PDF herunterladen
Horm Metab Res 2012; 44(07): 494-500
DOI: 10.1055/s-0032-1311567
Original Basic
© Georg Thieme Verlag KG Stuttgart · New York

Selective Regulation of Osteoblastic OPG and RANKL by Dehydroepiandrosterone Through Activation of the Estrogen Receptor β-mediated MAPK Signaling Pathway

Y.-D. Wang   *
1   International Peace Maternal and Child Health Hospital, Shanghai Jiaotong University, Shanghai, P. R. China
,
M.-F. Tao   *
2   Department of Obstetrics and Gynecology, the 6th People’s Hospital, Shanghai Jiaotong University, Shanghai, P. R. China
,
L. Wang
3   Laboratory for Reproductive Immunology, Hospital & Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai, P. R. China
,
W.-W. Cheng
1   International Peace Maternal and Child Health Hospital, Shanghai Jiaotong University, Shanghai, P. R. China
,
X.-P. Wan
1   International Peace Maternal and Child Health Hospital, Shanghai Jiaotong University, Shanghai, P. R. China
› Institutsangaben
Weitere Informationen

Publikationsverlauf

received 11. Dezember 2011

accepted after second revision 13. März 2012

Publikationsdatum:
03. Mai 2012 (online)

Auch verfügbar auf
    Lizenzen und Reprints

Abstract

The aim of the work was to investigate the differential regulation by dehydroepiandrosterone (DHEA) of the osteoblastic production via the estrogen receptor beta (ER β)-mediated signaling pathway. Having developed hMG63-ER β cells and hMG63-shER β cells, we analyzed the regulation by DHEA of human osteoblastic viability, the receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegerin (OPG), and the differential expression of ER β, ER α, or p-ERK1/2 (extracellular signal-regulated kinase) in hMG63, hMG63-shER β, and hMG63-ER β cells pretreated with or without U0126, flutamide, and ICI 182780, followed by DHEA culture. When the level of ER β was high, DHEA (10 − 7  mol/l) could effectively amplify the proliferation and inhibit the etoposide-induced apoptosis of hMG63 cells (p<0.01 and p<0.05, respectively), which was blocked by U0126. When the expression of ER β was silenced, DHEA could not significantly improve the viability of hMG63. In the presence of ER β, DHEA activated the pERK1/2-MAPK signaling pathway but not p38 and JNK. Besides, the regulation of p-ERK1/2 upon DHEA treatment was mainly modulated by ER β instead of androgen receptor and ER α. The secretion of OPG was declined following the silence of ER β (p<0.05). RANKL and ER α, however, were unaffected by culture with or without DHEA and U0126, regardless of the ER β level. DHEA seems to act selectively on osteoblasts via the dominant ER β receptor, which mediates amplified cell viability through the MAPK signaling pathway involving pERK1/2 and upregulates the production of OPG rather than RANKL.

Key words

dehydroepiandrosterone - estrogen receptor β - OPG - RANKL
*

*  These authors contributed equally to this work.


 

  • References

  • 1 Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature 2003; 423 (6937) 337-342
    CrossrefPubMedGoogle Scholar
  • 2 Enserink M. Women’s health. The vanishing promises of hormone replacement. Science 2002; 297 (5580) 325-326
    CrossrefPubMedGoogle Scholar
  • 3 Schramek D, Leibbrandt A, Sigl V, Kenner L, Pospisilik JA, Lee HJ, Hanada R, Joshi PA, Aliprantis A, Glimcher L, Pasparakis M, Khokha R, Ormandy CJ, Widschwendter M, Schett G, Penninger JM. Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer. Nature 2010; 468 (7320) 98-102
    CrossrefPubMedGoogle Scholar
  • 4 Balasch J. Sex steroids and bone: current perspectives. Hum Reprod Update 2003; 9: 207-222
    CrossrefPubMedGoogle Scholar
  • 5 Fedele S, Porter SR, D’Aiuto F, Aljohani S, Vescovi P, Manfredi M, Arduino PG, Broccoletti R, Musciotto A, Di Fede O, Lazarovici TS, Campisi G, Yarom N. Nonexposed variant of bisphosphonate-associated osteonecrosis of the jaw: a case series. Am J Med 2010; 123: 1060-1064
    CrossrefPubMedGoogle Scholar
  • 6 Frank GR. Growth and estrogen. Growth Genet Horm 2000; 16: 1-5
    PubMedGoogle Scholar
  • 7 Chen JR, Kousteni S, Bellido T, Han L, DiGregorio GB, Jilka RL, Manolagas SC. Gender-independent induction of murine osteoclast apoptosis in vitro by either estrogens or non-aromatizable androgens. J Bone Miner Res 2001; 16 (Suppl. 01) S159
    PubMedGoogle Scholar
  • 8 Yoshida S, Honda A, Matsuzaki Y, Fukushima S, Tanaka N, Takagiwa A, Fujimoto Y, Miyazaki H, Salen G. Anti-proliferative action of endogenous dehydroepiandrosterone metabolites on human cancer cell lines. Steroids 2003; 68: 73-83
    CrossrefPubMedGoogle Scholar
  • 9 Schwartz AG, Pashko L, Whitcomb JM. Inhibition of tumor development by dehydroepiandrosterone and related steroids. Toxicol Pathol 1986; 14: 357-362
    CrossrefPubMedGoogle Scholar
  • 10 Araghi-Niknam M, Ardestani SK, Molitor M, Inserra P, Eskelson CD, Watson RR. Dehydroepiandrosterone (DHEA) sulfate prevents reduction in tissue vitamin E and increased lipid peroxidation due to murine retrovirus infection of aged mice. Proc Soc Exp Biol Med 1998; 218: 210-217
    PubMedGoogle Scholar
  • 11 Matsuzaki Y, Honda A. Dehydroepiandrosterone and its derivatives: potentially novel anti-proliferative and chemopreventive agents. Curr Pharm Des 2006; 12: 3411-3421
    CrossrefPubMedGoogle Scholar
  • 12 Cormier C, Souberbielle JC, Kahan A. DHEA in bone and joint diseases. Joint Bone Spine 2001; 68: 588-594
    CrossrefPubMedGoogle Scholar
  • 13 Wang L, Wang YD, Wang WJ, Li DJ. Differential regulation of dehydroepiandrosterone and estrogen on bone and uterus in ovariectomized mice. Osteoporos Int 2009; 20: 79-92
    CrossrefPubMedGoogle Scholar
  • 14 Wang YD, Wang L, Li DJ, Wang WJ. Dehydroepiandrosterone inhibited the bone resorption through the upregulation of OPG/RANKL. Cell Mol Immunol 2006; 3: 41-45
    PubMedGoogle Scholar
  • 15 de Cremoux P, Tran-Perennou C, Elie C, Boudou E, Barbaroux C, Poupon MF, De Rycke Y, Asselain B, Magdelénat H. Quantitation of estradiol receptors alpha and beta and progesterone receptors in human breast tumors by real-time reverse transcription-polymerase chain reaction. Correlation with protein assays. Biochem Pharmacol 2002; 64: 507-515
    PubMedGoogle Scholar
  • 16 Lazennec G, Bresson D, Lucas A, Chauveau C, Vignon F. ER beta inhibits proliferation and invasion of breast cancer cells. Endocrinology 2001; 142: 4120-4130
    CrossrefPubMedGoogle Scholar
  • 17 Collado M, Medema RH, Garcia-Cao I, Dubuisson ML, Barradas M, Glassford J, Rivas C, Burgering BM, Serrano M, Lam EW. Inhibition of the phosphoinositide 3-kinase pathway induces a senescence-like arrest mediated by p27Kip1. J Biol Chem 2000; 275: 21960-21968
    CrossrefPubMedGoogle Scholar
  • 18 Harada S, Rodan GA. Control of osteoblast function and regulation of bone mass. Nature 2003; 423 (6937) 349-355
    CrossrefPubMedGoogle Scholar
  • 19 Akatsu T, Murakami T, Nishikawa M, Ono K, Shinomiya N, Tsuda E, Mochizuki S, Yamaguchi K, Kinosaki M, Higashio K, Yamamoto M, Motoyoshi K, Nagata N. Osteoclastogenesis inhibitory factor suppresses osteoclast survival by interfering in the interaction of stromal cells with osteoclast. Biochem Biophys Res Commun 1998; 250: 229-234
    CrossrefPubMedGoogle Scholar
  • 20 Kong YY, Feige U, Sarosi I, Bolon B, Tafuri A, Morony S, Capparelli C, Li J, Elliott R, McCabe S, Wong T, Campagnuolo G, Moran E, Bogoch ER, Van G, Nguyen LT, Ohashi PS, Lacey DL, Fish E, Boyle WJ, Penninger JM. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 1999; 402 (6759) 304-309
    CrossrefPubMedGoogle Scholar
  • 21 Canon JR, Roudier M, Bryant R, Morony S, Stolina M, Kostenuik PJ, Dougall WC. Inhibition of RANKL blocks skeletal tumor progression and improves survival in a mouse model of breast cancer bone metastasis. Clin Exp Metastasis 2008; 25: 119
    CrossrefPubMedGoogle Scholar
  • 22 Yonou H, Kanomata N, Goya M, Kamijo T, Yokose T, Hasebe T, Nagai K, Hatano T, Ogawa Y, Ochiai A. Osteoprotegerin/osteoclastogenesis inhibitory factor decreases human prostate cancer burden in human adult bone implanted into nonobese diabetic/severe combined immunodeficient mice. Cancer Res 2003; 63: 2096
    PubMedGoogle Scholar
  • 23 Feeley BT, Liu NQ, Conduah AH, Krenek L, Roth K, Dougall WC, Huard J, Dubinett S, Lieberman JR. Mixed metastatic lung cancer lesions in bone are inhibited by noggin overexpression and Rank:Fc administration. J Bone Miner Res 2006; 21: 1571-1580
    CrossrefPubMedGoogle Scholar
  • 24 Karsenty G, Wagner EF. Reaching a genetic and molecular understanding of skeletal development. Dev Cell 2002; 2: 389-406
    CrossrefPubMedGoogle Scholar
  • 25 Rodan GA, Martin TJ. Therapeutic approaches to bone diseases. Science 2000; 289: 1508-1514
    CrossrefPubMedGoogle Scholar
  • 26 Teitelbaum SL, Ross FP. Genetic regulation of osteoclast development and function. Nat Rev Genet 2003; 4: 638-649
    CrossrefPubMedGoogle Scholar
  • 27 Pike MC, Peters RK, Cozen W, Probst-Hensch NM, Felix JC, Wan PC, Mack TM. Estrogen-progestin replacement therapy and endometrial cancer. J Natl Cancer Inst 1997; 89: 1110-1116
    CrossrefPubMedGoogle Scholar
  • 28 Gonzalez-Suarez E, Jacob AP, Jones J, Miller R, Roudier-Meyer MP, Erwert R, Pinkas J, Branstetter D, Dougall WC. RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature 2010; 468 (7320) 103-107
    CrossrefPubMedGoogle Scholar
  • 29 Chambliss KL, Yuhanna IS, Anderson RG, Mendelsohn ME, Shaul PW. ERbeta has nongenomic action in caveolae. Mol Endocrinol 2002; 16: 938-946
    CrossrefPubMedGoogle Scholar
  • 30 Manolagas SC, Kousteni S, Jilka RL. Sex steroids and bone. Recent Prog Horm Res 2002; 57: 385-409
    CrossrefPubMedGoogle Scholar
  • 31 Kousteni S, Bellido T, Plotkin LI, O’Brien CA, Bodenner DL, Han L, Han K, DiGregorio GB, Katzenellenbogen JA, Katzenellenbogen BS, Roberson PK, Weinstein RS, Jilka RL, Manolagas SC. Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity. Cell 2001; 104: 719-730
    PubMedGoogle Scholar
  • 32 Nawata H, Yanase T, Goto K, Okabe T, Ashida K. Mechanism of action of anti-aging DHEA-S and the replacement of DHEA-S. Mech Ageing Dev 2002; 123: 1101-1106
    CrossrefPubMedGoogle Scholar
  • 33 Viereck V, Gründker C, Blaschke S, Niederkleine B, Siggelkow H, Frosch KH, Raddatz D, Emons G, Hofbauer LC. Raloxifene concurrently stimulates osteoprotegerin and inhibits interleukin-6 production by human trabecular osteoblasts. J Clin Endocrinol Metab 2003; 88: 4206-4213
    CrossrefPubMedGoogle Scholar
  • 34 Hofbauer LC, Khosla S, Dunstan CR, Lacey DL, Spelsberg TC, Riggs BL. Estrogen stimulates gene expression and protein production of osteoprotegerin in human osteoblastic cells. Endocrinology 1999; 140: 4367-4370
    CrossrefPubMedGoogle Scholar
  • 35 Wang Y, Li LZ, Zhang YL, Zhu YQ, Wu J, Sun WJ. LC, a novel estrone-rhein hybrid compound, concurrently stimulates osteoprotegerin and inhibits receptor activator of NF-κB ligand (RANKL) and interleukin-6 production by human osteoblastic cells. Mol Cell Endocrinol 2011; 337: 43-51
    CrossrefPubMedGoogle Scholar
  • 36 Sorensen MG, Henriksen K, Dziegiel MH, Tankó LB, Karsdal MA. Estrogen directly attenuates human osteoclastogenesis, but has no effect on resorption by mature steoclasts. DNA Cell Biol 2006; 25: 475-483
    CrossrefPubMedGoogle Scholar
  • 37 Wattanaroonwong N, Schoenmaker T, de Vries TJ, Everts V. Oestrogen inhibits osteoclast formation induced by periodontal ligament fibroblasts. Arch Oral Biol 2011; 56: 212-219
    CrossrefPubMedGoogle Scholar