Editors' ChoiceINFLAMMATORY BOWEL DISEASE

Measuring inflammation in IBD with an OSM-ostat

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Science Translational Medicine  03 May 2017:
Vol. 9, Issue 388, eaan3777
DOI: 10.1126/scitranslmed.aan3777

Abstract

Oncostatin M is elevated in inflammatory bowel disease, wherein it may promote intestinal stroma cell inflammation and predict nonresponsiveness to anti-TNF therapy.

Tumor necrosis factor (TNF) inhibitors are mainstays of inflammatory bowel disease (IBD) treatment. However, many IBD patients fail TNF blockade. Currently, there is no way to predict who will benefit and when alternative therapeutic strategies are needed.

West et al. report progress on both fronts, as they have identified oncostatin M (OSM) as a biomarker of anti-TNF treatment–resistant IBD as well as a potential new therapeutic target. Across multiple adult and pediatric cohorts, the authors found elevated intestinal mucosal OSM expression in IBD patients versus controls. Additionally, high pretreatment OSM levels predicted nonresponsiveness to TNF blockade with over 90% sensitivity and specificity.

So what is OSM? An interleukin-6 cytokine family member, OSM can act as an inflammatory mediator in many contexts. Mutations in the OSM pathway confer risk of IBD, but little is known about its pathogenic role. West et al. found that hematopoietic cells are the main producers of OSM in the intestinal mucosa, whereas stromal cells express the highest levels of its receptor (OSMR). In IBD, not only did OSM levels increase, but so did the numbers of OSMR-positive stromal cells. Exposure to OSM induced chemokine and cytokine production by stromal cells, a phenotype that was exaggerated in IBD patients and further magnified by concurrent exposure to TNF.

In a model of anti–TNF-resistant IBD, mice lacking OSM developed significantly less disease than their wild-type counterparts. Reduced colonic chemokine and cytokine production accompanied attenuated signs of inflammation, especially late in the disease course, and could be recapitulated by OSM neutralization.

These findings suggest that an OSM-induced proinflammatory stromal cell response promotes IBD severity or chronicity and lays the groundwork for evaluation of OSM blockade as a therapeutic target. More immediately, OSM emerges as a promising biomarker to predict response to anti-TNF therapy. Importantly, anti-TNF inhibitors are widely used in other inflammatory diseases, where they similarly benefit some but not all patients. Although the authors did not confirm a role for OSM in a mouse model of psoriasis, the potential diagnostic or therapeutic utility of OSM beyond IBD is an intriguing possibility.

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