Serum MMPs 7–9 and their inhibitors during glucocorticoid and anti-TNF-α therapy in pediatric inflammatory bowel disease

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.

Key Words::

• children
• IBD
• matrix metalloproteinase
• neutrophil elastase
• α2-macroglobulin

Acknowledgements

The authors thank Ms. Anne Nikkonen for excellent help in collecting the patient data. This study was supported by the Clinical Graduate School in Pediatrics and Obstetrics/Gynecology, University of Helsinki (H.R.), the Biomedicum Helsinki Foundation (L.M.), the Finnish Cultural Foundation (L.M.), the Finnish Medical Foundation (L.M.), the Finnish Pediatric Research Foundation (K-L.K.), the Helsinki University Central Hospital Research Fund (K-L.K), the Academy of Finland (T.S.), and the Päivikki and Sakari Sohlberg Foundation (K-L.K.). Funding: Supported by grants from the Clinical Graduate School in Pediatrics and Obstetrics/Gynecology, University of Helsinki, the Biomedicum Helsinki Foundation, the Finnish Cultural Foundation, the Finnish Medical Foundation, the Finnish Pediatric Research Foundation, the Helsinki University Central Hospital Research Fund, the Academy of Finland and the Päivikki and Sakari Sohlberg Foundation. None of the authors have conflict of financial interest.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.