Bone morphogenetic protein 2, a member of the TGF-b superfamily, has been implicated in the development of the skeleton, kidney and pancreas. It functions by binding to the type II receptor and recruiting a type I receptor, then phosphorylating intracellular substrates, i.e., Smad1, Smad5, and Smad8, which form complex with Smad4, translocate into the nucleus and regulate the transcription of various targets. BMP2 has an anti-fibrogenic function in multiple organs. For instance, it antagonizes TGF-binduced renal fibrogenic signals in renal fibroblasts. BMP2 prevents differentiation and cell migration of lung fibroblasts. BMP2 also attenuates pressure overload-induced cardiac fibrosis. However, whether BMP2 has an anti-fibrogenic function in the pancreas is largely unknown. BMP2 plays an anti-fibrogenic role in multiple organs. However, the function of BMP2 in the development of pancreatic fibrosis remains unclear. We have demonstrated previously that BMP2 inhibits TGF-b-induced PSC activation and ECM formation in vitro. In this study, we used BMPR2+/2 mice and demonstrated that BMPR2/Smad1/5/8 signaling plays an anti-fibrogenic role in the pancreas, which was probably through inhibiting TGF-b/Smad2 and/p38MAPK signaling pathways. BMPR2 is one of the three BMP type II receptors. Mutations of the BMPR2 gene have been implicated in the pathogenesis of pulmonary arterial hypertension in human. In mice, BMPR2 homozygous deficiency is embryonic lethal, while heterozygous mice are phenotypically normal. These mice are susceptible to the secondary inflammatory insults such as 5- MK-4827 lipoxygenase and develop PAH. Similarly, BMPR2+/2 mice in our study were morphologically healthy, presented normal pancreatic histology and function. A comparable basal pSmad1/ 5/8 level in the pancreas was observed in BMPR2+/2 mice as in wild-type control, indicating a functional pancreatic BMP signaling existing in the heterozygous mice, which may account for the normal development of the pancreas. Under CP induction, the pancreatic pSmad1/5/8 level was elevated in wild-type mice, whereas this effect was not seen in BMPR2+/2 mice. Furthermore, more severe pancreatic fibrosis and activated PSCs were observed in BMPR2+/2 mice. In vitro, in response to BMP2 stimulation, pSmad1/5/8 level was elevated in PSCs isolated from wild-type mice, and this effect was abolished in PSCs from BMPR2+/2 mice. Subsequently, the PSCs from BMPR2+/2 mice lost BMP29s inhibitory effect on TGF-b-induced ECM production. Together these in vivo and in vitro results establish the antifibrogenic role of BMPR2/Smad1/5/8 signaling in the pancreas via CP model. While more severe fibrosis following CP induction was observed in BMPR2 deficient mice versus their wild-type counterparts, neither persistent endocrine dysfunction nor overt diabetes was observed in either group. These results are not unexpected.