Open Access

Bone morphogenetic protein 2 regulates the differentiation of nitrergic enteric neurons by modulating Smad1 signaling in slow transit constipation

  • Authors:
    • Xuliang Liu
    • Shangming Liu
    • Yanan Xu
    • Xiuqin Liu
    • Daqing Sun
  • View Affiliations

  • Published online on: September 7, 2015     https://doi.org/10.3892/mmr.2015.4297
  • Pages: 6547-6554
  • Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Bone morphogenetic proteins (BMPs) belong to the transforming growth factor superfamily and have been implicated in chondrogenesis and neuronal differentiation. In order to examine the function of bone morphogenetic protein 2 (BMP‑2) on the differentiation of nitrergic enteric neurons in slow transit constipation (STC), the expression of BMP‑2 and neuronal nitric oxide synthase (nNOS) was investigated in the myenteric nerve plexus in STC and control tissues by immunohistochemical assays. The present study demonstrated that BMP‑2 and nNOS were expressed in the myenteric nerve plexus and their levels were differentially altered in the STC group and control group. In addition, the effect of BMP‑2 on primary myenteric neurons was investigated by measuring the neurite length. The results demonstrated that BMP‑2 regulated the differentiation of primary enteric neurons and increased the length of neurites compared with the control group. In addition, the effect of BMP‑2 on the expression of nNOS was also investigated in primary enteric neurons and the Smad1 signal transduction pathway by western blot analysis, reverse transcription quantitative polymerase chain reaction and immunofluorescence assay. The results suggested that BMP‑2 promoted the expression of nNOS in primary myenteric neurons and induced phosphorylation of Smad1. These data indicate a new role for BMP‑2 as an important transcriptional cofactor that regulates the differentiation of nitrergic enteric neurons through the Smad1 pathway. Intervention of BMP‑2 may be useful for the treatment of STC.

References

1 

Knowles CH and Martin JE: Slow transit constipation: A model of human gut dysmotility. Review of possible aetiologies. Neurogastroenterol Motil. 12:181–196. 2000. View Article : Google Scholar : PubMed/NCBI

2 

Bassotti G, Chistolini F, Nzepa FS and Morelli A: Colonic propulsive impairment in intractable slow-transit constipation. Arch Surg. 138:1302–1304. 2003. View Article : Google Scholar : PubMed/NCBI

3 

Bassotti G, Roberto GD, Sediari L and Morelli A: Toward a definition of colonic inertia. World J Gastroenterol. 10:2465–2467. 2004. View Article : Google Scholar : PubMed/NCBI

4 

Furness JB, Nguyen TV, Nurgali K and Shimizu Y: The enteric nervous system and its extrinsic connections. Textbook of Gastroenterology. Yamada T, Alpers DH, Kalloo AN, Kaplowitz N, Owyang C and Powell DW: 1. 5th edition. Blackwell Publishing; Philadelphia, PA: pp. 15–39. 2003

5 

Furness JB and Costa M: The Enteric Nervous System. Churchill Livingstone; Edinburgh: 1987

6 

Chevalier J, Derkinderen P, Gomes P, Thinard R, Naveilhan P, Vanden Berghe P and Neunlist M: Activity-dependent regulation of tyrosine hydroxylase expression in the enteric nervous system. J Physiol. 586:1963–1975. 2008. View Article : Google Scholar : PubMed/NCBI

7 

Ekblad E, Sjuve R, Arner A and Sundler F: Enteric neuronal plasticity and a reduced number of interstitial cells of Cajal in hypertrophic rat ileum. Gut. 42:836–844. 1998. View Article : Google Scholar : PubMed/NCBI

8 

Bassotti G, Villanacci V, Maurer CA, Fisogni S, Di Fabio F, Cadei M, Morelli A, Panagiotis T, Cathomas G and Salerni B: The role of glial cells and apoptosis of enteric neurones in the neuropathology of intractable slow transit constipation. Gut. 55:41–46. 2006. View Article : Google Scholar

9 

Bassotti G and Villanacci V: Slow transit constipation: A functional disorder becomes an enteric neuropathy. World J Gastroenterol. 12:4609–4613. 2006.PubMed/NCBI

10 

Lee JI, Park H, Kamm MA and Talbot IC: Decreased density of interstitial cells of Cajal and neuronal cells in patients with slow-transit constipation and acquired megacolon. J Gastroenterol Hepatol. 20:1292–1298. 2005. View Article : Google Scholar : PubMed/NCBI

11 

Anitha M, Shahnavaz N, Qayed E, Joseph I, Gossrau G, Mwangi S, Sitaraman SV, Greene JG and Srinivasan S: BMP2 promotes differentiation of nitrergic and catecholaminergic enteric neurons through a Smad1-dependent pathway. Am J Physiol Gastrointest Liver Physiol. 298:G375–G383. 2010. View Article : Google Scholar :

12 

Katagiri T, Akiyama S, Namiki M, Komaki M, Yamaguchi A, Rosen V, Wozney JM, Fujisawa-Sehara A and Suda T: Bone morphogenetic protein-2 inhibits terminal differentiation of myogenic cells by suppressing the transcriptional activity of MyoD and myogenin. Exp Cell Res. 230:342–351. 1997. View Article : Google Scholar : PubMed/NCBI

13 

Aoyama K, Yamane A, Suga T, Suzuki E, Fukui T and Nakamura Y: Bone morphogenetic protein-2 functions as a negative regulator in the differentiation of myoblasts, but not as an inducer for the formations of cartilage and bone in mouse embryonic tongue. BMC Dev Biol. 11:442011. View Article : Google Scholar : PubMed/NCBI

14 

Liu A and Niswander LA: Bone morphogenetic protein signalling and vertebrate nervous system development. Nat Rev Neurosci. 6:945–954. 2005. View Article : Google Scholar : PubMed/NCBI

15 

Chalazonitis A, D'Autréaux F, Guha U, Pham TD, Faure C, Chen JJ, Roman D, Kan L, Rothman TP, Kessler JA and Gershon MD: Bone morphogenetic protein-2 and -4 limit the number of enteric neurons but promote development of a TrkC-expressing neuro-trophin-3-dependent subset. J Neurosci. 24:4266–4282. 2004. View Article : Google Scholar : PubMed/NCBI

16 

Chen D, Zhao M and Mundy GR: Bone morphogenetic proteins. Growth Factors. 22:233–241. 2004. View Article : Google Scholar : PubMed/NCBI

17 

Kishigami S and Mishina Y: BMP signaling and early embryonic patterning. Cytokine Growth Factor Rev. 16:265–278. 2005. View Article : Google Scholar : PubMed/NCBI

18 

Roberts DJ, Johnson RL, Burke AC, Nelson CE, Morgan BA and Tabin C: Sonic hedgehog is an endodermal signal inducing Bmp-4 and Hox genes during induction and regionalization of the chick hindgut. Development. 121:3163–3174. 1995.PubMed/NCBI

19 

Goldstein AM, Brewer KC, Doyle AM, Nagy N and Roberts DJ: BMP signaling is necessary for neural crest cell migration and ganglion formation in the enteric nervous system. Mech Dev. 122:821–833. 2005. View Article : Google Scholar : PubMed/NCBI

20 

Kawabata M, Imamura T and Miyazono K: Signal transduction by bone morphogenetic proteins. Cytokine Growth Factor Rev. 9:49–61. 1998. View Article : Google Scholar : PubMed/NCBI

21 

Hoodless PA, Haerry T, Abdollah S, Stapleton M, O'Connor MB, Attisano L and Wrana JL: MADR1, a MAD-related protein that functions in BMP2 signaling pathways. Cell. 85:489–500. 1996. View Article : Google Scholar : PubMed/NCBI

22 

Chalazonitis A, Pham TD, Li Z, Roman D, Guha U, Gomes W, Kan L, Kessler JA and Gershon MD: Bone morphogenetic protein regulation of enteric neuronal phenotypic diversity: Relationship to timing of cell cycle exit. J Comp Neurol. 509:474–492. 2008. View Article : Google Scholar : PubMed/NCBI

23 

Chalazonitis A, D'Autreaux F, Pham TD, Kessler JA and Gershon MD: Bone morphogenetic proteins regulate enteric gliogenesis by modulating ErbB3 signaling. Dev Biol. 350:64–79. 2011. View Article : Google Scholar :

24 

Rossi E, Villanacci V, Fisogni S, Morelli A, Salerni B, Grigolato P and Bassotti G: Chromosomal study of enteric glial cells and neurons by fluorescence in situ hybridization in slow transit constipation. Neurogastroenterol Motil. 19:578–584. 2007. View Article : Google Scholar : PubMed/NCBI

25 

Tomita R, Fujisaki S, Ikeda T and Fukuzawa M: Role of nitric oxide in the colon of patients with slow-transit constipation. Dis Colon Rectum. 45:593–600. 2002. View Article : Google Scholar : PubMed/NCBI

26 

Moncada S, Palmer RM and Higgs EA: Nitric oxide: Physiology, pathophysiology, and pharmacology. Pharmacol Rev. 43:109–142. 1991.PubMed/NCBI

27 

Saur D, Paehge H, Schusdziarra V and Allescher HD: Distinct expression of splice variants of neuronal nitric oxide synthase in the human gastrointestinal tract. Gastroenterology. 118:849–858. 2000. View Article : Google Scholar : PubMed/NCBI

28 

Porter AJ, Wattchow DA, Hunter A and Costa M: Abnormalities of nerve fibers in the circular muscle of patients with slow transit constipation. Int J Colorectal Dis. 13:208–216. 1998. View Article : Google Scholar : PubMed/NCBI

29 

Kwon SJ, Lee GT, Lee JH, Kim WJ and Kim IY: Bone morphogenetic protein-6 induces the expression of inducible nitric oxide synthase in macrophages. Immunology. 128(Suppl 1): e758–e765. 2009. View Article : Google Scholar : PubMed/NCBI

30 

Fu M, Vohra BP, Wind D and Heuckeroth RO: BMP signaling regulates murine enteric nervous system precursor migration, neurite fasciculation, and patterning via altered Ncam1 polysialic acid addition. Dev Biol. 299:137–150. 2006. View Article : Google Scholar : PubMed/NCBI

31 

Piek E, Heldin CH and Ten Dijke P: Specificity, diversity, and regulation in TGF-beta superfamily signaling. FASEB J. 13:2105–2124. 1999.PubMed/NCBI

32 

Heldin CH, Miyazono K and Ten Dijke P: TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature. 390:465–471. 1997. View Article : Google Scholar : PubMed/NCBI

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November 2015
Volume 12 Issue 5

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Copy and paste a formatted citation
APA
Liu, X., Liu, S., Xu, Y., Liu, X., & Sun, D. (2015). Bone morphogenetic protein 2 regulates the differentiation of nitrergic enteric neurons by modulating Smad1 signaling in slow transit constipation. Molecular Medicine Reports, 12, 6547-6554. https://doi.org/10.3892/mmr.2015.4297
MLA
Liu, X., Liu, S., Xu, Y., Liu, X., Sun, D."Bone morphogenetic protein 2 regulates the differentiation of nitrergic enteric neurons by modulating Smad1 signaling in slow transit constipation". Molecular Medicine Reports 12.5 (2015): 6547-6554.
Chicago
Liu, X., Liu, S., Xu, Y., Liu, X., Sun, D."Bone morphogenetic protein 2 regulates the differentiation of nitrergic enteric neurons by modulating Smad1 signaling in slow transit constipation". Molecular Medicine Reports 12, no. 5 (2015): 6547-6554. https://doi.org/10.3892/mmr.2015.4297