Osteoporosis International

, Volume 21, Issue 3, pp 365–372 | Cite as

Sex hormones and their receptors in bone homeostasis: insights from genetically modified mouse models

Review

Abstract

In this review, we summarize available data regarding bone phenotypes in estrogen receptors α and β, androgen receptor, and aromatase enzyme-deficient mice. We examine sex differences in the trabecular and cortical bone compartments and we discuss these findings in relation to known estrogen effects in humans. We also report how estrogen influences the responsiveness of the skeleton to exercise. Although uncertainties remain, it is clear that both estrogen and androgen are important for both male and female skeleton. Estrogen receptor α mainly through its classical signaling pathway is particularly important for the male mice skeleton while both estrogen receptors α and β are required for female mice skeleton. These deletions also induce major hormonal alterations themselves impacting on bone metabolism. More investigations are needed to fully understand the respective role of all these receptors in periosteal expansion in both sexes and the way they affect the mechanical sensitivity of the periosteum.

Keywords

Androgen Androgen receptor Aromatase Estrogen Estrogen receptors Mice model 

Notes

Acknowledgements

Work in LV’s laboratory is supported by INSERM and Jean Monnet University of St-Etienne. Work in JMV's laboratory is funded by Agence Nationale pour la Recherche (grant GENOPAT-012), Association pour la Recherche sur le Cancer (Grant 1138) and Ligue contre le Cancer.

Conflicts of interest

None.

References

  1. 1.
    Khosla S, Amin S, Orwoll E (2008) Osteoporosis in men. Endocr Rev 29:441–464CrossRefPubMedGoogle Scholar
  2. 2.
    Smith EP, Boyd J, Frank GR, Takahashi H, Cohen RM, Specker B, Williams TC, Lubahn DB, Korach KS (1994) Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med 331:1056–1061CrossRefPubMedGoogle Scholar
  3. 3.
    Carani C, Qin K, Simoni M, Faustini-Fustini M, Serpente S, Boyd J, Korach KS, Simpson ER (1997) Effect of testosterone and estradiol in a man with aromatase deficiency. N Engl J Med 337:91–95CrossRefPubMedGoogle Scholar
  4. 4.
    Bilezikian JP, Morishima A, Bell J, Grumbach MM (1998) Increased bone mass as a result of estrogen therapy in a man with aromatase deficiency. N Engl J Med 339:599–603CrossRefPubMedGoogle Scholar
  5. 5.
    Manolagas SC, Kousteni S, Jilka RL (2002) Sex steroids and bone. Recent Prog Horm Res 57:385–409CrossRefPubMedGoogle Scholar
  6. 6.
    Onoe Y, Miyaura C, Ohta H, Nozawa S, Suda T (1997) Expression of estrogen receptor beta in rat bone. Endocrinol 138:4509–4512CrossRefGoogle Scholar
  7. 7.
    Bord S, Horner A, Beavan, Compston J (2001) Estrogen receptors alpha and beta are differentially expressed in developing human bone. J Clin Endocrinol Metab 86:2309–2314CrossRefPubMedGoogle Scholar
  8. 8.
    Mödder UI, Sanyal A, Kearns AE, Sibonga JD, Nishihara E, Xu J, O'Malley BW, Ritman EL, Riggs BL, Spelsberg TC, Khosla S (2004) Effects of loss of steroid receptor coactivator-1 on the skeletal response to estrogen in mice. Endocrinol 145:913–921CrossRefGoogle Scholar
  9. 9.
    Almeida M, Han L, Martin-Millan M, Plotkin LI, Stewart SA, Roberson PK, Kousteni S, O'Brien CA, Bellido T, Parfitt AM, Weinstein RS, Jilka RL, Manolagas SC (2007) Skeletal involution by age-associated oxidative stress and its acceleration by loss of sex steroids. J Biol Chem 282:27285–27297CrossRefPubMedGoogle Scholar
  10. 10.
    Couse JF, Curtis SW, Washburn TF, Lindzey J, Golding TS, Lubahn DB, Smithies O, Korach KS (1995) Analysis of transcription and estrogen insensitivity in the female mouse after targeted disruption of the estrogen receptor gene. Mol Endocrinol 9:1441–1454CrossRefPubMedGoogle Scholar
  11. 11.
    Flouriot G, Brand H, Denger S, Metivier R, Kos M, Reid G, Sonntag-Buck V, Gannon F (2000) Identification of a new isoform of the human estrogen receptor-alpha (hER-alpha) that is encoded by distinct transcripts and that is able to repress hER-alpha activation function 1. EMBO J 19:4688–4700CrossRefPubMedGoogle Scholar
  12. 12.
    Sims NA, Dupont S, Krust A, Clement-Lacroix P, Minet D, Resche-Rigon M, Gaillard-Kelly M, Baron R (2002) Deletion of estrogen receptors reveals a regulatory role for estrogen receptors-beta in bone remodeling in females but not in males. Bone 30:18–25CrossRefPubMedGoogle Scholar
  13. 13.
    Dupont S, Krust A, Gansmuller A, Dierich A, Chambon P, Mark M (2000) Effect of single and compound knockouts of estrogen receptors alpha (ERalpha) and beta (ERbeta) on mouse reproductive phenotypes. Development 127:4277–4291PubMedGoogle Scholar
  14. 14.
    Lindberg MK, Alatalo SL, Halleen JM, Mohan S, Gustafsson JA, Ohlsson C (2001) Estrogen receptor specificity in the regulation of the skeleton in female mice. J Endocrinol 171:229–236CrossRefPubMedGoogle Scholar
  15. 15.
    Windahl SH, Vidal O, Andersson G, Gustafsson JA, Ohlsson C (1999) Increased cortical bone mineral content but unchanged trabecular bone mineral density in female ERbeta(−/−) mice. J Clin Invest 104:895–901CrossRefPubMedGoogle Scholar
  16. 16.
    Ke HZ, Brown TA, Qi H, Crawford DT, Simmons HA, Petersen DN, Allen MR, McNeish JD, Thompson DD (2002) The role of estrogen receptor-beta, in the early age-related bone gain and later age-related bone loss in female mice. J Musculoskelet Neuronal Interact 2:479–488PubMedGoogle Scholar
  17. 17.
    Windahl SH, Hollberg K, Vidal O, Gustafsson JA, Ohlsson C, Andersson G (2001) Female estrogen receptor beta−/− mice are partially protected against age-related trabecular bone loss. J Bone Miner Res 16:1388–1398CrossRefPubMedGoogle Scholar
  18. 18.
    Lindberg MK, Movérare S, Skrtic S, Gao H, Dahlman-Wright K, Gustafsson JA, Ohlsson C (2003) Estrogen receptor (ER)-beta reduces ERalpha-regulated gene transcription, supporting a “yin yang” relationship between ERalpha and ERbeta in mice. Mol Endocrinol 17:203–208CrossRefPubMedGoogle Scholar
  19. 19.
    Parikka V, Peng Z, Hentunen T, Risteli J, Elo T, Vaananen HK, Harkonen P (2005) Estrogen responsiveness of bone formation in vitro and altered bone phenotype in aged estrogen receptor-alpha-deficient male and female mice. Eur J Endocrinol 152:301–314CrossRefPubMedGoogle Scholar
  20. 20.
    McDougall KE, Perry MJ, Gibson RL, Bright JM, Colley SM, Hodgin JB, Smithies O, Tobias JH (2002) Estrogen-induced osteogenesis in intact female mice lacking ERß. Am J Physiol Endocrinol Metab 283:E817–E823PubMedGoogle Scholar
  21. 21.
    Vidal O, Lindberg MK, Hollberg K, Baylink DJ, Andersson G, Lubahn DB, Mohan S, Gustafsson JA, Ohlsson C (2000) Estrogen receptor specificity in the regulation of skeletal growth and maturation in male mice. Proc Natl Acad Sci U S A 97:5474–5479CrossRefPubMedGoogle Scholar
  22. 22.
    Sims NA, Clement-Lacroix P, Minet D, Fraslon-Vanhulle C, Gaillard-Kelly M, Resche-Rigon M, Baron R (2003) A functional androgen receptor is not sufficient to allow estradiol to protect bone after gonadectomy in estradiol receptor-deficient mice. J Clin Invest 111:1319–1327PubMedGoogle Scholar
  23. 23.
    Krege JH, Hodgin JB, Couse JF, Enmark E, Warner M, Mahler JF, Sar M, Korach KS, Gustafsson JA, Smithies O (1998) Generation and reproductive phenotypes of mice lacking estrogen receptor β. Proc Natl Acad Sci U S A 95:15677–15682CrossRefPubMedGoogle Scholar
  24. 24.
    Weihua Z, Saji S, Makinen S, Cheng G, Jensen EV, Warner M, Gustafsson JA (2000) Estrogen receptor (ER) β, a modulator of ERα in the uterus. Proc Natl Acad Sci U S A 97:5936–5941CrossRefPubMedGoogle Scholar
  25. 25.
    Yang NN, Venugopalan M, Hardikar S, Glasebrook A (1996) Identification of an estrogen response element activated by metabolites of 17ß-estradiol and raloxifene. Science 273:1222–1225CrossRefPubMedGoogle Scholar
  26. 26.
    Umayahara Y, Kawamori R, Watada H, Imano E, Iwama N, Morishima T, Yamasaki Y, Kajimoto Y, Kamada T (1994) Estrogen regulation of the insulin-like growth factor I gene transcription involves an AP-1 enhancer. J Biol Chem 269:16433–16441PubMedGoogle Scholar
  27. 27.
    Kousteni S, Bellido T, Plotkin LI, O’Brien CA, Bodenner DL, Han L, Han K, DiGregorio GB, Katznellenbogen JA, Katznellenbogen BS, Roberson PK, Weinstein RS, Jilka RL, Manolagas SC (2001) Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity. Cell 104:1–20CrossRefGoogle Scholar
  28. 28.
    Mårtensson UE, Salehi SA, Windahl S, Gomez MF, Swärd K, Daszkiewicz-Nilsson J, Wendt A, Andersson N, Hellstrand P, Grände PO, Owman C, Rosen CJ, Adamo ML, Lundquist I, Rorsman P, Nilsson BO, Ohlsson C, Olde B, Leeb-Lundberg LM (2009) Deletion of the G protein-coupled receptor 30 impairs glucose tolerance, reduces bone growth, increases blood pressure, and eliminates estradiol-stimulated insulin release in female mice. Endocrinol 150:687–698CrossRefGoogle Scholar
  29. 29.
    Windahl SH, Andersson N, Chagin AS, Mårtensson UE, Carlsten H, Olde B, Swanson C, Movérare-Skrtic S, Sävendahl L, Lagerquist MK, Leeb-Lundberg LM, Ohlsson C (2009) The role of the G protein-coupled receptor GPR30 in the effects of estrogen in ovariectomized mice. Am J Physiol Endocrinol Metab 296:E490–E496CrossRefPubMedGoogle Scholar
  30. 30.
    Cheng MZ, Rawlinson SCF, Pitsillides AA, Zaman G, Mohan S, Baylink DJ, Lanyon LE (2002) Human osteoblasts’ proliferative responses to strain and 17ß-estradiol are mediated by the estrogen receptor and the receptor for insulin-like growth factor I. J Bone Miner Res 17:593–602CrossRefPubMedGoogle Scholar
  31. 31.
    Zaman G, Cheng MZ, Jessop HL, White R, Lanyon LE (2000) Mechanical strain activates estrogen response elements in bone cells. Bone 27:233–239CrossRefPubMedGoogle Scholar
  32. 32.
    Aguirre JI, Plotkin LI, Gortazar AR, Millan MM, O'Brien CA, Manolagas SC, Bellido T (2007) A novel ligand-independent function of the estrogen receptor is essential for osteocyte and osteoblast mechanotransduction. J Biol Chem 282:25501–25508CrossRefPubMedGoogle Scholar
  33. 33.
    Jakacka M, Ito M, Martinson F, Ishikawa T, Lee EJ, Jameson JL (2002) An estrogen receptor (ER) alpha deoxyribonucleic acid-binding domain knock-in mutation provides evidence for nonclassical ER pathway signaling in vivo. Mol Endocrinol 16:2188–2201CrossRefPubMedGoogle Scholar
  34. 34.
    Syed FA, Modder UI, Fraser DG, Spelsberg TC, Rosen CJ, Krust A, Chambon P, Jameson JL, Khosla S (2005) Skeletal effects of estrogen are mediated by opposing actions of classical and nonclassical estrogen receptor pathways. J Bone Miner Res 20:1992–2001CrossRefPubMedGoogle Scholar
  35. 35.
    Syed FA, Fraser DG, Spelsberg TC, Rosen CJ, Krust A, Chambon P, Jameson JL, Khosla S (2007) Effects of loss of classical estrogen response element signaling on bone in male mice. Endocrinol 148:1902–1910CrossRefGoogle Scholar
  36. 36.
    Eriksen EF, Colvard DS, Berg NJ, Graham ML, Mann KG, Spelsberg TC, Riggs BL (1988) Evidence of estrogen receptors in normal human osteoblast-like cells. Science 241:84–86CrossRefPubMedGoogle Scholar
  37. 37.
    Vidal O, Kindblom LG, Ohlsson C (1999) Expression and localization of estrogen receptor-beta in murine and human bone. J Bone Miner Res 14:923–929CrossRefPubMedGoogle Scholar
  38. 38.
    Braidman IP, Hainey L, Batra G, Selby PL, Saunders PT, Hoyland JA (2001) Localization of estrogen receptor beta protein expression in adult human bone. J Bone Miner Res 16:214–220CrossRefPubMedGoogle Scholar
  39. 39.
    Nakamura T, Imai Y, Matsumoto T, Sato S, Takeuchi K, Igarashi K, Harada Y, Azuma Y, Krust A, Yamamoto Y, Nishina H, Takeda S, Takayanagi H, Metzger D, Kanno J, Takaoka K, Martin TJ, Chambon P, Kato S (2007) Estrogen prevents bone loss via estrogen receptor a and induction of Fas ligand in osteoclasts. Cell 130:811–823CrossRefPubMedGoogle Scholar
  40. 40.
    Kameda T, Mano H, Yuasa T, Mori Y, Miyazawa K, Shiokawa M, Nakamaru Y, Hiroi E, Hiura K, Kameda A, Yang NN, Hakeda Y, Kumegawa M (1997) Estrogen inhibits bone resorption by directly inducing apoptosis of the bone-resorbing osteoclasts. J Exp Med 186:489–495CrossRefPubMedGoogle Scholar
  41. 41.
    Krum SA, Miranda-Carboni GA, Hauschka PV, Carroll JS, Lane TF, Freedman LP, Brown M (2008) Estrogen protects bone by inducing Fas ligand in osteoblasts to regulated osteoclast survival. EMBO J 27:535–545CrossRefPubMedGoogle Scholar
  42. 42.
    Fisher CR, Graves KH, Parlow AF, Simpson ER (1998) Characterization of mice deficient in aromatase (ArKO) because of targeted disruption of the cyp19 gene. Proc Natl Acad Sci U S A 95:6965–6970CrossRefPubMedGoogle Scholar
  43. 43.
    Oz OK, Zerwekh JE, Fisher C, Graves K, Nanu L, Millsaps R, Simpson ER (2000) Bone has a sexually dimorphic response to aromatase deficiency. J Bone Miner Res 15:507–514CrossRefPubMedGoogle Scholar
  44. 44.
    Miyaura C, Toda K, Inada M, Ohshiba T, Matsumoto C, Okada T, Ito M, Shizuta Y, Ito A (2001) Sex- and age-related response to aromatase deficiency in bone. Biochem Biophys Res Commun 280:1062–1068CrossRefPubMedGoogle Scholar
  45. 45.
    Jones MEE, McInnes KJ, Boon WC, Simpson ER (2007) Estrogen and adiposity - Utilizing models of aromatase deficiency to explore the relationship. J Steroid Biochem Mol Biol 106:3–7CrossRefPubMedGoogle Scholar
  46. 46.
    Onoe Y, Miyaura C, Ito M, Ohta H, Nozawa S, Suda T (2000) Comparative effects of estrogen and raloxifene on B-lymphopoiesis and bone loss induced by sex steroid deficiency in mice. J Bone Miner Res 15:541–549CrossRefPubMedGoogle Scholar
  47. 47.
    Moverare S, Venken K, Eriksson AL, Andersson N, Skrtic S, Wergedal J, Mohan S, Salmon P, Bouillon R, Gustafsson JA, Vanderschueren D, Ohlsson C (2003) Differential effects on bone of estrogen receptor alpha and androgen receptor activation in orchidectomized adult male mice. Proc Natl Acad Sci U S A 100:13573–13578 Erratum in: Proc Natl Acad Sci U S A. 2006 103:8298CrossRefPubMedGoogle Scholar
  48. 48.
    Kawano H, Sato T, Yamada T, Matsumoto T, Sekine K, Watanabe T, Nakamura T, Fukuba T, Yoshimura K, Yoshizawa T, Aihara K, Yamamoto Y, Nakamichi Y, Metzger D, Chambon P, Nakamura K, Kawaguchi H, Kato S (2003) Suppressive function of androgen receptor in bone resorption. Proc Natl Acad Sci U S A 100:9416–9421CrossRefPubMedGoogle Scholar
  49. 49.
    Venken K, De Gendt K, Boonen S, Ophoff J, Bouillon R, Swinnen JV, Verhoeven G, Vanderschueren D (2006) Relative impact of androgen and estrogen receptor activation in the effects of androgens on trabecular and cortical bone in growing male mice: a study in the androgen receptor knockout mouse model. J Bone Miner Res 21:576–585CrossRefPubMedGoogle Scholar
  50. 50.
    Callewaert F, Venken K, Ophoff J, De Gendt K, Torcasio A, van Lenthe GH, van Oosterwyck H, Boonen S, Bouillon R, Verhoeven G, Vanderschueren D (2009) Differential regulation of bone and body composition in male mice with combined inactivation of androgen and estrogen receptor-a. FASEB J. 23:232–240CrossRefPubMedGoogle Scholar
  51. 51.
    Khosla S, Melton LJ 3 rd, Riggs BL (2002) Clinical review 144: estrogen and the male skeleton. J Clin Endocrinol Metab 87:1443–1450CrossRefPubMedGoogle Scholar
  52. 52.
    Chagin AS, Savendahl L (2007) Oestrogen receptors and linear bone growth. Acta Paediatrica 96:1275–1279CrossRefPubMedGoogle Scholar
  53. 53.
    Nelson JF, Felicio LS, Osterburg HH, Finch CE (1992) Differential contributions of ovarian and extraovarian factors to age-related reductions in plasma estradiol and progesterone during the estrous cycle of C57BL/6 J mice. Endocrinol 130:805–810CrossRefGoogle Scholar
  54. 54.
    Albertsson-Wikland K, Rosberg S, Lannering B, Dunkel L, Selstam G, Norjavaara E (1997) Twenty-four-hour profiles of luteinizing hormone, follicle-stimulating hormone, testosterone, and estradiol levels: a semilongitudinal study throughout puberty in healthy boys. J Clin Endocrinol Metab 82:541–549CrossRefPubMedGoogle Scholar
  55. 55.
    Norjavaara E, Ankarberg C, Albertsson-Wikland K (1996) Diurnal rhythm of 17 beta-estradiol secretion throughout pubertal development in healthy girls: evaluation by a sensitive radioimmunoassay. J Clin Endocrinol Metab 81:4095–4102CrossRefPubMedGoogle Scholar
  56. 56.
    Chagin A, Nilsson M, Dahlman Wright K, Savendahl L (2006) Remaining estrogenic activity in the man with mutated estrogen receptor alpha. Horm Res 65(Suppl 4):28Google Scholar
  57. 57.
    Hall JM, Couse JF, Korach KS (2001) The multifaceted mechanisms of estradiol and estrogen receptor signaling. J Biol Chem 276:36869–36872CrossRefPubMedGoogle Scholar
  58. 58.
    Lee KC, Jessop H, Suswillo R, Zaman G, Lanyon LE (2004) The adaptive response of bone to mechanical loading in female transgenic mice is deficient in the absence of oestrogen receptor-alpha and -beta. J Endocrinol 182:193–201CrossRefPubMedGoogle Scholar
  59. 59.
    Saxon LK, Turner CH (2005) Estrogen receptor β: the anti-mechanostat? Bone 36:185–192CrossRefPubMedGoogle Scholar
  60. 60.
    Khosla S, Moedder UI, Syed FA (2005) Letter to the editor. Bone 38:289–289CrossRefPubMedGoogle Scholar
  61. 61.
    Bouillon R, Bex M, Vanderschueren D, Boonen S (2004) Estrogens are essential for male pubertal periosteal bone expansion. J Clin Endocrinol Metab 89:6025–6029CrossRefPubMedGoogle Scholar
  62. 62.
    Vanderschueren D, Venken K, Ophoff J, Bouillon R, Boonen S (2006) Clinical review: sex steroids and the periosteum—reconsidering the roles of androgens and estrogens in periosteal expansion. J Clin Endocrinol Metab 91:378–382CrossRefPubMedGoogle Scholar
  63. 63.
    Shah N, Evans WS, Bowers CY, Veldhuis JD (2000) Oral estradiol administration modulates continuous intravenous growth hormone (GH)-releasing peptide-2-driven GH secretion in postmenopausal women. J Clin Endocrinol Metab 85:2649–2659CrossRefPubMedGoogle Scholar
  64. 64.
    Ohlsson C, Jansson JO, Isaksson O (2000) Effects of growth hormone and insulin like growth factor-I on body growth and adult bone metabolism. Curr Opin Rheumatol 12:346–348CrossRefPubMedGoogle Scholar
  65. 65.
    Venken K, Schuit F, Van Lommel L, Tsukamoto K, Kopchick JJ, Coschigano K, Ohlsson C, Moverare S, Boonen S, Bouillon R, Vanderschueren D (2005) Growth without growth hormone receptor: estradiol is a major growth hormone-independent regulator of hepatic IGF-I synthesis. J Bone Miner Res 20:2138–2149CrossRefPubMedGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2009

Authors and Affiliations

  1. 1.Université de LyonSt-EtienneFrance
  2. 2.Institut de Génomique Fonctionnelle de LyonUniversité de LyonLyonFrance

Personalised recommendations