The effect of an inhibitor of matrix metalloproteinases on colonic inflammation in a trinitrobenzenesulphonic acid rat model of inflammatory bowel disease

Sykes, Akilah; Bhogal, Ranjev; Brampton, Christopher; Chander, C. L.; Whelan, C. J.; Parsons, Marie J.; Bird, John

doi:10.1046/j.1365-2036.1999.00633.x

Cited by 76 publications

(53 citation statements)

References 20 publications

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“…The studies published so far have confirmed the overexpression of MMPs, including MMP-3 and -9, both in ulcerative colitis and in Crohn's disease (CD). Alterations of MMPs activity depending on the degree of disease exacerbation have been observed in animal models with induced bowel inflammation [11,12]. Elevated concentrations of MMPs have also been noted in biopsy specimens collected from inflamed fragments of the alimentary tract [1,2,13,14].…”

Section: Discussionmentioning

confidence: 92%

Metalloproteinase-3 and -9 as Novel Markers in the Evaluation of Ulcerative Colitis Activity in Children

Kofla-Dłubacz¹,

Matusiewicz²,

Krzesiek³

et al. 2014

Adv Clin Exp Med

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Objectives. The enhanced activity of matrix endopeptidases (MMPs) involved in the degradation of connective tissue has been noted in tissue samples from the digestive tract in inflammatory bowel disease (IBD), however sera concentrations of MMPs, a potential tool for diagnostic tests in IBD patients, have not been established so far. The goal of the studies was to evaluate the concentrations of MMP-3 and MMP-9, in the sera of children suffering from ulcerative colitis (UC) in relation to disease activity. Material and Methods. The study was comprised of 31 children with UC (aged 3-18 years) and 37 children in the control group (aged 1-18 years). Disease activity was estimated using the Truelove-Witts scale. MMP-3 and -9 concentrations were determined using ELISA tests. Results. Median MMP-3 concentrations were 18.4 ng/mL (95% CI: 12.5-24.3) for moderate and severe, 4.35 ng/mL (95% CI: 2.5-7.8) for the mild form of UC and 1.8 ng/mL (95% CI: 1.2-2.5) for the control group. Median MMP-9 concentrations were 18.0 ng/mL (95% CI: 2.83-36.6) for moderate and severe, 1.55 ng/mL (95% CI: 0.4-3.0) for the mild form of UC and 1.3 ng/mL (95% CI: 0.7-1.96) for the control group. Serum MMP-3 and MMP-9 concentrations in the moderate group were higher than those in the mild and control groups (p < 0.001). MMP-3 concentrations in the mild group also differed from those in the control group (p < 0.001). Among the parameters studied (MMP-3, MMP-9, CRP and ESR), MMP-3 had the highest discriminative value (AUC = 0.9, p < 0.001, sensitivity = 71%, specificity = 92%) in distinguishing patients with UC from healthy individuals. Conclusions. Elevation of MMP-3 and MMP-9 concentrations along with the disease activity suggests the possibility of their application in the evaluation of the clinical activity of UC (Adv Clin Exp Med 2014, 23, 1, 103-110).

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Section: Discussionmentioning

confidence: 92%

Metalloproteinase-3 and -9 as Novel Markers in the Evaluation of Ulcerative Colitis Activity in Children

Kofla-Dłubacz¹,

Matusiewicz²,

Krzesiek³

et al. 2014

Adv Clin Exp Med

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“…Mesenchymal cells were identified as major producers of MMP-1 and -2 [6] . MMPs were implicated in the tissue destruction associated with inflammatory diseases and the role of MMPs in the pathogenesis of inflammatory bowel disease was also confirmed through improvement of experimentally induced colitis after treatment with a matrix metalloproteinase inhibitor [21] . Apart from protease-inhibitory action TIMP-1 serves [22,23] .…”

Section: Discussionmentioning

confidence: 94%

Plasma matrix metalloproteinase-1 and tissue inhibitor of metalloproteinases-1 as biomarkers of ulcerative colitis activity

Wiercińska–Drapało

Jaroszewicz²,

Flisiak³

et al. 2003

WJG

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AIM:Overexpression of mucosal metalloproteinases (MMP) have been demonstrated recently in inflammatory bowel disease. Their activity can be counterbalanced by the tissue inhibitor of metalloproteinases (TIMP). The aim of this study was to evaluate the effect of ulcerative colitis (UC) on MMP-1 and TIMP-1 plasma concentrations, as two possible biomarkers of the disease activity. METHODS:MMP-1 and TIMP-1 plasma concentrations were measured with an enzyme immunoassay in 16 patients with endoscopically confirmed active UC. RESULTS:Plasma concentrations of both MMP-1 (13.7±0.2 ng/ml) and TIMP-1 (799±140 ng/ml) were significantly elevated in UC patients in comparison to healthy controls (11.9±0.9 ng/ml and 220±7 ng/ml respectively). There was no correlation between TIMP-1 and MMP-1 concentrations (r=-0.02). TIMP-1 levels revealed significant positive correlations with scored endoscopic degree of mucosal injury, disease activity index and clinical activity index values as well as C-reactive protein concentration. There was no correlation between MMP-1 and laboratory, clinical or endoscopic indices of the disease activity. CONCLUSION:These results confirm the role of both MMP-1 and TIMP-1 in the pathogenesis of ulcerative colitis. However only TIMP-1 can be useful as a biomarker of the disease activity, demonstrating association with clinical and endoscopic pictures.Wiercinska-Drapalo A, Jaroszewicz J, Flisiak R, Prokopowicz D. Plasma matrix metalloproteinase-1 and tissue inhibitor of metalloproteinases-1 as biomarkers of ulcerative colitis activity.

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“…Considering that the IC 50 of Marimastat against MMP-13 is 4.59 nM, the margin between potency and toxicity is only ϳ2-fold. Marimastat also has nanomolar potency against other MMPs, with an IC 50 of 1.94 nM and 2.10 nM against collagenase 1 (MMP-1) and collagenase 2 (MMP-8), respectively (39).…”

Section: Discussionmentioning

confidence: 99%

A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: Evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat models

Baragi

Becher²,

Bendele³

et al. 2009

Arthritis & Rheumatism

152

127

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Objective. Matrix metalloproteinases (MMPs) have long been considered excellent targets for osteoarthritis (OA) treatment. However, clinical utility of broad-spectrum MMP inhibitors developed for this purpose has been restricted by dose-limiting musculoskeletal side effects observed in humans. This study was undertaken to identify a new class of potent and selective MMP-13 inhibitors that would provide histologic and clinical efficacy without musculoskeletal toxicity.Methods. Selectivity assays were developed using catalytic domains of human MMPs. Freshly isolated bovine articular cartilage or human OA cartilage was used in in vitro cartilage degradation assays. The rat model of monoiodoacetate (MIA)-induced OA was implemented for assessing the effects of MMP-13 inhibitors on cartilage degradation and joint pain. The surgical medial meniscus tear model in rats was used to evaluate the chondroprotective ability of MMP-13 inhibitors in a chronic disease model of OA. The rat model of musculoskeletal side effects (MSS) was used to assess whether selective MMP-13 inhibitors have the joint toxicity associated with broad-spectrum MMP inhibitors.Results. A number of non-hydroxamic acidcontaining compounds that showed a high degree of potency for MMP-13 and selectivity against other MMPs were designed and synthesized. Steady-state kinetics experiments and Lineweaver-Burk plot analysis of rate versus substrate concentration with one such compound, ALS 1-0635, indicated linear, noncompeti-

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The effect of an inhibitor of matrix metalloproteinases on colonic inflammation in a trinitrobenzenesulphonic acid rat model of inflammatory bowel disease

Abstract: Dosing rats with TNBS-induced colitis using sulphasalazine or marimastat produced a significant reduction in tissue injury and inflammation.

Cited by 76 publications

References 20 publications

Metalloproteinase-3 and -9 as Novel Markers in the Evaluation of Ulcerative Colitis Activity in Children

Metalloproteinase-3 and -9 as Novel Markers in the Evaluation of Ulcerative Colitis Activity in Children

Plasma matrix metalloproteinase-1 and tissue inhibitor of metalloproteinases-1 as biomarkers of ulcerative colitis activity

A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: Evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat models

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