Abstract
Flavones have the potential of being used as a dietary supplement for bone health promotion beyond calcium and vitamin D. Recent studies have showed that flavones enhanced bone formation and inhibited bone resorption by affecting osteoblast and osteoclast differentiation through various cell signaling pathways. In this study, we investigated the effects of a new flavone (2R,3S)-pinobanksin-3-cinnamate, isolated from the metabolites of the endophytic fungus Penicillium sp. FJ-1 of Acanthus ilicifolius L., Acanthaceae, on osteoblast differentiation by using MC3T3-E1 cells. It was observed that (2R,3S)-pinobanksin-3-cinnamate promoted osteoblast differentiation, as evidenced by increased mineralization process and alkaline phosphatase activity, as well as expression of genes encoding the bone differentiation. Moreover (2R,3S)-pinobanksin-3-cinnamate treatment upregulated the gene expression of wingless-type MMTV integration site family, bone morphogenetic protein and runt-related transcription factor 2, and protein expression of phosphor-Smad1/5/8, β-catenin and runt-related transcription factor 2 in MC3T3-E1 cells. The osteoblast differentiation effects induced by (2R,3S)-pinobanksin-3-cinnamate were attenuated by the bone morphogenetic protein antagonist Noggin, and wingless-type MMTV integration site family signaling pathway inhibitors Dickkopf-1. Co-treatment with adenosine 30,50-cyclic monophosphate and guanosine 30,50-cyclic monophosphate pathway inhibitors, H89 and KT5823, respectively, reversed the (2R,3S)-pinobanksin-3-cinnamate-induced activations of p-Smad1/5/8, β-catenin, and runt-related transcription factor 2. Our data demonstrated that (2R,3S)-pinobanksin-3-cinnamate promoted the osteoblast differentiation of MC3T3-E1 cells, at least partially through the adenosine 30,50-cyclic monophosphate and guanosine 30,50-cyclic monophosphate signaling pathways, providing the scientific rational to develop (2R,3S)-pinobanksin-3-cinnamate against bone loss-associated diseases.
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References
Aubin, J.E., 1998. Bone stem cells. J. Cell. Biol. 72, 73–82.
Augustine, M., Horwitz, M.J., 2013. Parathyroid hormone and parathyroid hormone-related protein analogs as therapies for osteoporosis. Curr. Osteoporos. Rep. 11, 400–406.
Chen, J., Zhang, H., Zhang, X., Yang, G., Lu, L., Lu, X., Wan, C., Ijiri, K., Ji, H., Li, Q., 2014. Epithelial sodium channel enhanced osteogenesis via cGMP/PKGII/ENaC signaling in rat osteoblast. Mol. Biol. Rep. 41, 2161–2169.
Chen, J.R., Lazarenko, O.P., Blackburn, M.L., Badeaux, J., Badger, T.M., Ronis, M.J.J., 2009. Infant formula promotes bone growth in neonatal piglets by enhancing osteoblastogenesis through bone morphogenic protein signaling. J. Nutr. 139, 1839–1847.
Chen, J.R., Singhal, R., Lazarenko, O., Liu, X., Hogue, W., Badger, T.M., Ronis, M.J., 2008. Short term effects on bone quality associated with consumption of soy protein isolate and other dietary protein sources in rapidly growing female rats. Exp. Biol. Med. 233, 1348–1358.
Chen, Y.M., Ho, S.C., Woo, J.L.F., 2006. Greater fruit and vegetable intake is associated with increase bone mass among postmenopaual Chinese women. Br. J. Nutr. 96, 745–751.
Corrado, A., Sanpaolo, E.R., Di Bello, S., Cantatore, F.P., 2017. Osteoblast as a target of anti-osteoporotic treatment. Postgrad. Med. 129, 858–865.
Hayashi, K., Yamaguchi, T., Yano, S., Kanazawa, I., Yamauchi, M., Yamamoto, M., Sugimoto, T., 2009. BMP/Wnt antagonists are upregulated by dexamethasone in osteoblasts and reversed byalendronate and PTH: potential therapeutic targets for glucocorticoid-induced osteoporosis. Biochem. Biophys. Res. Commun. 379, 261–266.
Jia, T.L., Wang, H.Z., Xie, L.P., Wang, X.Y., Zhang, R.Q., 2003. Daidzein enhances osteoblast growth that may be mediated by increased bone morphogenetic protein (BMP) production. Biochem. Pharmacol. 65, 709–715.
Kikuchi, A., 2000. Regulation of beta-catenin signaling in the Wnt pathway. Biochem. Biophys. Res. Commun. 268, 243–248.
Kim, M.B., Song, Y., Hwang, J.K., 2014. Kirenol stimulates osteoblast differentiation through activation ofthe BMP and Wnt/ß-catenin signaling pathways in MC3T3-E1 cells. Fitoterapia 98, 59–65.
Kinoshita, T., Kobayashi, S., Ebara, S., Yoshimura, Y., Horiuchi, H., Tsutsumimoto, T., Wakabayashi, S., Takaoka, K., 2000. Phosphodiesterase inhibitors, pentoxifylline and rolipram, increase bone mass mainly by promoting bone formation in normal mice. Bone 27, 811–817.
Krishnan, V., Bryant, H.U., Macdougald, O.A., 2006. Regulation of bone mass by Wnt signaling. J. Clin. Invest. 116, 1202–1209.
Lee, M.H., Kim, Y.J., Kim, HJ., Park, H.D., Kang, A.R., Kyung, H.M., 2003. BMP-2-induced Runx2 expression is mediated by Dlx5, and TGF-beta 1 opposes the BMP-2-induced osteoblast differentiation by suppression of Dlx5 expression. J. Biol. Chem. 278, 34387–34394.
Liou, S.F., Hsu, J.H., Chu, H.C., Lin, H.H., Chen, I.J., Yeh, J.L., 2015. KMUP-1 promotes osteoblast differentiation through cAMP and cGMP pathways and signaling of BMP-2/Smad1/5/8 and Wnt/ß-Catenin. J. Cell. Physiol. 230, 2038–2048.
Liu, H., Zhao, M., Yang, S., Gong, D.R., Chen, D.Z., Du, D.Y., 2015. (2R, 3S)-pinobanksin-3-cinnamate improves cognition and reduces oxidative stress in rats with vascular dementia. J. Nat. Med. 69, 358–365.
Liu, J.F., Chen, W.J., Xin, B.R., Lu, J., 2014. Metabolites ofthe endophytic fungus Penicillium sp. FJ-1 of Acanthus ilicifolius. Nat. Prod. Commun. 9, 799–801.
Lo, Y.C., Chang, Y.H., Wei, B.L., Huang, Y.L., Chiou, W.F., 2010. Betulinic acid stimulates the differentiation and mineralization of osteoblastic MC3T3-E1 cells: involvement of BMP/Runx2 and beta-catenin signals. J. Agric. Food Chem. 58, 6643–6649.
Long, F., 2011. Building strong bones: molecular regulation ofthe osteoblast lineage. Nat. Rev. Mol. Cell. Biol. 13, 27–38.
MacDonald, B.T., He, X., 2012. Frizzled and LRP5/6 receptors for Wnt/beta-catenin signaling. Cold Spring Harb. Perspect. Biol. 4, a007880.
Marie, P.J., Kassem, M., 2011. Osteoblasts in osteoporosis: past, emerging, and future anabolic targets. Eur. J. Endocrinol. 165, 1–10.
Nakagawa, K., Imai, Y., Ohta, Y., Takaoka, K., 2007. Prostaglandin E2 EP4 agonist (ONO-4819) accelerates BMP-induced osteoblastic differentiation. Bone 41, 543–548.
Niu, Y.B., Li, Y.H., Kong, X.H., Zhang, R., Sun, Y., Li, Q., Li, C., Liu, L., Wang, J., Mei, Q.B., 2012. The beneficial effect of Radix dipsaci total saponins on bone metabolism in vitro and in vivo and the possible mechanisms of action. Osteoporos. Int. 23, 2649–2660.
Prynne, C.J., Mishra, G.D., O’Connell, M.A., Muniz, G., Laskey, M.A., Yan, L., Prentice, A., Ginty, F., 2006. Fruit and vegetable intakes and bone mineral status: a cross-sectional study in 5 age and sex cohorts. Am. J. Clin. Nutr. 83, 1420–1428.
Riggs, B.L., Parfitt, A.M., 2005. Drugs used to treat osteoporosis: the critical need for a uniform nomenclature based on their action on bone remodeling. J. Bone Miner. Res. 20, 177–184.
Rodan, G.A., Martin, T.J., 2000. Therapeutic approaches to bone diseases. Science 289, 1508–1514.
Sun, X., Yang, X., Zhao, Y., Li, Y., Guo, L., 2018. Effects of 17ß-estradiol on mitophagy in the murine MC3T3-E1 osteoblast cell line is mediated via G protein-coupled estrogen receptor and the ERK1/2 signaling pathway. Med. Sci. Monit. 24, 903–911.
Tang, X., Zhu, X., Liu, S., Wang, S., Ni, X., 2011. Isoflavones suppress cyclic adenoise 3/, 5′-monophoaphate regulatory element-mediated transcription in osteoblastic cell lines. J. Nutr. Biochem. 22, 865–873.
Wakabayashi, S., Tsutsumimoto, T., Kawasaki, S., Kinoshita, T., Horiuchi, H., Takaoka, K., 2002. Involvement of phosphodiesterase isozymes in osteoblastic differentiation. J. Bone Miner. Res. 17, 249–256.
Wan, M., Cao, X., 2005. BMP signaling in skeletal development. Biochem. Biophys. Res. Commun. 328, 651–657.
Wang, D.H., Hu, Y.S., Du, J.J., Hu, Y.Y., Zhong, W.D., Qin, W.J., 2009. Ghrelin stimulates proliferation of human osteoblastic TE85 cells via NO/cGMP signaling pathway. Endocrine 35, 112–117.
Yoon, H.J., Seo, C.R., Kim, M., Kim, Y.J., Song, N.J., Jang, W.S., Kim, B.J., Lee, J., Hong, J.W., Nho, C.W., Park, K.W., 2013. Dichloromethane extracts of Sophorajaponica L. stimulate osteoblast differentiation in mesenchymal stem cells. Nutr. Res. 33, 1053–1062.
Zhao, M., Harris, S.E., Horn, D., Geng, Z., Nishimura, R., Mundy, G.R., 2002. Bone morphogenetic protein receptor signaling is necessary for normal murine postnatal bone formation. J. Cell. Biol. 157, 1049–1060.
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Study concepts and design: Z-FG; Experimental studies: HZ, G-PZ, HJ; data analysis: HZ, G-PZ; manuscript preparation: HZ, G-PZ, HJ, Z-FG.
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Zhang, H., Zhang, GP., Jiang, H. et al. (2R, 3S)-Pinobanksin-3-cinnamate promotes osteoblast differentiation through cAMP and cGMP pathways. Rev. Bras. Farmacogn. 28, 468–473 (2018). https://doi.org/10.1016/j.bjp.2018.05.006
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DOI: https://doi.org/10.1016/j.bjp.2018.05.006