MMP9 expression in intestinal fistula from patients with fistulizing CD and from human xenograft mouse model.

Abstract

Fistula treatment represents a major unmet medical need in the therapy of Crohn's disease (CD). Current medical therapies, such as anti-TNF antibody treatments, are often insufficient and do not achieve permanent fistula closure. Previously published data point toward a critical role for metalloproteinase-9 (MMP-9)/gelatinase B in fistula pathogenesis. The aim of this project was to investigate in detail MMP-9 expression in different fistula types and to confirm that MMP-9 is a potential target for fistula therapy in CD patients.Immunohistochemistry for total and active MMP-9, Cytokeratin 8 (CK-8) and co-staining of active MMP-9/CK-8 was performed in specimen derived from perianal fistulas, entero-enteric fistulas and fistulas from patients not responding to anti-TNF therapy. In addition, fistulas from the xenograft mouse model (anti-TNF treated or untreated) were analyzed.Total and active MMP-9 protein was detectable in cells lining the tracts of perianal and entero-enteric fistulas. Of note, total and active MMP-9 was also expressed in fistulas of CD patients non-responding to anti-TNF treatment. Interestingly, we detected considerable co-staining of active MMP-9 and CK-8 in particular in cells lining the fistula tract and in transitional cells around the fistulas. Furthermore, total and active MMP-9 are detectable in both anti-TNF treated and untreated xenograft fistulas.Taken together, our data suggest that MMP-9 is involved in fistula pathogenesis in CD patients, in fistulas of different origins and particularly in patients non-responding to anti-TNF therapy. Our xenograft fistula model is suitable for in vivo studies investigating a possible therapeutic role for MMP-9 targeting as fistula therapy.

• Authors: Céline Mamie, Ramona S Bruckner, Silvia Lang, Nahum Y Shpigel, Matthias Turina, Andreas Rickenbacher, Daniela Cabalzar-Wondberg, Yolanda Chvatchko, Gerhard Rogler, Michael Scharl
• Journal: Tissue barriers (Tissue Barriers) Vol. 10 Issue 2 Pg. 1994350 (04 03 2022) ISSN: 2168-8370 [Electronic] United States
• PMID: 34709129 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Tumor Necrosis Factor Inhibitors
• MMP9 protein, human
• Matrix Metalloproteinase 9

Topics

• Animals
• Crohn Disease (complications, drug therapy, pathology)
• Heterografts
• Humans
• Intestinal Fistula (drug therapy, etiology)
• Matrix Metalloproteinase 9 (therapeutic use)
• Mice
• Tumor Necrosis Factor Inhibitors