Regulation and function of bone morphogenetic protein signaling in colonic injury and inflammation

Ji, Tuo; Takabayashi, Hidehiko; Mao, M.; Han, Xu; Xue, Xiang; Brazil, Jennifer C.; Eaton, Kathryn A.; Shah, Yatrik M.; Todisco, Andrea

doi:10.1152/ajpgi.00169.2016

Cited by 16 publications

(31 citation statements)

References 34 publications

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“…Previous work in the colon and skin has suggested that physiological attenuation of the BMP pathway is required for regeneration 21,22 and this was consistent with our finding that autocrine ligand exposure impaired secretory cell dedifferentiation capacity. Next, we mapped the BMP signalling landscape in human inflammatory bowel disease (IBD) and two distinct mouse intestinal regeneration models ( Supplementary Fig.4a,b).…”

Section: Mapping the Bmp Signalling Landscape In Mouse And Human Colosupporting

confidence: 93%

BMP pathway antagonism byGrem1regulates epithelial cell fate in intestinal regeneration

Koppens

Belnoue-Davis

Valbuena

et al. 2021

Preprint

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In the intestine, the homeostatic effect of Bone Morphogenetic Protein (BMP) on cell fate has predominantly been inferred through pathway inactivation. Here, we assessed the impact of autocrine Bmp4 expression on secretory cell fate. Ligand exposure reduced proliferation, expedited terminal differentiation, abrogated long-term secretory cell survival and prevented dedifferentiation. As stem cell plasticity is required for regenerative adaptive reprogramming, we spatiotemporally mapped and functionally explored BMP’s role in epithelial restitution. Following ulceration, physiological attenuation of BMP signalling arose through upregulation of the secreted antagonist, Grem1, from topographically distinct populations of stromal cells. Concomitant expression supported functional compensation, following Grem1 deletion from tissue-resident fibroblasts. BMP pathway manipulation showed that antagonist-mediated BMP attenuation was obligatory, but functionally sub-maximal, as regeneration was impaired or enhanced by epithelial overexpression of Bmp4 or Grem1 respectively. Mechanistically, Bmp4 abrogated regenerative stem cell reprogramming, despite a convergent impact of YAP/TAZ on cell fate in remodelled wounds.

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Section: Mapping the Bmp Signalling Landscape In Mouse And Human Colosupporting

confidence: 93%

BMP pathway antagonism byGrem1regulates epithelial cell fate in intestinal regeneration

Koppens

Belnoue-Davis

Valbuena

et al. 2021

Preprint

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“…Evidence indicated that the anticancer activity of HNK can also be mediated by upregulating p53 in CRC (14), but how HNK regulates p53 is unknown. Bone morphogenetic proteins (BMPs) belong to the transforming growth factor-β (TGF-β) super-family and plays an important role in regulating the proliferation and differentiation in epithelium of colon and rectum (17,18). The aberrant signal of BMPs has been involved in the cause and progress of CRC (19,20).…”

Section: Introductionmentioning

confidence: 99%

BMP7 mediates the anticancer effect of honokiol by upregulating p53 in HCT116 cells

Liu

Ren

et al. 2017

International Journal of Oncology

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Colorectal cancer (CRC) is the second leading cause of cancer death. Hence, there is a great need to explore new efficacious drugs for the treatment of CRC. Honokiol (HNK), a natural product extracted from magnolia bark, processes various biological activities, including anticancer. In this study, we introduced cell viability assay, western blotting, real-time PCR and immunofluorescent staining to determine the anticancer effect of HNK, and the possible mechanism underlying this biological process. We found that HNK can inhibit the proliferation and induce apoptosis in HCT116 cells in a concentration- and time-dependent manner. HNK activates p53 in HCT116 and other colon cancer cells. Exogenous p53 potentiates the anticancer of HNK, while p53 inhibitor decreases this effect of HNK. Moreover, HNK upregulates the expression of bone morphogenetic protein 7 (BMP7) in colon cancer cells; Exogenous BMP7 enhances the anticancer activity of HNK and BMP7 specific antibody reduces this effect of HNK. For mechanism, we found that HNK cannot increase the level of Smad1/5/8; Exogenous BMP7 potentiates the HNK-induced activation of p53. On the contrary, BMP7 specific antibody inhibits the HNK-induced activation of p53 in colon cancer cells and partly decreases the total level of p53. Our findings suggested that HNK may be a promising anticancer drug for CRC; activation of p53 plays an important role in the anticancer activity of HNK, which may be initialized partly by the HNK-induced upregulation of BMP7.

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“… 44 , 45 The anti-inflammatory effect of BMP signaling was further substantiated by the observation that deletion of Bmpr1a in the colonic mucosa leads to enhancement of Dextran Sulfate Sodium-induced colonic injury and inflammation. 45 Finally, transgenic expression of BMP-4 in the skin of mice treated with both the carcinogen N-methyl-N′-nitrosoguanidine and the tumor promoter 12-O-tetradecanoylphorbol-13-acetate leads to a marked decrease in the degree of cellular hyperproliferation and inflammation induced by these agents. 46 The significance of these findings has been further confirmed by the observation that patients with inflammatory bowel disease can exhibit alterations in the TGF-β signaling cascade and that these abnormalities can render patients unable to mount an effective anti-inflammatory response in the gastrointestinal tract.…”

Section: Bone Morphogenetic Protein Signaling Regulates Gastric Inflamentioning

confidence: 99%

“…Moreover, BMP-7 appears to decrease the degree of inflammation seen during ischemic acute renal failure in rats 43 . Similarly, BMP-7 ameliorates the severity of colonic inflammation, and it accelerates the healing of colitis in rats exposed to trinitrobenzenesulfonic acid, a well-established inducer of experimental colitis in rodents 44, 45. The anti-inflammatory effect of BMP signaling was further substantiated by the observation that deletion of Bmpr1a in the colonic mucosa leads to enhancement of Dextran Sulfate Sodium-induced colonic injury and inflammation 45 .…”

Section: Bone Morphogenetic Protein Signaling Regulates Gastric Inflamentioning

confidence: 99%

“…Similarly, BMP-7 ameliorates the severity of colonic inflammation, and it accelerates the healing of colitis in rats exposed to trinitrobenzenesulfonic acid, a well-established inducer of experimental colitis in rodents 44, 45. The anti-inflammatory effect of BMP signaling was further substantiated by the observation that deletion of Bmpr1a in the colonic mucosa leads to enhancement of Dextran Sulfate Sodium-induced colonic injury and inflammation 45 . Finally, transgenic expression of BMP-4 in the skin of mice treated with both the carcinogen N-methyl-N′-nitrosoguanidine and the tumor promoter 12-O-tetradecanoylphorbol-13-acetate leads to a marked decrease in the degree of cellular hyperproliferation and inflammation induced by these agents 46 .…”

Section: Bone Morphogenetic Protein Signaling Regulates Gastric Inflamentioning

confidence: 99%

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Regulation of Gastric Metaplasia, Dysplasia, and Neoplasia by Bone Morphogenetic Protein Signaling

Todisco

2017

Cellular and Molecular Gastroenterology and Hepatology

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The bone morphogenetic proteins, (BMP)s are regulatory peptides that have significant effects on the growth and differentiation of gastrointestinal tissues. In addition, the BMPs have been shown to exert anti-inflammatory actions in the gut and to negatively regulate the growth of gastric neoplasms. The role of BMP signaling in the regulation of gastric metaplasia, dysplasia and neoplasia has been poorly characterized. Transgenic expression in the mouse stomach of the BMP inhibitor noggin leads to decreased parietal cell number, increased epithelial cell proliferation, and to the emergence of SPEM. Moreover, expression of noggin increases Helicobacter-induced inflammation and epithelial cell proliferation, accelerates the development of dysplasia, and it increases the expression of signal transducer and activator of transcription 3 (STAT3) and of activation-induced cytidine deaminase (AID). These findings provide new clues for a better understanding of the pathophysiological mechanisms that regulate gastric inflammation and the development of both dysplastic and neoplastic lesions of the stomach.

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Regulation and function of bone morphogenetic protein signaling in colonic injury and inflammation

Cited by 16 publications

References 34 publications

BMP pathway antagonism byGrem1regulates epithelial cell fate in intestinal regeneration

BMP pathway antagonism byGrem1regulates epithelial cell fate in intestinal regeneration

BMP7 mediates the anticancer effect of honokiol by upregulating p53 in HCT116 cells

Regulation of Gastric Metaplasia, Dysplasia, and Neoplasia by Bone Morphogenetic Protein Signaling

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