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

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.