Skip to main content
NCBI home page
Protein & Cell logoLink to Protein & Cell
. 2013 Jun 6;4(7):539–547. doi: 10.1007/s13238-013-3003-3

Chrysin promotes osteogenic differentiation via ERK/MAPK activation

Wenfeng Zeng 13003,23003, Yan Yan 33003, Fayun Zhang 13003, Chunling Zhang 13003,✉, Wei Liang 13003,✉
PMCID: PMC4875509  PMID: 23744338

Abstract

The effect of the anti-inflammatory flavonoid chrysin on osteogenesis was determined in preosteoblast MC3T3-E1 cells. Results demonstrated that chrysin could induce osteogenic differentiation in the absence of other osteogenic agents. Chrysin treatment promoted the expression of transcription factors (Runx2 and Osx) and bone formation marker genes (Col1A1, OCN, and OPN) as well as enhanced the formation of mineralized nodules. During osteogenic differentiation, chrysin preferentially activated ERK1/2, but not JNK nor the p38 MAPKs. Further experiments with inhibitors revealed the co-treatment of U0126, PD98059, or ICI182780 (a general ER antagonist) with chrysin effectively abrogated the chrysin-induced osteogenesis and ERK1/2 activation. Thus, the effect of chrysin on osteogenesis is ERK1/2-dependent and involves ER. Therefore, chrysin has the significant potential to enhance osteogenesis for osteoporosis prevention and treatment.

Electronic Supplementary Material

Supplementary material is available for this article at 10.1007/s13238-013-3003-3 and is accessible for authorized users.

Keywords: chrysin, osteogenesis, ERK1/2, estrogen receptor

Electronic supplementary material

13238_2013_3003_MOESM1_ESM.pdf (82KB, pdf)

Supplementary material, approximately 78.8 KB.

Footnotes

These authors contributed equally to the work.

Electronic Supplementary Material

Supplementary material is available for this article at 10.1007/s13238-013-3003-3 and is accessible for authorized users.

Contributor Information

Chunling Zhang, Email: zhangcl@moon.ibp.ac.cn.

Wei Liang, Email: weixx@sun5.ibp.ac.cn.

References

  1. Becker DJ, Kilgore ML, Morrisey MA. The societal burden of osteoporosis. Curr Rheumatol Rep. 2010;12:186–191. doi: 10.1007/s11926-010-0097-y. [DOI] [PubMed] [Google Scholar]
  2. Celil AB, Campbell PG. BMP-2 and insulin-like growth factor-I mediate Osterix (Osx) expression in human mesenchymal stem cells via the MAPK and protein kinase D signaling pathways. J Biol Chem. 2005;280:31353–31359. doi: 10.1074/jbc.M503845200. [DOI] [PubMed] [Google Scholar]
  3. Chang L, Karin M. Mammalian MAP kinase signalling cascades. Nature. 2001;410:37–40. doi: 10.1038/35065000. [DOI] [PubMed] [Google Scholar]
  4. Franceschi RT, Ge C, Xiao G, Roca H, Jiang D. Transcriptional regulation of osteoblasts. Ann N Y Acad Sci. 2007;1116:196–207. doi: 10.1196/annals.1402.081. [DOI] [PubMed] [Google Scholar]
  5. Ge C, Xiao G, Jiang D, Franceschi RT. Critical role of the extracellular signal-regulated kinase-MAPK pathway in osteoblast differentiation and skeletal development. J Cell Biol. 2007;176:709–718. doi: 10.1083/jcb.200610046. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Ha S K, Moon E, Kim SY. Chrysin suppresses LPSstimulated proinflammatory responses by blocking NF-kappaB and JNK activations in microglia cells. Neurosci Lett. 2010;485:143–147. doi: 10.1016/j.neulet.2010.08.064. [DOI] [PubMed] [Google Scholar]
  7. Higuchi C, Myoui A, Hashimoto N, Kuriyama K, Yoshioka K, Yoshikawa H, Itoh K. Continuous inhibition of MAPK signaling promotes the early osteoblastic differentiation and mineralization of the extracellular matrix. J Bone Miner Res. 2002;17:1785–1794. doi: 10.1359/jbmr.2002.17.10.1785. [DOI] [PubMed] [Google Scholar]
  8. Hsieh TP, Sheu SY, Sun JS, Chen MH. Icariin inhibits osteoclast differentiation and bone resorption by suppression of MAPKs/NF-kappaB regulated HIF-1alpha and PGE(2) synthesis. Phytomedicine. 2011;18:176–185. doi: 10.1016/j.phymed.2010.04.003. [DOI] [PubMed] [Google Scholar]
  9. Hsu YL, Kuo PL. Diosmetin induces human osteoblastic differentiation through the protein kinase C/p38 and extracellular signal-regulated kinase 1/2 pathway. J Bone Miner Res. 2008;23:949–960. doi: 10.1359/jbmr.080219. [DOI] [PubMed] [Google Scholar]
  10. Jia TL, Wang HZ, Xie LP, Wang XY, Zhang RQ. Daidzein enhances osteoblast growth that may be mediated by increased bone morphogenetic protein (BMP) production. Biochem Pharmacol. 2003;65:709–715. doi: 10.1016/S0006-2952(02)01585-X. [DOI] [PubMed] [Google Scholar]
  11. Jungbauer A, Medjakovic S. J Steroid Biochem Mol Biol. 2013. Phytoestrogens and the metabolic syndrome. [DOI] [PubMed] [Google Scholar]
  12. Kawai M, Modder UI, Khosla S, Rosen CJ. Emerging therapeutic opportunities for skeletal restoration. Nat Rev Drug Discov. 2011;10:141–156. doi: 10.1038/nrd3299. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Khosla S, Melton LJ, 3rd, Riggs BL. The unitary model for estrogen deficiency and the pathogenesis of osteoporosis: is a revision needed? J Bone Miner Res. 2011;26:441–451. doi: 10.1002/jbmr.262. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Komori T, Yagi H, Nomura S, Yamaguchi A, Sasaki K, Deguchi K, Shimizu Y, Bronson RT, Gao YH, Inada M, et al. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell. 1997;89:755–764. doi: 10.1016/S0092-8674(00)80258-5. [DOI] [PubMed] [Google Scholar]
  15. Kousteni S, Bellido T, Plotkin LI, O’Brien CA, Bodenner DL, Han L, Han K, DiGregorio GB, Katzenellenbogen JA, Katzenellenbogen BS, et al. Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity. Cell. 2001;104:719–730. [PubMed] [Google Scholar]
  16. Kozawa O, Hatakeyama D, Uematsu T. Divergent regulation by p44/p42 MAP kinase and p38 MAP kinase of bone morphogenetic protein-4-stimulated osteocalcin synthesis in osteoblasts. J Cell Biochem. 2002;84:583–589. doi: 10.1002/jcb.10056. [DOI] [PubMed] [Google Scholar]
  17. Kunath T, Saba-El-Leil MK, Almousailleakh M, Wray J, Meloche S, Smith A. FGF stimulation of the Erk1/2 signalling cascade triggers transition of pluripotent embryonic stem cells from self-renewal to lineage commitment. Development. 2007;134:2895–2902. doi: 10.1242/dev.02880. [DOI] [PubMed] [Google Scholar]
  18. Lai CF, Chaudhary L, Fausto A, Halstead LR, Ory DS, Avioli LV, Cheng SL. Erk is essential for growth, differentiation, integrin expression, and cell function in human osteoblastic cells. J Biol Chem. 2001;276:14443–14450. doi: 10.1074/jbc.M010021200. [DOI] [PubMed] [Google Scholar]
  19. Nakashima K, Zhou X, Kunkel G, Zhang Z, Deng JM, Behringer RR, de Crombrugghe B. The novel zinc fingercontaining transcription factor osterix is required for osteoblast differentiation and bone formation. Cell. 2002;108:17–29. doi: 10.1016/S0092-8674(01)00622-5. [DOI] [PubMed] [Google Scholar]
  20. Nakayama K, Tamura Y, Suzawa M, Harada S, Fukumoto S, Kato M, Miyazono K, Rodan GA, Takeuchi Y, Fujita T. Receptor tyrosine kinases inhibit bone morphogenetic protein-Smad responsive promoter activity and differentiation of murine MC3T3-E1 osteoblast-like cells. J Bone Miner Res. 2003;18:827–835. doi: 10.1359/jbmr.2003.18.5.827. [DOI] [PubMed] [Google Scholar]
  21. Penckofer SM, Hackbarth D, Schwertz DW. Estrogen plus progestin therapy: the cardiovascular risks exceed the benefits. J Cardiovasc Nurs. 2003;18:347–355. doi: 10.1097/00005082-200311000-00005. [DOI] [PubMed] [Google Scholar]
  22. Pileggi R, Antony K, Johnson K, Zuo J, Shannon Holliday L. Propolis inhibits osteoclast maturation. Dent Traumatol. 2009;25:584–588. doi: 10.1111/j.1600-9657.2009.00821.x. [DOI] [PubMed] [Google Scholar]
  23. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288:321–333. doi: 10.1001/jama.288.3.321. [DOI] [PubMed] [Google Scholar]
  24. Schindeler A, Little DG. Ras-MAPK signaling in osteogenic differentiation: friend or foe? J Bone Miner Res. 2006;21:1331–1338. doi: 10.1359/jbmr.060603. [DOI] [PubMed] [Google Scholar]
  25. Shin EK, Kwon HS, Kim YH, Shin HK, Kim JK. Chrysin, a natural flavone, improves murine inflammatory bowel diseases. Biochem Biophys Res Commun. 2009;381:502–507. doi: 10.1016/j.bbrc.2009.02.071. [DOI] [PubMed] [Google Scholar]
  26. Suzawa M, Takeuchi Y, Fukumoto S, Kato S, Ueno N, Miyazono K, Matsumoto T, Fujita T. Extracellular matrix-associated bone morphogenetic proteins are essential for differentiation of murine osteoblastic cells in vitro. Endocrinology. 1999;140:2125–2133. doi: 10.1210/endo.140.5.6704. [DOI] [PubMed] [Google Scholar]
  27. Swarnkar G, Sharan K, Siddiqui JA, Mishra JS, Khan K, Khan MP, Gupta V, Rawat P, Maurya R, Dwivedi AK, et al. A naturally occurring naringenin derivative exerts potent bone anabolic effects by mimicking oestrogen action on osteoblasts. Br J Pharmacol. 2012;165:1526–1542. doi: 10.1111/j.1476-5381.2011.01637.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Trzeciakiewicz A, Habauzit V, Mercier S, Lebecque P, Davicco MJ, Coxam V, Demigne C, Horcajada MN. Hesperetin stimulates differentiation of primary rat osteoblasts involving the BMP signalling pathway. J Nutr Biochem. 2010;21:424–431. doi: 10.1016/j.jnutbio.2009.01.017. [DOI] [PubMed] [Google Scholar]
  29. Weng MS, Ho YS, Lin JK. Chrysin induces G1 phase cell cycle arrest in C6 glioma cells through inducing p21Waf1/Cip1 expression: involvement of p38 mitogen-activated protein kinase. Biochem Pharmacol. 2005;69:1815–1827. doi: 10.1016/j.bcp.2005.03.011. [DOI] [PubMed] [Google Scholar]
  30. Woo KJ, Jeong YJ, Park JW, Kwon TK. Chrysin induced apoptosis is mediated through caspase activation and Akt inactivation in U937 leukemia cells. Biochem Biophys Res Commun. 2004;325:1215–1222. doi: 10.1016/j.bbrc.2004.09.225. [DOI] [PubMed] [Google Scholar]
  31. Xiao G, Gopalakrishnan R, Jiang D, Reith E, Benson MD, Franceschi RT. Bone morphogenetic proteins, extracellular matrix, and mitogen-activated protein kinase signaling pathways are required for osteoblast-specific gene expression and differentiation in MC3T3-E1 cells. J Bone Miner Res. 2002;17:101–110. doi: 10.1359/jbmr.2002.17.1.101. [DOI] [PubMed] [Google Scholar]
  32. Xiao G, Jiang D, Thomas P, Benson MD, Guan K, Karsenty G, Franceschi RT. MAPK pathways activate and phosphorylate the osteoblast-specific transcription factor, Cbfa1. J Biol Chem. 2000;275:4453–4459. doi: 10.1074/jbc.275.6.4453. [DOI] [PubMed] [Google Scholar]
  33. Zhao J, Ohba S, Shinkai M, Chung UI, Nagamune T. Icariin induces osteogenic differentiation in vitro in a BMP- and Runx2-dependent manner. Biochem Biophys Res Commun. 2008;369:444–448. doi: 10.1016/j.bbrc.2008.02.054. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

13238_2013_3003_MOESM1_ESM.pdf (82KB, pdf)

Supplementary material, approximately 78.8 KB.

Articles from Protein & Cell are provided here courtesy of Oxford University Press

RESOURCES