, Volume 70, Issue 1, pp 215–224 | Cite as

Bergenin increases osteogenic differentiation and prevents methylglyoxal-induced cytotoxicity in MC3T3-E1 osteoblasts

  • Kwang Sik Suh
  • Suk Chon
  • Eun Mi ChoiEmail author
Original Article


Bergenin, an active component of plants in the genus Bergenia, has multiple biological activities, including anti-inflammatory and immunomodulatory properties. We investigated the effects of bergenin on MC3T3-E1 osteoblasts. Bergenin treatment significantly elevated collagen synthesis, alkaline phosphatase activity, osteocalcin synthesis, and mineralization in the cells (p < 0.05). Additionally, bergenin increased the ratio of osteoprotegerin to receptor activator of nuclear factor kappa-B ligand, and cyclophilin B release. Methylglyoxal (MG), a highly reactive dicarbonyl compound, is the major precursor in the formation of advanced glycation end products. Pretreatment of MC3T3-E1 cells with bergenin prevented MG-induced cell death. Furthermore, bergenin treatment significantly reduced the induction of activating transcription factor 6 and autophagy by MG. These results indicate that bergenin may have positive effects on critical osteoblastic cell functions.


Bergenin Cytotoxicity Differentiation Methylglyoxal Osteoblasts 



This research was supported by the Basic Science Research Program of the National Research Foundation of Korea (NRF), funded by the Ministry of Education (NRF-2016R1D1A1B03930082).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Andreeva L, Heads R, Green CJ (1999) Cyclophilins and their possible role in the stress response. Int J Exp Pathol 80:305–315CrossRefGoogle Scholar
  2. Banerjee R, Starkov AA, Beal MF, Thomas B (2009) Mitochondrial dysfunction in the limelight of Parkinson’s disease pathogenesis. Biochem Biophys Acta 1792:651–663Google Scholar
  3. Blatnik M, Frizzell N, Thorpe SR, Baynes JW (2008) Inactivation of glyceraldehyde-3-phosphate dehydrogenase by fumarate in diabetes: formation of S-(2-succinyl)cysteine, a novel chemical modification of protein and possible biomarker of mitochondrial stress. Diabetes 57:41–49CrossRefGoogle Scholar
  4. Boyce BF, Xing L (2007) The RANKL/RANK/OPG pathway. Curr Osteoporos Rep 5:98–104CrossRefGoogle Scholar
  5. Boyle WJ, Simonet WS, Lacey DL (2003) Osteoclast differentiation and activation. Nature 423:337–342CrossRefGoogle Scholar
  6. Cabral WA, Perdivara I, Weis M, Terajima M, Blissett AR, Chang W, Perosky JE, Makareeva EN, Mertz EL, Leikin S, Tomer KB, Kozloff KM, Eyre DR, Yamauchi M, Marini JC (2014) Abnormal type I collagen post-translational modification and crosslinking in a cyclophilin B KO mouse model of recessive osteogenesis imperfecta. PLoS Genet 10:e1004465CrossRefGoogle Scholar
  7. Chen Y, Gibson SB (2007) Is mitochondrial generation of reactive oxygen species a trigger for autophagy? Autophagy 4:246–248CrossRefGoogle Scholar
  8. Cornish W (2014) Safe and appropriate use of insulin and other antihyperglycemic agents in hospital. Can J Diabetes 38:94–100CrossRefGoogle Scholar
  9. Crockett JC, Mellis DJ, Scott DI, Helfrich MH (2011) New knowledge on critical osteoclast formation and activation pathways from study of rare genetic diseases of osteoclasts: focus on the RANK/RANKL axis. Osteoporos Int 22:1–20CrossRefGoogle Scholar
  10. Dallas SL, Prideaux M, Bonewald LF (2013) The osteocyte: an endocrine cell… and more. Endocr Rev 34:658–690CrossRefGoogle Scholar
  11. Ducy P, Desbois C, Boyce B, Pinero G, Story B, Dunstan C, Smith E, Bonadio J, Goldstein S, Gundberg C, Bradley A, Karsenty G (1996) Increased bone formation in osteocalcin-deficient mice. Nature 382:448–452CrossRefGoogle Scholar
  12. Galat A (2003) Peptidylprolyl cis/trans isomerases (immunophilins): biological diversity-targets-functions. Curr Top Med Chem 3:1315–1347CrossRefGoogle Scholar
  13. Galluzzi L, Aaronson SA, Abrams J, Alnemri ES, Andrews DW, Baehrecke EH, Bazan NG, Blagosklonny MV, Blomgren K, Borner C, Bredesen DE, Brenner C, Castedo M, Cidlowski JA, Ciechanover A, Cohen GM, De Laurenzi V, De Maria R, Deshmukh M, Dynlacht BD, El-Deiry WS, Flavell RA, Fulda S, Garrido C, Golstein P, Gougeon ML, Green DR, Gronemeyer H, Hajnóczky G, Hardwick JM, Hengartner MO, Ichijo H, Jäättelä M, Kepp O, Kimchi A, Klionsky DJ, Knight RA, Kornbluth S, Kumar S, Levine B, Lipton SA, Lugli E, Madeo F, Malomi W, Marine JC, Martin SJ, Medema JP, Mehlen P, Melino G, Moll UM, Morselli E, Nagata S, Nicholson DW, Nicotera P, Nuñez G, Oren M, Penninger J, Pervaiz S, Peter ME, Piacentini M, Prehn JH, Puthalakath H, Rabinovich GA, Rizzuto R, Rodrigues CM, Rubinsztein DC, Rudel T, Scorrano L, Simon HU, Steller H, Tschopp J, Tsujimoto Y, Vandenabeele P, Vitale I, Vousden KH, Youle RJ, Yuan J, Zhivotovsky B, Kroemer G (2009) Guidelines for the use and interpretation of assays for monitoring cell death in higher eukaryotes. Cell Death Differ 16:1093–1107CrossRefGoogle Scholar
  14. Hamada Y, Kitazawa S, Kitazawa R, Fujii H, Kasuga M, Fukagawa M (2007) Histomorphometric analysis of diabetic osteopenia in streptozotocin-induced diabetic mice: a possible role of oxidative stress. Bone 40:1408–1414CrossRefGoogle Scholar
  15. Hamada Y, Fujii H, Kitazawa R, Yodoi J, Kitazawa S, Fukagawa M (2009) Thioredoxin-1 overexpression in transgenic mice attenuates streptozotocin induced diabetic osteopenia: a novel role of oxidative stress and therapeutic implications. Bone 44:936–941CrossRefGoogle Scholar
  16. He L, Lee J, Jang JH, Sakchaisri K, Hwang J, Cha-Molstad HJ, Kim KA, Ryoo IJ, Lee HG, Kim SO, Soung NK, Lee KS, Kwon YT, Erikson RL, Ahn JS, Kim BY (2013) Osteoporosis regulation by salubrinal through eIF2α mediated differentiation of osteoclast and osteoblast. Cell Signal 25:552–560CrossRefGoogle Scholar
  17. Hough FS, Pierroz DD, Cooper C, Ferrari SL, IOF CSA Bone and Diabetes Working Group (2016) Mechanisms in endocrinology: mechanisms and evaluation of bone fragility in type 1 diabetes mellitus. Eur J Endocrinol 174:R127–R138CrossRefGoogle Scholar
  18. Hoyer-Hansen M, Jaattela M (2007) Connecting endoplasmic reticulum stress to autophagy by unfolded protein response and calcium. Cell Death Differ 14:1576–1582CrossRefGoogle Scholar
  19. Khan H, Amin H, Ullah A, Saba S, Rafique J, Khan K, Ahmad N, Badshah SL (2016) Antioxidant and antiplasmodial activities of bergenin and 11-O-galloylbergenin isolated from Mallotus philippensis. Oxid Med Cell Longev 2016:1051925CrossRefGoogle Scholar
  20. Khosla S (2001) Minireview: the OPG/RANKL/RANK system. Endocrinology 142:5050–5055CrossRefGoogle Scholar
  21. Kirkland RA, Adibhatla RM, Hatcher JF, Franklin JL (2002) Loss of cardiolipin and mitochondria during programmed neuronal death: evidence of a role for lipid peroxidation and autophagy. Neuroscience 115:587–602CrossRefGoogle Scholar
  22. Levine B, Sinha S, Kroemer G (2008) Bcl-2 family members: dual regulators of apoptosis and autophagy. Autophagy 4:600–606CrossRefGoogle Scholar
  23. Li RW, Leach DN, Myers SP, Lin GD, Leach GJ, Waterman PG (2004) A new anti-inflammatory glucoside from Ficus racemosa L. Planta Med 70:421–426CrossRefGoogle Scholar
  24. Li YF, Hu LH, Lou FC, Li J, Shen Q (2005) PTP1B inhibitors from Ardisia japonica. J Asian Nat Prod Res 7:13–18CrossRefGoogle Scholar
  25. Lim HK, Kim HS, Choi HS, Oh S, Choi J (2000) Hepatoprotective effects of bergenin, a major constituent of Mallotus japonicus, on carbon tetrachloride-intoxicated rats. Ethnopharmacology 72:469–474CrossRefGoogle Scholar
  26. Myllyharju J, Kivirikko KI (2004) Collagens, modifying enzymes and their mutations in humans, flies and worms. Trends Genet 20:33–43CrossRefGoogle Scholar
  27. Nazir N, Koul S, Qurishi MA, Taneja SC, Ahmad SF, Bani S, Qzai GN (2007) Immunomodulatory effect of bergenin and norbergenin against adjuvant induced arthritis—a flow cytometric study. J Ethnopharmacol 112:401–405CrossRefGoogle Scholar
  28. Nishitoh H, Matsuzawa A, Tobiume K, Saegusa K, Takeda K, Inoue K, Hori S, Kakizuka A, Ichijo H (2002) ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Genes Dev 16:1345–1355CrossRefGoogle Scholar
  29. Park CS, Bang BR, Kwon HS, Moon KA, Kim TB, Lee KY, Moon HB, Cho YS (2012) Metformin reduces airway inflammation and remodeling via activation of AMP-activated protein kinase. Biochem Pharmacol 84:1660–1670CrossRefGoogle Scholar
  30. Phan TCA, Xu J, Zheng MH (2004) Interaction between osteoblast and osteoclast: impact in bone disease. Histol Histopathol 19:1325–1344Google Scholar
  31. Piacente S, Pizza C, De Tommasi N, Mahmood N (1996) Constituents of Ardisia japonica and their in vitro anti-HIV activity. J Nat Prod 59:565–569CrossRefGoogle Scholar
  32. Price DL, Rhett PM, Thorpe SR, Baynes JW (2001) Chelating activity of advanced glycation end-product inhibitors. J Biol Chem 276:48967–48972CrossRefGoogle Scholar
  33. Pu HL, Huang X, Zhao JH, Hong A (2002) Bergenin is the antiarrhythmic principle of Fluggea virosa. Planta Med 68:372–374CrossRefGoogle Scholar
  34. Rubinsztein DC (2006) The roles of intracellular protein-degradation pathways in neurodegeneration. Nature 443:780–786CrossRefGoogle Scholar
  35. Rutkowski DT, Wu J, Back SH, Callaghan MU, Ferris SP, Iqbal J, Clark R, Miao H, Hassler JR, Fornek J, Katze MG, Hussain MM, Song B, Swathirajan J, Wang J, Yau GD, Kaufman RJ (2008) UPR pathways combine to prevent hepatic steatosis caused by ER stress-mediated suppression of transcriptional master regulators. Dev Cell 15:829–840CrossRefGoogle Scholar
  36. Schroder M, Kaufman RJ (2005) ER stress and the unfolded protein response. Mut Res 569:29–63CrossRefGoogle Scholar
  37. Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Lüthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliott R, Colombero A, Tan HL, Trail G, Sullivan J, Davy E, Bucay N, Renshaw-Gegg L, Hughes TM, Hill D, Pattison W, Campbell P, Sander S, Van G, Tarpley J, Derby P, Lee R, Boyle WJ (1997) Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89:309–319CrossRefGoogle Scholar
  38. Smith T, Ferreira LR, Hebert C, Norris K, Sauk JJ (1995) Hsp47 and cyclophilin B traverse the endoplasmic reticulum with procollagen into pre-Golgi intermediate vesicles. A role for Hsp47 and cyclophilin B in the export of procollagen from the endoplasmic reticulum. J Biol Chem 270:18323–18328CrossRefGoogle Scholar
  39. Suh KS, Choi EM, Rhee SY, Kim YS (2014) Methylglyoxal induces oxidative stress and mitochondrial dysfunction in osteoblastic MC3T3-E1 cells. Free Radical Res 48:206–217CrossRefGoogle Scholar
  40. Thomas MC, Baynes JW, Thorpe SR, Cooper ME (2005) The role of AGEs and AGE inhibitors in diabetic cardiovascular disease. Curr Drug Targets 6:453–474CrossRefGoogle Scholar
  41. Thornalley PJ, Langborg A, Minhas HS (1999) Formation of glyoxal, methylglyoxal and 3-deoxyglucosone in the glycation of proteins by glucose. Biochem J 344:109–116CrossRefGoogle Scholar
  42. Tullberg-Reinert H, Jundt G (1999) In situ measurement of collagen synthesis by human bone cells with a sirius red-based colorimetric microassay: effects of transforming growth factor beta2 and ascorbic acid 2-phosphate. Histochem Cell Biol 112:271–276CrossRefGoogle Scholar
  43. van Dijk FS, Nesbitt IM, Zwikstra EH, Nikkels PG, Piersma SR, Fratantoni SA, Jimenez CR, Huizer M, Morsman AC, Cobben JM, van Roij MH, Elting MW, Verbeke JI, Wijnaendts LC, Shaw NJ, Hogler W, McKeown C, Sistermans EA, Dalton A, Meijers-Heijboer H, Pals G (2009) PPIB mutations cause severe osteogenesis imperfecta. Am J Hum Genet 85:521–527CrossRefGoogle Scholar
  44. Wang P, Heitman J (2005) The cyclophilins. Genome Biol 6:226CrossRefGoogle Scholar
  45. Xie JX, Wang L, Liu CX, Zhang DY (1981) The identification total synthesis of aichasu, an antitussive agent. Acta Pharmacol Sin 6:425–428Google Scholar
  46. Xue LZ, Fletcher GC, Tolkovsky AM (1999) Autophagy is activated by apoptotic signalling in sympathetic neurons: an alternative mechanism of death execution. Mol Cell Neurosci 14:180–198CrossRefGoogle Scholar
  47. Yan DB, Zhang DP, Li M, Liu WY, Feng F, Di B, Guo QL, Xie N (2014) Synthesis and cytotoxic activity of 3,4,11-trihydroxyl modified derivatives of bergenin. Chin J Nat Med 12:929–936Google Scholar
  48. Ye J, Rawson RB, Komuro R, Chen X, Dave UP, Prywes R, Brown MS, Goldstein JL (2000) ER stress induces cleavage of membrane-boundATF6 by the same proteases that process SREBPs. Mol Cell 6:1355–1364CrossRefGoogle Scholar
  49. Zofková I (2003) Pathophysiological and clinical importance of insulin-like growth factor-I with respect to bone metabolism. Physiol Res 52:657–679Google Scholar

Copyright information

© Springer Science+Business Media B.V. 2017

Authors and Affiliations

  1. 1.Department of Endocrinology and Metabolism, School of MedicineKyung Hee UniversitySeoulRepublic of Korea

Personalised recommendations