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Changes in matrix metalloproteinase (MMP) and tissue inhibitors of metalloproteinases (TIMP) expression profile in Crohn's disease after immunosuppressive treatment correlate with histological score and calprotectin values

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Abstract

Background

Matrix metalloproteinases (MMPs) constitute a family of enzymes capable of degrading various extracellular matrices (ECM) and basement membrane components playing a role in ECM turnover. They activate and degrade signaling molecules, such as cytokines and chemokines. MMPs are involved in inflammation and have been implicated in tissue degradation and repair occurring in inflammatory bowel disease. The aim of this study was to investigate the MMP profile of intestinal Crohn's disease (CD) patients before and after immunosuppressive treatment (anti-TNF-α agents or corticosteroids and conventional immunosuppressants azathioprine or methotrexate) to learn more about the therapeutic pathways for immunosuppressive agents.

Methods

Expression of MMP-1, MMP-7, MMP-9, MMP-10, and MMP-26 and tissue inhibitors of metalloproteinases (TIMP)-1 and TIMP-3 was studied by immunohistochemistry in pretreatment and post-treatment tissue samples. Semiquantitative immunohistochemical scores were tested for correlations with fecal and serum inflammation markers as well as endoscopic and clinical disease activity scores.

Results

Neutrophil MMP-9 (p = 0.039) and MMP-26 (p = 0.030) and stromal TIMP-1 (p = 0.041) and TIMP-3 (p = 0.029) decreased along with treatment. However, expression of TIMP-3 by enterocytes tended to increase. Total histological score demonstrated positive correlation with neutrophil MMP-9 (p = 0.000), MMP-26 (p = 0.014), and macrophage TIMP-1 (p = 0.001). Calprotectin followed a similar pattern with stromal MMP-26 (p = 0.011), TIMP-1 (p = 0.000), and TIMP-3 (p = 0.001). Crohn's disease endoscopic index of severity (CDEIS) value correlated positively with macrophage TIMP-1 (p = 0.007) and stromal TIMP-3 (p = 0.005). Epithelial TIMP-3 presented with negative correlations with CDEIS (p = 0.006) and C-reactive protein values (p = 0.004).

Conclusions

Our results suggest that immunosuppressive drugs modulate disease activity in CD by downregulation of MMP-9 and MMP-26 positive neutrophils and stromal TIMP-1 and TIMP-3.

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Abbreviations

CD:

Crohn's disease

MMP:

matrix metalloproteinase

TIMP:

tissue inhibitor of metalloproteinase

CDAI:

Crohn's disease activity index

CDEIS:

Crohn's disease endoscopic index of severity

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Acknowledgments

We thank Ms. Alli Tallqvist for the skillful technical assistance. This study was supported by the Academy of Finland, the Sigrid Juselius Foundation, Finska Läkaresällskapet, the Finnish Cultural Foundation (T.S, L.M.), the Mary and George C. Ehrnrooth Foundation (T.S.), the Orion-Farmos Research Foundation (T.S.), the Päivikki and Sakari Sohlberg Foundation (K.-L.K.), the Pediatric Research Foundation (K-L.K), Helsinki University Central Hospital Research Fund and Biomedicum Foundation (L.M.), Finland, and the Swedish Research Council (U.S-K.), Sweden.

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Authors and Affiliations

  1. Department of Dermatology, Helsinki University Central Hospital and Biomedicum Helsinki, University of Helsinki, Meilahdentie 2, 00250, Helsinki, Finland

    Laura Mäkitalo & Ulpu Saarialho-Kere

  2. Division of Gastroenterology, Department of Medicine, Helsinki University Central Hospital and Haartman Institute, University of Helsinki, Helsinki, Finland

    Taina Sipponen

  3. Department of Pathology, Helsinki University Central Hospital and Haartman Institute, University of Helsinki, Helsinki, Finland

    Päivi Kärkkäinen

  4. Hospital for Children and Adolescents, Helsinki University Central Hospital, Helsinki, Finland

    Kaija-Leena Kolho

  5. Department of Clinical Science and Education and Section of Dermatology, Karolinska Institutet at Stockholm Söder Hospital, Stockholm, Sweden

    Ulpu Saarialho-Kere

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  1. Laura Mäkitalo
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Correspondence to Ulpu Saarialho-Kere.

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Mäkitalo, L., Sipponen, T., Kärkkäinen, P. et al. Changes in matrix metalloproteinase (MMP) and tissue inhibitors of metalloproteinases (TIMP) expression profile in Crohn's disease after immunosuppressive treatment correlate with histological score and calprotectin values. Int J Colorectal Dis 24, 1157–1167 (2009). https://doi.org/10.1007/s00384-009-0756-5

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