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. Wild type mice and 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;Bmpr1a^flox/flox), were treated with DSS to induce colonic injury and inflammation. Expression of BMP-4, β-gal, BMPR1A, IL-8, α-SMA, and phosphorylated Smad1-5-8, were assessed by X-Gal staining, QRT-PCR and immunohistochemistry. Morphology of the colonic mucosa was examined by staining with H&E. The effect of IFN-, TNF-α, IL-1β, and IL-6 on BMP-4 mRNA expression was investigated in human intestinal fibroblasts, while that of BMP-4 on IL-8 was assessed in human colonic organoids. BMP-4 was localized in α-SMA-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 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- stimulated BMP-4 expression, while IL-6 had no effect. BMP-4 reduced IL-8 mRNA expression in the organoids. Inflammation and injury inhibit BMP-4 expression and signaling, leading to enhanced colonic damage. These observations underscore the importance of BMP signaling in the regulation of intestinal inflammation and homeostasis.