title: WNT signaling in bone homeostasis and disease: from human mutations to treatments.
abstract: Low bone mass and strength lead to fragility fractures, for example, in elderly individuals affected by osteoporosis or children with osteogenesis imperfecta. A decade ago, rare human mutations affecting bone negatively (osteoporosis-pseudoglioma syndrome) or positively (high-bone mass phenotype, sclerosteosis and Van Buchem disease) have been identified and found to all reside in components of the canonical WNT signaling machinery. Mouse genetics confirmed the importance of canonical Wnt signaling in the regulation of bone homeostasis, with activation of the pathway leading to increased, and inhibition leading to decreased, bone mass and strength. The importance of WNT signaling for bone has also been highlighted since then in the general population in numerous genome-wide association studies. The pathway is now the target for therapeutic intervention to restore bone strength in millions of patients at risk for fracture. This paper reviews our current understanding of the mechanisms by which WNT signalng regulates bone homeostasis.
authors: Department of Medicine, Harvard Medical School, Harvard University, Boston, Massachusetts, USA. roland_baron@hsdm.harvard.edu
authors: Roland
authors: R
authors: Baron
authors: Michaela
authors: M
authors: Kneissel
mesh_terms: D000818:Animals; D015519:Bone Density; D001846:Bone Development; D019485:Bone Morphogenetic Proteins / Q000502:physiology; D001842:Bone and Bones / Q000378:metabolism*; D006410:Hematopoiesis; D006706:Homeostasis; D006801:Humans; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000502:physiology; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000502:physiology; D051379:Mice; D009154:Mutation; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000502:physiology
chemical_list: D019485:Bone Morphogenetic Proteins; C555482:LRP5 protein, human; C555475:LRP6 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D051176:beta Catenin
references: Arch Intern Med. 2005 Aug 8-22;165(15):1762-8
references: 16087825
references: J Cell Physiol. 2009 Jul;220(1):174-81
references: 19301255
references: Endocrinology. 2011 Aug;152(8):2963-75
references: 21652726
references: Bone. 2011 Apr 1;48(4):677-92
references: 21145999
references: Nature. 2003 Oct 23;425(6960):841-6
references: 14574413
references: J Biol Chem. 2011 Apr 1;286(13):10950-9
references: 21270130
references: Bone. 2011 Aug;49(2):184-93
references: 21419885
references: Mol Endocrinol. 2007 Feb;21(2):376-87
references: 17095577
references: Development. 2010 Oct;137(19):3221-31
references: 20724449
references: BMC Med Genet. 2012 Apr 10;13:26
references: 22487062
references: Endocrinology. 2012 Apr;153(4):1616-26
references: 22334719
references: J Clin Endocrinol Metab. 2010 May;95(5):2248-53
references: 20305005
references: PLoS One. 2007 Sep 05;2(9):e837
references: 17786208
references: Development. 2009 Aug;136(16):2747-56
references: 19605502
references: Nat Genet. 2012 Apr 15;44(5):491-501
references: 22504420
references: J Clin Invest. 2003 Sep;112(5):785-94
references: 12952927
references: Nat Genet. 2009 Nov;41(11):1199-206
references: 19801982
references: Lancet. 2010 May 15;375(9727):1729-36
references: 20472174
references: Proc Natl Acad Sci U S A. 2012 Jul 24;109(30):12207-12
references: 22761317
references: Am J Hum Genet. 2006 Aug;79(2):402-8
references: 16826533
references: J Biol Chem. 2011 Jun 3;286(22):19489-500
references: 21471202
references: Cell Metab. 2010 Feb 3;11(2):161-71
references: 20142103
references: J Clin Endocrinol Metab. 2011 Dec;96(12):3804-10
references: 21937621
references: J Cell Sci. 2009 Oct 1;122(Pt 19):3566-78
references: 19737815
references: J Bone Miner Res. 2011 May;26(5):1035-46
references: 21140374
references: Nat Med. 2011 Sep 11;17(10):1235-41
references: 21909103
references: J Bone Miner Res. 2005 Jul;20(7):1103-13
references: 15940363
references: Cell. 1987 Aug 14;50(4):659-63
references: 2440586
references: Am J Hum Genet. 2001 Mar;68(3):577-89
references: 11179006
references: Cell. 1982 Nov;31(1):99-109
references: 6297757
references: Curr Top Dev Biol. 2010;93:189-227
references: 20959167
references: J Bone Miner Res. 2008 Jun;23(6):860-9
references: 18269310
references: Trends Cell Biol. 2009 Mar;19(3):119-29
references: 19208479
references: J Bone Miner Res. 2010 Jan;25(1):82-90
references: 20209645
references: J Bone Miner Res. 2012 Aug;27(8):1757-72
references: 22492547
references: Endocrinology. 2011 Aug;152(8):2957-62
references: 21610157
references: Nature. 1995 Mar 23;374(6520):350-3
references: 7885472
references: Nat Med. 2012 Feb 19;18(3):405-12
references: 22344299
references: Cell Stem Cell. 2008 Mar 6;2(3):274-83
references: 18371452
references: Cell Stem Cell. 2009 Aug 7;5(2):157-67
references: 19664990
references: Nature. 2011 Jul 04;476(7360):293-7
references: 21727895
references: J Bone Miner Res. 2013 Jan;28(1):73-80
references: 22836659
references: J Bone Miner Res. 2010 Oct;25(10):2138-47
references: 20499361
references: J Bone Miner Res. 2001 Jul;16(7):1318-28
references: 11450708
references: J Biol Chem. 2005 Jul 22;280(29):26770-5
references: 15908424
references: Am J Hum Genet. 2003 Mar;72(3):763-71
references: 12579474
references: Bone. 2009 Jun;44(6):1063-8
references: 19254787
references: J Cell Sci. 2010 Aug 1;123(Pt 15):2640-8
references: 20605916
references: Bioorg Med Chem. 2010 Jan 1;18(1):190-201
references: 19932972
references: Nat Genet. 2009 Jan;41(1):15-7
references: 19079262
references: Cell. 2001 Feb 9;104(3):341-51
references: 11239392
references: JAMA. 2008 Mar 19;299(11):1277-90
references: 18349089
references: J Bone Miner Res. 2006 Jun;21(6):910-20
references: 16753022
references: BMC Dev Biol. 2009 Apr 08;9:26
references: 19356224
references: Eur J Hum Genet. 2011 Aug;19(8):875-81
references: 21407258
references: Blood. 2011 Sep 1;118(9):2420-9
references: 21652676
references: J Biol Chem. 2010 Mar 19;285(12):9172-9
references: 20093360
references: Development. 2006 Aug;133(16):3231-44
references: 16854976
references: J Bone Miner Res. 2004 Nov;19(11):1873-81
references: 15476588
references: Genes Dev. 2004 Oct 1;18(19):2404-17
references: 15371327
references: Dev Cell. 2007 Jan;12(1):113-27
references: 17199045
references: EMBO J. 2003 Dec 1;22(23):6267-76
references: 14633986
references: Cell Metab. 2009 Sep;10(3):229-40
references: 19723499
references: Nat Med. 2011 Jun;17(6):684-91
references: 21602802
references: J Bone Miner Res. 2010 Feb;25(2):190-9
references: 19594295
references: Nat Rev Rheumatol. 2011 Feb;7(2):78-80
references: 21289612
references: Proc Natl Acad Sci U S A. 2011 Jul 12;108(28):11452-7
references: 21693646
references: Endocrinology. 2011 May;152(5):2031-6
references: 21427221
references: J Biol Chem. 2009 May 22;284(21):14117-25
references: 19213727
references: PLoS One. 2008 Aug 13;3(8):e2942
references: 18698360
references: Dev Cell. 2011 May 17;20(5):583-596
references: 21571217
references: J Biol Chem. 2005 May 20;280(20):19883-7
references: 15778503
references: Proc Natl Acad Sci U S A. 2010 Aug 10;107(32):14211-6
references: 20660756
references: J Cell Biol. 2011 Mar 21;192(6):1057-72
references: 21402791
references: Nature. 1980 Oct 30;287(5785):795-801
references: 6776413
references: Cell Calcium. 2005 Sep-Oct;38(3-4):439-46
references: 16099039
references: J Clin Invest. 2011 Sep;121(9):3492-504
references: 21804192
references: Genes Dev. 2008 Nov 1;22(21):2968-79
references: 18981475
references: Proc Natl Acad Sci U S A. 2005 Nov 29;102(48):17406-11
references: 16293698
references: Endocr Rev. 2005 Aug;26(5):688-703
references: 15769903
references: Dev Dyn. 2010 Aug;239(8):2266-77
references: 20593419
references: J Bone Miner Res. 2010 Nov;25(11):2412-8
references: 20499342
references: Arthritis Rheum. 2009 Nov;60(11):3257-62
references: 19877044
references: J Cell Biochem. 2006 Mar 1;97(4):661-72
references: 16447163
references: J Cell Biochem. 2011 Dec;112(12):3491-501
references: 21793042
references: Osteoporos Int. 2010 Nov;21(11):1793-802
references: 20309524
references: Hum Genet. 2011 May;129(5):497-502
references: 21221996
references: Bone. 2007 Jul;41(1 Suppl 1):S3-8
references: 17466615
references: Hum Mol Genet. 2005 Nov 15;14(22):3523-38
references: 16207730
references: PLoS One. 2010 Apr 27;5(4):e10309
references: 20436912
references: J Endocrinol. 2011 Apr;209(1):21-32
references: 21220409
references: Development. 2004 Apr;131(8):1663-77
references: 15084453
references: Bone. 2008 Apr;42(4):606-15
references: 18280232
references: Calcif Tissue Int. 2008 Jun;82(6):445-53
references: 18521528
references: J Biol Chem. 2007 Sep 14;282(37):27298-27305
references: 17623658
references: Curr Mol Pharmacol. 2012 Jun;5(2):153-63
references: 21787290
references: Dev Cell. 2005 May;8(5):739-50
references: 15866164
references: J Bone Miner Res. 2007 Dec;22(12):1957-67
references: 17696759
references: J Bone Miner Res. 2005 May;20(5):878-85
references: 15824861
references: J Biol Chem. 2006 Aug 18;281(33):23698-711
references: 16790443
references: J Biol Chem. 2007 Feb 9;282(6):4057-68
references: 17158104
references: J Bone Miner Res. 2006 Nov;21(11):1738-49
references: 17002572
references: Ann Rheum Dis. 2010 Mar;69(3):592-7
references: 19304568
references: Nat Rev Mol Cell Biol. 2011 Dec 22;13(1):27-38
references: 22189423
references: Trends Endocrinol Metab. 2010 Apr;21(4):237-44
references: 20074973
references: Bone. 2006 Sep;39(3):470-6
references: 16679074
references: J Bone Miner Res. 2006 Jun;21(6):934-45
references: 16753024
references: Nat Genet. 2000 Mar;24(3):271-4
references: 10700181
references: Am J Hum Genet. 2005 Nov;77(5):741-53
references: 16252235
references: Cell. 2008 Nov 28;135(5):825-37
references: 19041748
references: Bone. 2011 Sep;49(3):568-71
references: 21600326
references: Hum Genet. 2010 Mar;127(3):249-85
references: 20101412
references: Dev Cell. 2005 May;8(5):751-64
references: 15866165
references: Eur J Endocrinol. 2010 Nov;163(5):833-7
references: 20817762
references: FASEB J. 2005 Nov;19(13):1842-4
references: 16123173
references: Endocrinology. 2005 Nov;146(11):4577-83
references: 16081646
references: Calcif Tissue Int. 2005 Jul;77(1):1-8
references: 16007481
references: Am J Hum Genet. 2002 Jan;70(1):11-9
references: 11741193
references: Bone. 2010 Apr;46(4):985-92
references: 20060080
references: PLoS One. 2009 Nov 20;4(11):e7930
references: 19936252
references: Blood. 2009 Jul 9;114(2):371-9
references: 19417213
references: Mol Cell Endocrinol. 2009 Oct 30;310(1-2):21-9
references: 19376193
references: Dev Biol. 2011 Nov 15;359(2):222-9
references: 21924256
references: Science. 1991 Aug 9;253(5020):665-9
references: 1651563
references: Cold Spring Harb Perspect Biol. 2009 Aug;1(2):a002881
references: 20066091
references: J Pediatr Endocrinol Metab. 2008 Aug;21(8):811-8
references: 18825883
references: J Cell Physiol. 2007 Feb;210(2):352-7
references: 17044082
references: J Biol Chem. 2008 Aug 1;283(31):21427-32
references: 18505732
references: Bone. 2007 Sep;41(3):321-30
references: 17573250
references: Arthritis Rheum. 2010 Aug;62(8):2303-12
references: 20506554
references: Biochem Biophys Res Commun. 2011 Oct 22;414(2):326-30
references: 21945937
references: Am J Hum Genet. 2004 Mar;74(3):558-63
references: 14872406
references: Bone. 2007 Feb;40(2):485-92
references: 17055793
references: J Biol Chem. 2009 Oct 30;284(44):30167-76
references: 19720827
references: J Clin Endocrinol Metab. 2010 Nov;95(11):5056-62
references: 20631014
references: J Bone Miner Res. 2011 Feb;26(2):229-38
references: 21254230
references: Dev Biol. 2010 Jun 15;342(2):169-79
references: 20359476
references: Nat Med. 2011 Sep 11;17(10):1231-4
references: 21909105
references: J Clin Psychopharmacol. 2008 Aug;28(4):384-91
references: 18626264
references: Cell. 2001 Nov 16;107(4):513-23
references: 11719191
references: J Bone Miner Res. 2009 Mar;24(3):425-36
references: 19016584
references: J Orthop Res. 2010 Jul;28(7):928-36
references: 20063381
references: J Bone Miner Res. 2003 Jun;18(6):960-74
references: 12817748
references: J Cell Biol. 2002 Apr 15;157(2):303-14
references: 11956231
references: J Cell Physiol. 2008 Oct;217(1):127-37
references: 18446812
references: Genes Dev. 1999 Mar 15;13(6):709-17
references: 10090727
references: Bone. 2009 Aug;45(2):289-94
references: 19371798
references: Bone. 2006 Oct;39(4):754-66
references: 16730481
references: Nat Cell Biol. 2007 Nov;9(11):1273-85
references: 17952062
references: Cytokine Growth Factor Rev. 2009 Oct-Dec;20(5-6):343-55
references: 19897402
references: J Biol Chem. 2007 Nov 9;282(45):33086-97
references: 17690103
references: J Biol Chem. 2008 Feb 29;283(9):5866-75
references: 18089564
references: J Bone Miner Res. 2011 Dec;26(12):2804-11
references: 21786318
references: J Clin Invest. 2009 Apr;119(4):837-51
references: 19307728
references: Biochem Biophys Res Commun. 2003 Jan 31;301(1):84-91
references: 12535644
references: Blood. 2009 Jan 15;113(3):517-25
references: 18687985
references: J Bone Miner Res. 2011 May;26(5):1012-21
references: 21542004
references: Proc Natl Acad Sci U S A. 2008 Dec 30;105(52):20764-9
references: 19075223
references: Lancet. 2008 May 3;371(9623):1505-12
references: 18455228
references: Hum Mol Genet. 2011 Jan 15;20(2):271-85
references: 20962035
references: Mol Cell Biol. 2011 Dec;31(23):4706-19
references: 21876000
references: J Bone Miner Res. 2011 Jan;26(1):19-26
references: 20593411
references: Methods Enzymol. 2010;484:357-73
references: 21036241
references: J Bone Miner Res. 2010 May;25(5):948-59
references: 20200929
references: J Bone Miner Res. 2004 Dec;19(12):2033-40
references: 15537447
references: J Biol Chem. 2006 May 12;281(19):13247-13257
references: 16543246
references: J Bone Miner Res. 2007 Dec;22(12):1924-32
references: 17708715
references: Proc Natl Acad Sci U S A. 2012 Aug 14;109(33):E2197-204
references: 22745162
references: Biochem Biophys Res Commun. 2012 Jan 6;417(1):223-30
references: 22142846
references: N Engl J Med. 2002 May 16;346(20):1513-21
references: 12015390
references: J Med Genet. 2002 Feb;39(2):91-7
references: 11836356
references: Mol Cell Biol. 2009 Feb;29(4):953-64
references: 19075000
references: J Biol Chem. 2009 Aug 21;284(34):23159-68
references: 19553665
references: J Biol Chem. 2010 Dec 31;285(53):41614-26
references: 20952383
references: Mol Cell Biol. 2010 Jun;30(12):3071-85
references: 20404086
references: Bone. 2010 Aug;47(2):263-71
references: 20472109
references: J Bone Miner Res. 2007 Apr;22(4):495-502
references: 17227219
references: J Biol Chem. 2006 Oct 20;281(42):31720-8
references: 16908522
references: Bone. 2005 Aug;37(2):148-58
references: 15946907
references: J Exp Med. 2004 Mar 15;199(6):805-14
references: 15024046
references: Bioorg Med Chem Lett. 2009 Nov 15;19(22):6337-9
references: 19819694
references: Nat Genet. 2005 Sep;37(9):945-52
references: 16056226
references: Sci Signal. 2009 Apr 28;2(68):pt3
references: 19401590
references: N Engl J Med. 2008 May 29;358(22):2355-65
references: 18445777
references: Genome Res. 2005 Jul;15(7):928-35
references: 15965026
references: Proc Natl Acad Sci U S A. 2005 Mar 1;102(9):3324-9
references: 15728361
references: Development. 2009 Oct;136(19):3205-14
references: 19736321
references: J Bone Miner Res. 2009 Dec;24(12):2039-49
references: 19453261
references: Mol Cell Biol. 2005 Jun;25(12):4946-55
references: 15923613
references: Bone. 2008 Sep;43(3):584-90
references: 18602879
references: J Bone Miner Res. 2010 Feb;25(2):178-89
references: 19594304
references: J Biol Chem. 2005 Jun 24;280(25):24004-10
references: 15849360
references: J Bone Miner Res. 2010 Sep;25(9):1897-904
references: 20564241
references: Bone. 2009 Jun;44(6):1069-77
references: 19254785
references: Science. 1991 Mar 15;251(4999):1366-70
references: 1848370
references: Dev Cell. 2005 May;8(5):727-38
references: 15866163
references: Proc Natl Acad Sci U S A. 2007 Sep 11;104(37):14700-5
references: 17804805
references: Mol Endocrinol. 2004 May;18(5):1222-37
references: 14976225
references: J Pharmacol Exp Ther. 2011 Aug;338(2):568-78
references: 21531794
references: Assay Drug Dev Technol. 2005 Apr;3(2):133-41
references: 15871688
references: Bone. 2011 Feb;48(2):197-201
references: 20850580
references: Bone. 2011 May 1;48(5):988-96
references: 21329773
references: J Biol Chem. 2009 Apr 17;284(16):10890-900
references: 19208630
references: J Bone Miner Res. 2009 Oct;24(10):1651-61
references: 19419300
references: J Bone Miner Res. 2011 Nov;26(11):2610-21
references: 21773994
references: Dev Biol. 2011 Apr 1;352(1):1-13
references: 21237142
references: J Bone Miner Res. 2009 Apr;24(4):578-88
references: 19049336
references: Cell. 2011 Mar 4;144(5):796-809
references: 21333348
references: J Bone Miner Res. 2008 Oct;23(10):1661-71
references: 18505367
references: Trends Endocrinol Metab. 2004 Mar;15(2):60-5
references: 15036251
references: Drugs. 2005;65(17):2481-98
references: 16296873
references: Nat Med. 2007 Feb;13(2):156-63
references: 17237793
references: J Biol Chem. 2005 Jun 3;280(22):21162-8
references: 15802266
references: Development. 2005 Jan;132(1):49-60
references: 15576404
references: Exp Clin Endocrinol Diabetes. 2011 Jul;119(7):440-4
references: 21667439
references: Biochem Biophys Res Commun. 2009 Dec 4;390(1):65-70
references: 19778523
references: Science. 2007 Mar 2;315(5816):1278-82
references: 17332414
references: Structure. 2011 Oct 12;19(10):1433-42
references: 21944579
references: Biochem Biophys Res Commun. 2009 Feb 27;380(1):160-5
references: 19166819
references: J Bone Miner Res. 2008 Apr;23(4):499-506
references: 18021006
references: FEBS Lett. 2008 Mar 5;582(5):643-50
references: 18242177
references: J Bone Miner Res. 2008 Feb;23(2):271-7
references: 17907918
references: J Bone Miner Res. 2006 Dec;21(12):1821-7
references: 17002562
references: PLoS One. 2011 Apr 29;6(4):e19185
references: 21559429
references: Cell Res. 2009 Jan;19(1):71-88
references: 19002158