title: The role of estrogen and androgen receptors in bone health and disease.
abstract: Mouse models with cell-specific deletion of the estrogen receptor (ER) α, the androgen receptor (AR) or the receptor activator of nuclear factor κB ligand (RANKL), as well as cascade-selective estrogenic compounds have provided novel insights into the function and signalling of ERα and AR. The studies reveal that the effects of estrogens on trabecular versus cortical bone mass are mediated by direct effects on osteoclasts and osteoblasts, respectively. The protection of cortical bone mass by estrogens is mediated via ERα, using a non-nucleus-initiated mechanism. By contrast, the AR of mature osteoblasts is indispensable for the maintenance of trabecular bone mass in male mammals, but not required for the anabolic effects of androgens on cortical bone. Most unexpectedly, and independently of estrogens, ERα in osteoblast progenitors stimulates Wnt signalling and periosteal bone accrual in response to mechanical strain. RANKL expression in B lymphocytes, but not T lymphocytes, contributes to the loss of trabecular bone caused by estrogen deficiency. In this Review, we summarize this evidence and discuss its implications for understanding the regulation of trabecular and cortical bone mass; the integration of hormonal and mechanical signals; the relative importance of estrogens versus androgens in the male skeleton; and, finally, the pathogenesis and treatment of osteoporosis.
authors.affiliation: Division of Endocrinology and Metabolism, Centre for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, 4301 West Markham, Little Rock, AR 72205-7199, USA.
authors.forename: Stavros C
authors.initials: SC
authors.lastname: Manolagas
authors.affiliation: Division of Endocrinology and Metabolism, Centre for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, 4301 West Markham, Little Rock, AR 72205-7199, USA.
authors.forename: Charles A
authors.initials: CA
authors.lastname: O'Brien
authors.affiliation: Division of Endocrinology and Metabolism, Centre for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, 4301 West Markham, Little Rock, AR 72205-7199, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Almeida
mesh_terms: D000818:Animals; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D011944:Receptors, Androgen / Q000378:metabolism*
chemical_list: D047628:Estrogen Receptor alpha; D011944:Receptors, Androgen
references.citation: Breast Dis. 2003;18:3-9
references.pmid: 15687684
references.citation: FASEB J. 2009 Jan;23(1):232-40
references.pmid: 18809737
references.citation: Annu Rev Biochem. 1994;63:451-86
references.pmid: 7979245
references.citation: J Exp Med. 1997 Aug 18;186(4):489-95
references.pmid: 9254647
references.citation: J Biol Chem. 2009 Oct 2;284(40):27438-48
references.pmid: 19657144
references.citation: Trends Endocrinol Metab. 2012 Nov;23(11):576-81
references.pmid: 22595550
references.citation: J Bone Miner Res. 2007 Mar;22(3):347-56
references.pmid: 17147488
references.citation: Endocrinology. 1999 Apr;140(4):1893-900
references.pmid: 10098529
references.citation: J Bone Miner Res. 1995 Mar;10(3):466-73
references.pmid: 7785469
references.citation: J Bone Miner Res. 2009 Apr;24(4):621-31
references.pmid: 19049333
references.citation: Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6653-8
references.pmid: 15100414
references.citation: J Bone Miner Res. 2010 Nov;25(11):2438-46
references.pmid: 20499336
references.citation: Mol Endocrinol. 2010 Feb;24(2):323-34
references.pmid: 20053716
references.citation: Endocrinology. 2010 Dec;151(12):5582-90
references.pmid: 20943807
references.citation: J Am Geriatr Soc. 2002 May;50(5):889-96
references.pmid: 12028177
references.citation: Lancet. 2010 May 15;375(9727):1729-36
references.pmid: 20472174
references.citation: Bone. 2008 Jul;43(1):92-100
references.pmid: 18407820
references.citation: N Engl J Med. 2003 Jul 24;349(4):327-34
references.pmid: 12878739
references.citation: J Bone Miner Res. 1997 Apr;12(4):498-508
references.pmid: 9101361
references.citation: J Clin Invest. 1988 Jun;81(6):1804-9
references.pmid: 3384952
references.citation: Bone. 2000 Oct;27(4):487-94
references.pmid: 11033443
references.citation: Cell Mol Life Sci. 2002 May;59(5):821-31
references.pmid: 12088282
references.citation: J Clin Endocrinol Metab. 2000 Mar;85(3):1032-7
references.pmid: 10720035
references.citation: J Biol Chem. 2007 Aug 31;282(35):25501-8
references.pmid: 17609204
references.citation: Proc Natl Acad Sci U S A. 2013 Feb 5;110(6):2294-9
references.pmid: 23345419
references.citation: Aging Cell. 2010 Apr;9(2):147-61
references.pmid: 20047574
references.citation: Endocr Rev. 2003 Dec;24(6):782-801
references.pmid: 14671005
references.citation: Mol Endocrinol. 2013 Apr;27(4):649-56
references.pmid: 23443267
references.citation: N Engl J Med. 2003 Jul 24;349(4):320-3
references.pmid: 12878736
references.citation: J Clin Endocrinol Metab. 1997 Sep;82(9):3128-35
references.pmid: 9284757
references.citation: Trends Endocrinol Metab. 2010 Oct;21(10):637-41
references.pmid: 20674386
references.citation: J Clin Invest. 2003 Apr;111(8):1221-30
references.pmid: 12697741
references.citation: Mol Endocrinol. 2006 Mar;20(3):491-502
references.pmid: 16306086
references.citation: Endocr Rev. 2010 Jun;31(3):266-300
references.pmid: 20051526
references.citation: J Clin Endocrinol Metab. 2008 Aug;93(8):3088-96
references.pmid: 18505767
references.citation: J Bone Miner Res. 2006 May;21(5):695-702
references.pmid: 16734384
references.citation: EMBO J. 1994 Mar 1;13(5):1189-96
references.pmid: 8131749
references.citation: Histochem J. 1998 Jul;30(7):467-72
references.pmid: 10192529
references.citation: Mol Cell Biol. 2007 Feb;27(4):1516-30
references.pmid: 17158928
references.citation: N Engl J Med. 1997 Jul 10;337(2):91-5
references.pmid: 9211678
references.citation: J Bone Miner Res. 2006 Apr;21(4):576-85
references.pmid: 16598378
references.citation: Bone. 2007 Jun;40(6):1662-8
references.pmid: 17400043
references.citation: Am J Physiol Endocrinol Metab. 2012 Jun 1;302(11):E1381-9
references.pmid: 22414805
references.citation: Steroids. 1999 May;64(5):310-9
references.pmid: 10406480
references.citation: EMBO J. 2008 Feb 6;27(3):535-45
references.pmid: 18219273
references.citation: Mol Endocrinol. 2010 Oct;24(10):2030-7
references.pmid: 20685851
references.citation: J Bone Miner Res. 2006 Nov;21(11):1704-12
references.pmid: 17002560
references.citation: J Bone Miner Res. 2013 Feb;28(2):291-301
references.pmid: 22972752
references.citation: JAMA. 2002 Jul 17;288(3):321-33
references.pmid: 12117397
references.citation: Mol Endocrinol. 2009 Apr;23(4):444-53
references.pmid: 19164450
references.citation: Circ Res. 2002 Nov 1;91(9):814-20
references.pmid: 12411396
references.citation: Development. 2006 Aug;133(16):3231-44
references.pmid: 16854976
references.citation: J Bone Joint Surg Am. 1960 Jan;42-A:144-50
references.pmid: 13849862
references.citation: Bone. 2013 Jun;54(2):272-8
references.pmid: 23010104
references.citation: J Clin Invest. 2001 Apr;107(7):803-12
references.pmid: 11285299
references.citation: Trends Endocrinol Metab. 2010 Jun;21(6):369-74
references.pmid: 20223679
references.citation: J Bone Miner Res. 2012 Feb;27(2):231-9
references.pmid: 22271394
references.citation: Endocr Rev. 2008 Apr;29(2):155-92
references.pmid: 18057140
references.citation: J Bone Miner Res. 2000 Mar;15(3):541-9
references.pmid: 10750569
references.citation: J Bone Miner Res. 2010 Apr;25(4):769-81
references.pmid: 19821774
references.citation: Bone. 2012 Jan;50(1):209-17
references.pmid: 22075208
references.citation: Bone. 2005 Feb;36(2):185-92
references.pmid: 15780944
references.citation: J Clin Invest. 1994 Sep;94(3):1090-7
references.pmid: 8083350
references.citation: Nat Cell Biol. 2003 Mar;5(3):179-82
references.pmid: 12646868
references.citation: Nature. 2003 May 15;423(6937):332-6
references.pmid: 12748651
references.citation: J Clin Endocrinol Metab. 2004 Dec;89(12):6025-9
references.pmid: 15579754
references.citation: J Bone Miner Res. 2003 Sep;18(9):1657-63
references.pmid: 12968675
references.citation: Bone. 2013 Jul;55(1):84-92
references.pmid: 23567159
references.citation: Mol Endocrinol. 2005 Jun;19(6):1606-17
references.pmid: 15831524
references.citation: J Clin Invest. 2000 Dec;106(12):1553-60
references.pmid: 11120762
references.citation: J Clin Invest. 2010 Jul;120(7):2319-30
references.pmid: 20577047
references.citation: N Engl J Med. 1995 Feb 2;332(5):305-11
references.pmid: 7816067
references.citation: Proc Natl Acad Sci U S A. 1997 Aug 19;94(17):9360-5
references.pmid: 9256487
references.citation: J Biol Chem. 2007 Sep 14;282(37):27298-27305
references.pmid: 17623658
references.citation: Hum Reprod Update. 2000 May-Jun;6(3):225-36
references.pmid: 10874567
references.citation: Gravit Space Biol Bull. 2003 Jun;16(2):45-54
references.pmid: 12959131
references.citation: J Biol Chem. 2006 Aug 18;281(33):23698-711
references.pmid: 16790443
references.citation: J Nutr Health Aging. 2008 Aug-Sep;12(7):427-32
references.pmid: 18615224
references.citation: Cell. 1998 Apr 17;93(2):165-76
references.pmid: 9568710
references.citation: J Biol Chem. 2007 Sep 14;282(37):27285-27297
references.pmid: 17623659
references.citation: Bone. 2010 May;46(5):1226-37
references.pmid: 20149904
references.citation: Bone. 2002 Jan;30(1):18-25
references.pmid: 11792560
references.citation: J Bone Miner Res. 2012 Mar;27(3):637-44
references.pmid: 22095490
references.citation: J Steroid Biochem Mol Biol. 2006 Jan;98(1):25-35
references.pmid: 16203130
references.citation: Cell. 2007 Sep 7;130(5):811-23
references.pmid: 17803905
references.citation: J Immunol. 2011 Sep 1;187(5):2386-93
references.pmid: 21810607
references.citation: J Bone Miner Res. 1998 May;13(5):763-73
references.pmid: 9610739
references.citation: J Clin Invest. 2006 Sep;116(9):2500-9
references.pmid: 16955145
references.citation: J Steroid Biochem Mol Biol. 2008 Jul;111(1-2):95-100
references.pmid: 18606537
references.citation: Shock. 2000 Oct;14(4):465-70
references.pmid: 11049111
references.citation: Ann Intern Med. 1987 Mar;106(3):354-61
references.pmid: 3544993
references.citation: J Bone Miner Res. 2010 Mar;25(3):617-26
references.pmid: 19888832
references.citation: J Cell Biochem. 1994 Jul;55(3):287-99
references.pmid: 7962159
references.citation: Bone. 2010 Sep;47(3):472-9
references.pmid: 20601290
references.citation: J Clin Invest. 2006 Nov;116(11):2834
references.pmid: 17080186
references.citation: Bone. 2012 Mar;50(3):628-37
references.pmid: 22154841
references.citation: Endocrinology. 2008 Apr;149(4):1987-93
references.pmid: 18096666
references.citation: J Biol Chem. 2012 Aug 24;287(35):29851-60
references.pmid: 22782898
references.citation: Osteoporos Int. 2008 Feb;19(2):193-9
references.pmid: 17768586
references.citation: Osteoporos Int. 2008 Sep;19(9):1323-30
references.pmid: 18274695
references.citation: J Biol Chem. 2007 Jul 13;282(28):20715-27
references.pmid: 17491024
references.citation: J Clin Invest. 2013 Jan;123(1):394-404
references.pmid: 23221342
references.citation: Endocrinology. 2004 Feb;145(2):913-21
references.pmid: 14563705
references.citation: J Clin Endocrinol Metab. 2006 Feb;91(2):378-82
references.pmid: 16303833
references.citation: Endocrinology. 2001 Jun;142(6):2200-4
references.pmid: 11356663
references.citation: Osteoporos Int. 1994 Nov;4(6):382-98
references.pmid: 7696836
references.citation: Menopause. 2010 Mar;17(2):242-55
references.pmid: 20154637
references.citation: Osteoporos Int. 2010 Mar;21(3):365-72
references.pmid: 19495826
references.citation: Kidney Int Suppl. 2004 Oct;(91):S41-9
references.pmid: 15461702
references.citation: Angew Chem Int Ed Engl. 2006 Nov 6;45(43):7243-8
references.pmid: 17024710
references.citation: Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):15131-6
references.pmid: 11752459
references.citation: J Clin Endocrinol Metab. 1996 Dec;81(12):4358-65
references.pmid: 8954042
references.citation: J Bone Miner Res. 2006 Apr;21(4):605-15
references.pmid: 16598381
references.citation: Bone. 2010 Mar;46(3):577-83
references.pmid: 19925896
references.citation: Blood. 1995 Mar 15;85(6):1535-9
references.pmid: 7534134
references.citation: Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):125-30
references.pmid: 12490655
references.citation: Nucleic Acids Res. 1997 Jun 15;25(12):2424-9
references.pmid: 9171095
references.citation: J Bone Miner Res. 2011 Feb;26(2):229-38
references.pmid: 21254230
references.citation: Proc Natl Acad Sci U S A. 2011 Apr 12;108(15):6288-93
references.pmid: 21444817
references.citation: J Clin Invest. 1995 Jun;95(6):2886-95
references.pmid: 7769130
references.citation: Anat Rec. 1987 Sep;219(1):1-9
references.pmid: 3688455
references.citation: J Cell Biochem. 2007 Apr 15;100(6):1370-5
references.pmid: 17131364
references.citation: Recent Prog Horm Res. 2002;57:385-409
references.pmid: 12017554
references.citation: Science. 1997 Oct 17;278(5337):419-24
references.pmid: 9334293
references.citation: J Bone Miner Res. 2011 Mar;26(3):441-51
references.pmid: 20928874
references.citation: Osteoporos Int. 1994;4 Suppl 1:15-25
references.pmid: 8081052
references.citation: Bone. 2008 Sep;43(3):440-51
references.pmid: 18595795
references.citation: J Bone Miner Res. 2012 Dec;27(12):2535-43
references.pmid: 22836391
references.citation: J Urol. 1997 Feb;157(2):439-44
references.pmid: 8996327
references.citation: Gen Comp Endocrinol. 2011 Jan 1;170(1):3-17
references.pmid: 20338175
references.citation: J Bone Miner Res. 1999 Oct;14(10):1796-802
references.pmid: 10491228
references.citation: Gravit Space Biol Bull. 1997 Jun;10(2):119-35
references.pmid: 11540113
references.citation: Bone. 2002 Feb;30(2):337-9
references.pmid: 11856639
references.citation: J Biol Chem. 2005 Feb 11;280(6):4632-8
references.pmid: 15557324
references.citation: J Clin Invest. 2003 Jun;111(11):1651-64
references.pmid: 12782668
references.citation: Bone. 2013 Jul;55(1):179-88
references.pmid: 23486182
references.citation: Osteoporos Int. 1990 Oct;1(1):30-4
references.pmid: 2133638
references.citation: J Bone Miner Res. 2010 Dec;25(12):2690-700
references.pmid: 20564247
references.citation: Science. 2002 Oct 25;298(5594):843-6
references.pmid: 12399595
references.citation: Nat Med. 1996 Oct;2(10):1132-6
references.pmid: 8837613
references.citation: Aging Cell. 2010 Oct;9(5):851-67
references.pmid: 20698835
references.citation: Cell. 2001 Mar 9;104(5):719-30
references.pmid: 11257226
references.citation: J Endocrinol. 2004 Aug;182(2):193-201
references.pmid: 15283680
references.citation: Crit Rev Eukaryot Gene Expr. 2001;11(1-3):131-44
references.pmid: 11693958
references.citation: Bone. 2009 Feb;44(2):275-86
references.pmid: 19010455
references.citation: Calcif Tissue Int. 2004 Oct;75(4):329-37
references.pmid: 15549648
references.citation: Endocr Rev. 2007 Dec;28(7):726-41
references.pmid: 17916740
references.citation: J Biol Chem. 2006 Oct 20;281(42):31720-8
references.pmid: 16908522
references.citation: FASEB J. 2013 Feb;27(2):478-88
references.pmid: 23073829
references.citation: J Bone Miner Res. 2010 Jan;25(1):124-31
references.pmid: 19821763
references.citation: Trends Endocrinol Metab. 2010 Feb;21(2):89-95
references.pmid: 19837603
references.citation: J Endocrinol. 2010 Nov;207(2):127-34
references.pmid: 20807726
references.citation: N Engl J Med. 1998 Aug 27;339(9):599-603
references.pmid: 9718379
references.citation: Mol Endocrinol. 2007 Jan;21(1):1-13
references.pmid: 16556737
references.citation: Endocrinol Metab Clin North Am. 2011 Sep;40(3):461-71, vii
references.pmid: 21889714
references.citation: Cell Metab. 2007 Jun;5(6):464-75
references.pmid: 17550781
references.citation: Endocr Rev. 2000 Apr;21(2):115-37
references.pmid: 10782361
references.citation: PLoS One. 2011;6(6):e21402
references.pmid: 21731732
references.citation: Science. 1992 Jul 3;257(5066):88-91
references.pmid: 1621100
references.citation: Anat Rec. 1990 Apr;226(4):403-13
references.pmid: 2184695
references.citation: J Bone Miner Res. 2009 Apr;24(4):597-605
references.pmid: 19049324
references.citation: J Orthop Res. 1990 Jul;8(4):612-7
references.pmid: 2355301
references.citation: PLoS One. 2011;6(6):e21216
references.pmid: 21731677
references.citation: Osteoporos Int. 1998;8(5):468-89
references.pmid: 9850356
references.citation: Curr Opin Rheumatol. 2012 Nov;24(6):623-7
references.pmid: 22955023
references.citation: Horm Res. 1998;49 Suppl 1:2-8
references.pmid: 9554463
references.citation: Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9416-21
references.pmid: 12872002
references.citation: Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13498-503
references.pmid: 12370412
references.citation: Proc Natl Acad Sci U S A. 2011 Jan 11;108(2):768-73
references.pmid: 21187391