Investigating beta inducible growth hormone 3 (BIGH3) as a mediator of fibrosis in inflammatory bowel disease

Abstract

Inflammatory bowel diseases (IBD) are characterized by chronic inflammation and development of fibrosis. Current therapeutics attempt to address inflammation, while fibrotic areas are surgically removed. Fibrosis is caused by excessive production of extracellular matrix (ECM) by activated fibroblasts. Fibroblast activation and ECM expression is mainly driven by transforming growth factor beta (TGFß) signaling. This project sought to identify a “co-factor” to TGFß, meaning a protein that acts synergistically in fibrosis with TGFß. One candidate is beta-inducible growth hormone 3 (BIGH3), which has been associated with increased collagen from lung fibroblasts and increased expression in patients with fibrotic IBD. BIGH3’s mechanistic role in colon fibrosis is previously unexplored. Following acute administration of dextran sulfate sodium (DSS) in drinking water, mice lacking BIGH3 (Bigh3-/-) did not exhibit differences from wildtype in inflammatory indicators. To assess fibrosis during chronic disease, three cycles of DSS were administered. Bigh3-/- colons did not show differences from wildtype in fibrosis scoring, however they showed increased inflammatory indicators. This suggested that BIGH3 did not affect histological signs of fibrosis but might have regulate colon inflammation. Understanding how inflammation and fibrosis are regulated in the colon will inform development of “co-factor” therapeutics.