Membrane estrogen receptor α is essential for estrogen signaling in the male skeleton

in Journal of Endocrinology
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  • 1 Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
  • 2 Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden
  • 3 Unit of Cancer Research and Translational Medicine, MRC Oulu and Department of Anatomy and Cell Biology, University of Oulu, Oulu, Finland
  • 4 Division of Endocrinology, Departments of Medicine and Biochemistry, University of California, Irvine, California, USA
  • 5 The Long Beach VA Medical Center, Long Beach, California, USA

Correspondence should be addressed to H H Farman: helen.farman@gu.se

*(C Ohlsson and M K Lagerquist contributed equally to this work)

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The importance of estrogen receptor α (ERα) for the regulation of bone mass in males is well established. ERα mediates estrogenic effects both via nuclear and membrane-initiated ERα (mERα) signaling. The role of mERα signaling for the effects of estrogen on bone in male mice is unknown. To investigate the role of mERα signaling, we have used mice (Nuclear-Only-ER; NOER) with a point mutation (C451A), which results in inhibited trafficking of ERα to the plasma membrane. Gonadal-intact male NOER mice had a significantly decreased total body areal bone mineral density (aBMD) compared to WT littermates at 3, 6 and 9 months of age as measured by dual-energy X-ray absorptiometry (DEXA). High-resolution microcomputed tomography (µCT) analysis of tibia in 3-month-old males demonstrated a decrease in cortical and trabecular thickness in NOER mice compared to WT littermates. As expected, estradiol (E2) treatment of orchidectomized (ORX) WT mice increased total body aBMD, trabecular BV/TV and cortical thickness in tibia compared to placebo treatment. E2 treatment increased these skeletal parameters also in ORX NOER mice. However, the estrogenic responses were significantly decreased in ORX NOER mice compared with ORX WT mice. In conclusion, mERα is essential for normal estrogen signaling in both trabecular and cortical bone in male mice. Increased knowledge of estrogen signaling mechanisms in the regulation of the male skeleton may aid in the development of new treatment options for male osteoporosis.

 

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  • Acconcia F, Ascenzi P, Bocedi A, Spisni E, Tomasi V, Trentalance A, Visca P & Marino M 2005 Palmitoylation-dependent estrogen receptor alpha membrane localization: regulation by 17beta-estradiol. Molecular Biology of the Cell 16 231237. (https://doi.org/10.1091/mbc.e04-07-0547)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Adlanmerini M, Solinhac R, Abot A, Fabre A, Raymond-Letron I, Guihot AL, Boudou F, Sautier L, Vessieres E, Kim SH, 2014 Mutation of the palmitoylation site of estrogen receptor alpha in vivo reveals tissue-specific roles for membrane versus nuclear actions. PNAS 111 26. (https://doi.org/10.1073/pnas.1322057111)

    • Search Google Scholar
    • Export Citation
  • Arao Y, Hamilton KJ, Ray MK, Scott G, Mishina Y & Korach KS 2011 Estrogen receptor alpha AF-2 mutation results in antagonist reversal and reveals tissue selective function of estrogen receptor modulators. PNAS 108 1498614991. (https://doi.org/10.1073/pnas.1109180108)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Banerjee S, Chambliss KL, Mineo C & Shaul PW 2014 Recent insights into non-nuclear actions of estrogen receptor alpha. Steroids 81 6469. (https://doi.org/10.1016/j.steroids.2013.11.002)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bartell SM, Han L, Kim HN, Kim SH, Katzenellenbogen JA, Katzenellenbogen BS, Chambliss KL, Shaul PW, Roberson PK, Weinstein RS, 2013 Non-nuclear-initiated actions of the estrogen receptor protect cortical bone mass. Molecular Endocrinology 27 649656. (https://doi.org/10.1210/me.2012-1368)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Billon-Gales A, Fontaine C, Filipe C, Douin-Echinard V, Fouque MJ, Flouriot G, Gourdy P, Lenfant F, Laurell H, Krust A, 2009 The transactivating function 1 of estrogen receptor alpha is dispensable for the vasculoprotective actions of 17beta-estradiol. PNAS 106 20532058. (https://doi.org/10.1073/pnas.0808742106)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Borjesson AE, Windahl SH, Lagerquist MK, Engdahl C, Frenkel B, Moverare-Skrtic S, Sjogren K, Kindblom JM, Stubelius A, Islander U, 2011 Roles of transactivating functions 1 and 2 of estrogen receptor-alpha in bone. PNAS 108 62886293. (https://doi.org/10.1073/pnas.1100454108)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Borjesson AE, Farman HH, Engdahl C, Koskela A, Sjogren K, Kindblom JM, Stubelius A, Islander U, Carlsten H, Antal MC, 2013 The role of activation functions 1 and 2 of estrogen receptor-alpha for the effects of estradiol and selective estrogen receptor modulators in male mice. Journal of Bone and Mineral Research 28 11171126. (https://doi.org/10.1002/jbmr.1842)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Cooke PS, Nanjappa MK, Ko C, Prins GS & Hess RA 2017 Estrogens in male physiology. Physiological Reviews 97 9951043. (https://doi.org/10.1152/physrev.00018.2016)

  • Couse JF & Korach KS 1999 Estrogen receptor null mice: what have we learned and where will they lead us? Endocrine Reviews 20 358417. (https://doi.org/10.1210/edrv.20.3.0370)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Couse JF, Yates MM, Walker VR & Korach KS 2003 Characterization of the hypothalamic-pituitary-gonadal axis in estrogen receptor (ER) Null mice reveals hypergonadism and endocrine sex reversal in females lacking ERalpha but not ERbeta. Molecular Endocrinology 17 10391053. (https://doi.org/10.1210/me.2002-0398)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Dempster DW, Compston JE, Drezner MK, Glorieux FH, Kanis JA, Malluche H, Meunier PJ, Ott SM, Recker RR & Parfitt AM 2013 Standardized nomenclature, symbols, and units for bone histomorphometry: a 2012 update of the report of the ASBMR Histomorphometry Nomenclature Committee. Journal of Bone and Mineral Research 28 217. (https://doi.org/10.1002/jbmr.1805)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Eriksson AL, Perry JRB, Coviello AD, Delgado GE, Ferrucci L, Hoffman AR, Huhtaniemi IT, Ikram MA, Karlsson MK, Kleber ME, 2018 Genetic determinants of circulating estrogen levels and evidence of a causal effect of estradiol on bone density in men. Journal of Clinical Endocrinology and Metabolism 103 9911004. (https://doi.org/10.1210/jc.2017-02060)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Farman HH, Wu J, Gustafsson KL, Windahl SH, Kim SH, Katzenellenbogen JA, Ohlsson C & Lagerquist MK 2017 Extra-nuclear effects of estrogen on cortical bone in males require ERalphaAF-1. Journal of Molecular Endocrinology 58 105111. (https://doi.org/10.1530/JME-16-0209)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Goulding EH, Hewitt SC, Nakamura N, Hamilton K, Korach KS & Eddy EM 2010 Ex3alphaERKO male infertility phenotype recapitulates the alphaERKO male phenotype. Journal of Endocrinology 207 281288. (https://doi.org/10.1677/JOE-10-0290)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Gustafsson KL, Farman H, Henning P, Lionikaite V, Moverare-Skrtic S, Wu J, Ryberg H, Koskela A, Gustafsson JA, Tuukkanen J, 2016 The role of membrane ERalpha signaling in bone and other major estrogen responsive tissues. Scientific Reports 6 29473. (https://doi.org/10.1038/srep29473)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Harrington WR, Kim SH, Funk CC, Madak-Erdogan Z, Schiff R, Katzenellenbogen JA & Katzenellenbogen BS 2006 Estrogen dendrimer conjugates that preferentially activate extranuclear, nongenomic versus genomic pathways of estrogen action. Molecular Endocrinology 20 491502. (https://doi.org/10.1210/me.2005-0186)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Khosla S 2013 Pathogenesis of age-related bone loss in humans. Journals of Gerontology, Series A: Biological Sciences and Medical Sciences 68 12261235. (https://doi.org/10.1093/gerona/gls163)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Levin ER 2015 Extranuclear steroid receptors are essential for steroid hormone actions. Annual Review of Medicine 66 271280. (https://doi.org/10.1146/annurev-med-050913-021703)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lindberg MK, Weihua Z, Andersson N, Moverare S, Gao H, Vidal O, Erlandsson M, Windahl S, Andersson G, Lubahn DB, 2002 Estrogen receptor specificity for the effects of estrogen in ovariectomized mice. Journal of Endocrinology 174 167178. (https://doi.org/10.1677/joe.0.1740167)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Lindsay R, Hart DM, Aitken JM, MacDonald EB, Anderson JB & Clarke AC 1976 Long-term prevention of postmenopausal osteoporosis by oestrogen. Evidence for an increased bone mass after delayed onset of oestrogen treatment. Lancet 1 10381041.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Manolagas SC, O’Brien CA & Almeida M 2013 The role of estrogen and androgen receptors in bone health and disease. Nature Reviews Endocrinology 9 699712. (https://doi.org/10.1038/nrendo.2013.179)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Marino M, Ascenzi P & Acconcia F 2006 s-Palmitoylation modulates estrogen receptor alpha localization and functions. Steroids 71 298303. (https://doi.org/10.1016/j.steroids.2005.09.011)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Mellstrom D, Vandenput L, Mallmin H, Holmberg AH, Lorentzon M, Oden A, Johansson H, Orwoll ES, Labrie F, Karlsson MK, 2008 Older men with low serum estradiol and high serum SHBG have an increased risk of fractures. Journal of Bone and Mineral Research 23 15521560. (https://doi.org/10.1359/jbmr.080518)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Moverare-Skrtic S, Henning P, Liu X, Nagano K, Saito H, Borjesson AE, Sjogren K, Windahl SH, Farman H, Kindlund B, 2014 Osteoblast-derived WNT16 represses osteoclastogenesis and prevents cortical bone fragility fractures. Nature Medicine 20 12791288. (https://doi.org/10.1038/nm.3654)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Nanjappa MK, Hess RA, Medrano TI, Locker SH, Levin ER & Cooke PS 2016 Membrane-localized estrogen receptor 1 is required for normal male reproductive development and function in mice. Endocrinology 157 29092919. (https://doi.org/10.1210/en.2016-1085)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Nilsson ME, Vandenput L, Tivesten A, Norlen AK, Lagerquist MK, Windahl SH, Borjesson AE, Farman HH, Poutanen M, Benrick A, 2015 Measurement of a comprehensive sex steroid profile in rodent serum by high-sensitive gas chromatography-tandem mass spectrometry. Endocrinology 156 24922502. (https://doi.org/10.1210/en.2014-1890)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Pappas TC, Gametchu B & Watson CS 1995 Membrane estrogen receptors identified by multiple antibody labeling and impeded-ligand binding. FASEB Journal 9 404410. (https://doi.org/10.1096/fasebj.9.5.7896011)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Pedram A, Razandi M, Lewis M, Hammes S & Levin ER 2014 Membrane-localized estrogen receptor alpha is required for normal organ development and function. Developmental Cell 29 482490. (https://doi.org/10.1016/j.devcel.2014.04.016)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Razandi M, Pedram A, Greene GL & Levin ER 1999 Cell membrane and nuclear estrogen receptors (ERs) originate from a single transcript: studies of ERalpha and ERbeta expressed in Chinese hamster ovary cells. Molecular Endocrinology 13 307319. (https://doi.org/10.1210/mend.13.2.0239)

    • Search Google Scholar
    • Export Citation
  • 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. Journal of Clinical Investigation 111 13191327. (https://doi.org/10.1172/JCI17246)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Slemenda CW, Longcope C, Zhou L, Hui SL, Peacock M & Johnston CC 1997 Sex steroids and bone mass in older men. Positive associations with serum estrogens and negative associations with androgens. Journal of Clinical Investigation 100 17551759. (https://doi.org/10.1172/JCI119701)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Sozen T, Ozisik L & Basaran NC 2017 An overview and management of osteoporosis. European Journal of Rheumatology 4 4656. (https://doi.org/10.5152/eurjrheum.2016.048)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Vanderschueren D, Laurent MR, Claessens F, Gielen E, Lagerquist MK, Vandenput L, Borjesson AE & Ohlsson C 2014 Sex steroid actions in male bone. Endocrine Reviews 35 906960. (https://doi.org/10.1210/er.2014-1024)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 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. PNAS 97 54745479. (https://doi.org/10.1073/pnas.97.10.5474)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Vinel A, Hay E, Valera MC, Buscato M, Adlanmerini M, Guillaume M, Cohen-Solal M, Ohlsson C, Lenfant F, Arnal JF, 2016 Role of ERalphaMISS in the effect of estradiol on cancellous and cortical femoral bone in growing female mice. Endocrinology 157 25332544. (https://doi.org/10.1210/en.2015-1994)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation