Matrix Metalloproteinase-9: Its Interplay with Angiogenic Factors in Inflammatory Bowel Diseases

Matusiewicz, Małgorzata; Neubauer, Katarzyna; Mierzchała-Pasierb, Magdalena; Gamian, Andrzej; Krzystek−Korpacka, Małgorzata

doi:10.1155/2014/643645

Cited by 52 publications

(43 citation statements)

References 50 publications

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“…Functional data in experimental models of inflammation have suggested an important role of MMP9 in impairing colonic epi thelial permeability and augmenting inflammation via activation of myosin light chain kinase (MLCK) 74 . Furthermore, MMP9 favoured angiogenesis and created a proteolytic environment in the inflamed gut of a mouse model of colitis that stimulated the influx of myeloid cells into the colonic epithelium and the prod uction of TNF 75,76 . Consecutively, a potent and highly selective allosteric MMP9 inhibitor (humanized mono clonal antibody GS 5745) has been developed and is currently being tested in clinical trials in patients with IBD 76 (FIG.…”

Section: Emerging Targets In Fibrosis and Tissue Remodellingmentioning

confidence: 99%

Current and emerging therapeutic targets for IBD

Neurath

2017

Nat Rev Gastroenterol Hepatol

528

403

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Inflammatory bowel diseases (including IBD, exempli fied by Crohn's disease and ulcerative colitis) are chronic relapsing disorders affecting the gastrointestinal tract. IBD has a progressive and destructive nature and, there fore, can cause various complications including steno ses, abscesses, fistulas, extraintestinal manifestations and colitis associated neoplasias and cancer 1,2 . Thus, effective therapeutic approaches are of high clinical rele vance in patients with IBD. This Review summarizes current therapeutic strategies and highlights emerging new treatment approaches for IBD with special refer ence to the proposed molecular mechanisms of action of anti inflammatory drugs. Current IBD therapiesClassic anti-inflammatory drugs. 5 Aminosalicylates (5 ASAs) are important anti inflammatory drugs that are frequently used for anti inflammatory therapy in patients with ulcerative colitis 3 . By contrast, 5 ASA based drugs show little or no efficacy in inducing res olution of clinical symptoms and tissue inflammation in patients with Crohn's disease 4 .5 ASAs are effective for induction and mainten ance of remission in ulcerative colitis and might also reduce the risk of developing colitis associated tumours in these patients 5 . Several mechanisms of action for 5 ASAs have been proposed, including reduction of prostaglandin synthesis via inhibition of cyclooxygenase, suppression of proinflammatory cytokine production and oxygen free radicals, inhib ition of lipoxygenase, blockade of neutrophil chemo taxis and mast cell activation, and impairment of nuclear factor κB activation (NF κB) in immune cells 3 . Moreover, studies in mice revealed that 5 ASA based drugs augment peroxisome proliferator activated receptor γ (PPARγ) expression and promote PPARγ translocation from the cytoplasm to the nucleus where they result in activation of peroxisome proliferator hormone response element driven genes to suppress colitis activity 6,7 .In addition to 5 ASAs, corticosteroids (systemically or topically delivered) have been used for remission induction in ulcerative colitis 2 . Although cortico steroids favour induction of remission in both ulcer ative colitis and Crohn's disease, they are not suitable for mainten ance of remission in IBD 1,2 . Mechanistically, gluco corticoids bind to a specific cytosolic receptor fol lowed by translocation of the complex to the nucleus to either activate or repress gene transcription (via bind ing to DNA corticosteroid response elements) 8,9 . Additionally, the glucocorticoid-receptor complex can inactivate pro inflammatory transcription factors such as NF κB and activator protein 1 (AP1) via proteinprotein inter actions, thereby preventing their activation of inflammatory mediators (for example, leukotrienes and cytokines such as IL 1 and IL 6). REVIEWS© 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d .

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Section: Emerging Targets In Fibrosis and Tissue Remodellingmentioning

confidence: 99%

Current and emerging therapeutic targets for IBD

Neurath

2017

Nat Rev Gastroenterol Hepatol

528

403

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“…Matrix metalloproteinase‐9 mucosal expression, protein and serum antigen levels, and activity have all been shown to be significantly higher in UC patients than in healthy controls and to correspond to disease activity . Faecal matrix metalloproteinase‐9 levels, which are significantly increased in patients with UC compared with healthy controls and those with irritable bowel syndrome, are correlated with clinical and endoscopic activity scores, serum C‐reactive protein (CRP) and faecal calprotectin, and are highly sensitive for the detection of endoscopically active UC …”

Section: Introductionmentioning

confidence: 99%

Randomised clinical trial: a phase 1, dose‐ranging study of the anti‐matrix metalloproteinase‐9 monoclonal antibody GS‐5745 versus placebo for ulcerative colitis

Sandborn

Bhandari

Fogel

et al. 2016

Aliment Pharmacol Ther

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SummaryBackgroundMatrix metalloproteinase‐9 is a proteolytic enzyme whose expression is increased in ulcerative colitis.AimTo evaluate the safety and efficacy of GS‐5745, a fully humanised anti‐matrix metalloproteinase‐9 monoclonal antibody, in moderately‐to‐severely active ulcerative colitis.MethodsWe randomised 74 patients with ulcerative colitis to treatment with single or multiple ascending intravenous or subcutaneous doses of GS‐5745 or placebo. Multiple‐dose cohorts received either IV infusions (0.3, 1.0, 2.5 or 5.0 mg/kg GS‐5745 or placebo) every 2 weeks (three total IV infusions) or five weekly SC injections (150 mg GS‐5745 or placebo). The primary outcomes were the safety, tolerability and pharmacokinetics of escalating single and multiple doses of GS‐5745. Exploratory analyses in the multiple‐dose cohorts included clinical response (≥3 points or 30% decrease from baseline in Mayo Clinic score and ≥1 point decrease in the rectal bleeding subscore or a rectal bleeding subscore ≤1) and clinical remission (a complete Mayo Clinic score ≤2 with no subscore >1) at Day 36. Biological effects associated with a clinical response to GS‐5745 were explored using histological and molecular approaches.ResultsTwenty‐three of the 42 patients (55%) receiving multiple doses of GS‐5745 had adverse events, compared with 5/8 patients (63%) receiving placebo. GS‐5745 showed target‐mediated drug disposition, approximately dose‐proportional increases in maximum plasma concentration and more than dose‐proportional increases in the area under the plasma drug concentration‐time curve. Clinical response occurred in 18/42 patients (43%) receiving GS‐5745 compared with 1/8 patients (13%) receiving placebo. Clinical remission occurred in 6/42 patients (14%) receiving GS‐5745 and 0/8 (0%) receiving placebo. Patients with a clinical response to GS‐5745 had reductions in matrix metalloproteinase‐9 tissue levels (mean 48.9% decrease from baseline compared with a mean 18.5% increase in nonresponders, P = 0.008) significant improvements in histopathology scores (confirmed with three separate histological disease activity indices), as well as changes in colonic gene expression that were consistent with reduced inflammation.ConclusionThis phase 1 trial provides preliminary evidence for the safety and therapeutic potential of GS‐5745 in the treatment of ulcerative colitis.

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“…32 Similarly, the pro-fibrogenic/proangiogenic PDGF, which is able to increase the production of collagen but not that of TIMP-1, is high in the serum of IBD patients. 35 …”

Section: Growth Factorsmentioning

confidence: 99%

Biomarkers of intestinal fibrosis – one step towards clinical trials for stricturing inflammatory bowel disease

Giuffrida

Pinzani

Corazza

et al. 2016

United European Gastroenterology Journal

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Intestinal fibrosis, caused by an excessive deposition of extracellular matrix components, and subsequent stricture development are a common complication of inflammatory bowel disease. However, currently there are no biomarkers which reliably predict the risk of developing intestinal strictures or identify early stages of fibrosis prior to clinical symptoms. Candidate biomarkers of intestinal fibrosis, including gene variants (i.e. nucleotide-binding oligomerization domain-2 gene), serum microRNAs (miR-19, miR-29), serum extracellular matrix proteins (i.e. collagen, fibronectin) or enzymes (i.e. tissue inhibitor of matrix metalloproteinase-1), serum growth factors (i.e. basic fibroblast growth factor, YKL-40), serum anti-microbial antibodies (i.e. anti-Saccharomyces cerevisiae) and circulating cells (i.e. fibrocytes) have shown conflicting results on relatively heterogeneous patients' cohorts, and none of them was proven to be strictly specific for fibrostenosis, but rather predictive of a disease disabling course. In this review we critically reassess the diagnostic and prognostic value of serum biomarkers of intestinal fibrosis in inflammatory bowel disease.

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Matrix Metalloproteinase-9: Its Interplay with Angiogenic Factors in Inflammatory Bowel Diseases

Cited by 52 publications

References 50 publications

Current and emerging therapeutic targets for IBD

Current and emerging therapeutic targets for IBD

Randomised clinical trial: a phase 1, dose‐ranging study of the anti‐matrix metalloproteinase‐9 monoclonal antibody GS‐5745 versus placebo for ulcerative colitis

Biomarkers of intestinal fibrosis – one step towards clinical trials for stricturing inflammatory bowel disease

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