The bone morphogenetic protein signaling pathway is upregulated in a mouse model of total parenteral nutrition.
Total parenteral nutrition (TPN) results in intestinal mucosal atrophic changes due to an absence of enteral nutrition; however, the mechanisms responsible for this are not fully understood. It has been shown that bone morphogenetic protein (BMP) activation inhibits intestinal epithelial cell (EC) proliferation. Therefore, we hypothesized that the BMP pathway could be upregulated by TPN. To address this, we randomly assigned mice to receive TPN or to be enterally fed (control) for 7 d. Mucosal EC isolates were harvested from the entire length of small intestine for RNA and protein measurements. Full-thickness, mid-small bowel was processed for histological examination. TPN increased the abundance of BMP2, BMP4, and BMP type II receptor at the RNA and protein levels. Phosphorylation of Smad1, Smad5, and Smad8 also was greater in the TPN group than in the control, which helped to confirm activation of this pathway. Interestingly, the TPN and control groups did not differ in the mRNA expression of the extracellular soluble bmp antagonists, noggin, gremlin, chordin, or follistatin. Compared to the control group, the expression of c-Myc (cellular myelocytomatosis) mRNA was lower, whereas the level of p21(WAF1/CIP1) was greater, in the TPN group. Because the BMP family may function through suppression of Wnt-beta-catenin signaling, this pathway was also examined. mRNA expression of Wnt 3, Wnt5a, and the Wnt receptor Lrp5 were lower in the TPN group compared to controls. The results suggest that the BMP signaling pathway may be involved in the development of intestinal mucosal atrophy due to TPN administration.
Zhang
Chaojun
C
Section of Pediatric Surgery, Department of Surgery, University of Michigan Medical School and C. S. Mott Children's Hospital, Ann Arbor, MI 48109, USA.
Feng
Yongjia
Y
Yang
Hua
H
Koga
Hiroyuki
H
Teitelbaum
Daniel H
DH
D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics*; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics*; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000502:physiology*; D004151:Dipeptides / Q000494:pharmacology; D005786:Gene Expression Regulation; D005973:Glutamine / Q000494:pharmacology; D007421:Intestine, Small / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D010289:Parenteral Nutrition, Total; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics; D012016:Reference Values; D015398:Signal Transduction
C525719:Bmp2 protein, mouse; C525810:Bmp4 protein, mouse; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D004151:Dipeptides; D005973:Glutamine; D012313:RNA; D052006:Bone Morphogenetic Protein Receptors, Type II; C054122:alanylglutamine