcerative colitis, the two major types of inflammatory bowel disease (IBD) are summarized. Intestinal antigens composed of bacterial flora along with antigen presentation and impaired mucosal barrier have an important role in the initiation of IBD. The bacterial community may be modified by the use of antibiotics and probiotics. The dentritic cells recognize the antigens by cell surface Toll like receptor and the cytoplasmic CARD/NOD system. The balance between Th1/Th2/Th17 cell populations being the source of a variety of cytokines regulates the inflammatory mechanisms and the clearance of microbes. The intracellular killing and digestion, including autophagy, are important in the protection against microbes and their toxins. The homing process determines the location and distribution of the immune cells along the gut. All these players are potential targets of pharmacological manipulation of disease status.
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Affiliation(s)
- Laszlo Bene
- Department of Internal Medicine, Peterfy Hospital, Budapest, Hungary
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Puthenedam M, Wu F, Shetye A, Michaels A, Rhee KJ, Kwon JH. Matrilysin-1 (MMP7) cleaves galectin-3 and inhibits wound healing in intestinal epithelial cells. Inflamm Bowel Dis 2011; 17:260-7. [PMID: 20812334 PMCID: PMC2998582 DOI: 10.1002/ibd.21443] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2010] [Accepted: 07/14/2010] [Indexed: 12/17/2022]
Abstract
BACKGROUND Galectin-3 is an animal lectin that has been implicated in wound healing and is decreased in inflammatory bowel disease (IBD). Matrix metalloproteinase-7 (MMP7), also known as matrilysin-1, a protease shown to cleave extracellular matrix proteins, is highly expressed in IBD tissues, especially at the leading edge of gastrointestinal ulcers. The ability of MMP7 to cleave galectin-3 and influence wound healing has not been reported previously. The aim was to determine whether MMP7 cleaves galectin-3 and modulates wound healing in intestinal epithelial cells. METHODS The cleaved fragments of galectin-3 were identified by N-terminal sequencing and mass spectrometry. Western blotting was used to detect the cleaved galectin-3 products in a colonic epithelial cell line (T84 cells). Cell migration was studied by the in vitro scratch method. RESULTS We demonstrate for the first time that MMP7 cleaves galectin-3 in vitro, resulting in three cleaved fragments (20.2 kDa, 18.9 kDa, and 15.5 kDa). Exogenous treatment of T84 cells with recombinant MMP7 resulted in the appearance of secreted galectin-3 cleavage fragments in the supernatant. MMP7 inhibited cell migration and resulted in wound retraction and the addition of MMP7 to galectin-3 abrogated the wound healing and cell migration induced by galectin-3. CONCLUSIONS We have demonstrated that galectin-3 is a substrate for MMP7. Cleavage of galectin-3 may be one mechanism by which MMP7 inhibits wound healing. This study has significance in understanding delayed wound healing in chronic intestinal diseases like intestinal ulcers and IBD, where MMP7 protein expression is elevated with a decreased galectin-3 protein expression.
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Affiliation(s)
- Manjula Puthenedam
- Department of Medicine, Division of Gastroenterology, Johns Hopkins University, Baltimore, MD 21205
| | - Feng Wu
- Department of Medicine, Section of Gastroenterology, University of Chicago, Chicago, IL 60637
| | - Alysha Shetye
- Department of Medicine, Division of Gastroenterology, Johns Hopkins University, Baltimore, MD 21205
| | - Alex Michaels
- Department of Medicine, Division of Gastroenterology, Johns Hopkins University, Baltimore, MD 21205
| | - Ki-Jong Rhee
- Section of Digestive Diseases and Nutrition, School of Medicine, University of Illinois at Chicago, Chicago, IL 60612
| | - John H Kwon
- Department of Medicine, Section of Gastroenterology, University of Chicago, Chicago, IL 60637
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