The
bone morphogenetic proteins (BMPs) regulate gastrointestinal homeostasis. We investigated the expression of BMP-4 and the localization and function of BMP signaling during colonic injury and
inflammation. Mice expressing the β-
galactosidase (β-gal) gene under the control of a BMP-responsive
element (BRE), BMP-4-β-gal/ mice, and animals generated by crossing
villin-Cre mice to mice with floxed alleles of
BMP receptor 1A (
villin-Cre;Bmpr1aflox/flox) were treated with
dextran sodium sulfate (DSS) to induce colonic injury and
inflammation. Expression of BMP-4, β-gal, BMPR1A,
IL-8, α-smooth muscle actin, and phosphorylated Smad1, -5, and -8 was assessed by
X-Gal staining, quantitative RT-PCR, and immunohistochemistry. Morphology of the colonic mucosa was examined by staining with
hematoxylin and
eosin. The effect of IFN-γ, TNF-α, IL-1β, and
IL-6 on BMP-4
mRNA expression was investigated in human intestinal fibroblasts, whereas that of BMP-4 on
IL-8 was assessed in human colonic organoids. BMP-4 was localized in α-smooth muscle actin-positive mesenchymal cells while the majority of BMP-generated signals targeted the epithelium. DSS caused injury and
inflammation leading to reduced expression of BMP-4 and of BMPR1A mRNAs, and to decreased BMP signaling. Deletion of BMPR1A enhanced colonic
inflammation and damage. Administration of anti-TNF-α
antibodies to DSS-treated mice ameliorated colonic
inflammation and increased the expression of BMP-4 and BMPR1A mRNAs. TNF-α and IL-1β inhibited both basal and IFN-γ-stimulated BMP-4 expression, whereas
IL-6 had no effect. BMP-4 reduced TNF-α-stimulated
IL-8 mRNA expressor
IL-8 mRNA expression in the organoids.
Inflammation and injury inhibit BMP-4 expression and signaling, leading to enhanced colonic damage and
inflammation. These observations underscore the importance of BMP signaling in the regulation of intestinal
inflammation and homeostasis.
NEW & NOTEWORTHY: In this study we report a series of novel observations that underscore the importance of
bone morphogenetic protein (BMP) signaling in the regulation of colonic homeostasis during the development of injury and
inflammation. In particular, we present evidence that BMP signaling mitigates the response of the colonic epithelium to injury and
inflammation and that
cytokines, such as TNF-α and IL-1β, inhibit the expression of BMP-4.