title: Canonical Wnt signaling inhibits osteoclastogenesis independent of osteoprotegerin.
abstract: Although Wnt signaling is considered a key regulatory pathway for bone formation, inactivation of β-catenin in osteoblasts does not affect their activity but rather causes increased osteoclastogenesis due to insufficient production of osteoprotegerin (Opg). By monitoring the expression pattern of all known genes encoding Wnt receptors in mouse tissues and bone cells we identified Frizzled 8 (Fzd8) as a candidate regulator of bone remodeling. Fzd8-deficient mice displayed osteopenia with normal bone formation and increased osteoclastogenesis, but this phenotype was not associated with impaired Wnt signaling or Opg production by osteoblasts. The deduced direct negative influence of canonical Wnt signaling on osteoclastogenesis was confirmed in vitro and through the generation of mice lacking β-catenin in the osteoclast lineage. Here, we observed increased bone resorption despite normal Opg production and a resistance to the anti-osteoclastogenic effect of Wnt3a. These results demonstrate that Fzd8 and β-catenin negatively regulate osteoclast differentiation independent of osteoblasts and that canonical Wnt signaling controls bone resorption by two different mechanisms.
authors: Department of Osteology and Biomechanics, University Medical Center Hamburg Eppendorf, Hamburg 20246, Germany.
authors: Joachim
authors: J
authors: Albers
authors: Johannes
authors: J
authors: Keller
authors: Anke
authors: A
authors: Baranowsky
authors: Frank Timo
authors: FT
authors: Beil
authors: Philip
authors: P
authors: Catala-Lehnen
authors: Jochen
authors: J
authors: Schulze
authors: Michael
authors: M
authors: Amling
authors: Thorsten
authors: T
authors: Schinke
mesh_terms: D000818:Animals; D001862:Bone Resorption; D002454:Cell Differentiation; D020869:Gene Expression Profiling; D051379:Mice; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism; D010012:Osteogenesis / Q000502:physiology; D053244:Osteoprotegerin / Q000378:metabolism / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D060490:Receptors, Wnt / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000502:physiology*; D060509:Wnt3A Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism / Q000502:physiology
chemical_list: D053244:Osteoprotegerin; D043562:Receptors, G-Protein-Coupled; D060490:Receptors, Wnt; D060509:Wnt3A Protein; D051176:beta Catenin; C555511:Wnt3a protein, mouse; C511610:Fzd8 protein, mouse
references: Genes Dev. 1998 May 1;12(9):1260-8
references: 9573043
references: Nature. 2003 May 15;423(6937):349-55
references: 12748654
references: Nat Med. 2011 Jun;17(6):684-91
references: 21602802
references: Trends Pharmacol Sci. 2007 Oct;28(10):518-25
references: 17884187
references: J Cell Biol. 2011 Mar 21;192(6):1057-72
references: 21402791
references: PLoS One. 2010 Apr 27;5(4):e10309
references: 20436912
references: Dev Cell. 2005 May;8(5):739-50
references: 15866164
references: J Bone Miner Res. 1987 Dec;2(6):595-610
references: 3455637
references: Nature. 2001 Jul 5;412(6842):86-90
references: 11452312
references: Mol Cell Biol. 2011 Dec;31(23):4706-19
references: 21876000
references: Transgenic Res. 1999 Aug;8(4):265-77
references: 10621974
references: N Engl J Med. 2002 May 16;346(20):1513-21
references: 12015390
references: Mol Cell Biol. 2010 Jun;30(12):3071-85
references: 20404086
references: Lancet. 2011 Apr 9;377(9773):1276-87
references: 21450337
references: Development. 2001 Apr;128(8):1253-64
references: 11262227
references: Dev Cell. 2005 May;8(5):727-38
references: 15866163
references: J Biol Chem. 2005 Jun 3;280(22):21162-8
references: 15802266
references: N Engl J Med. 2003 Dec 25;349(26):2483-94
references: 14695408
references: Nature. 2003 May 15;423(6937):337-42
references: 12748652
references: Drug Discov Today. 2002 Feb 15;7(4):235-46
references: 11839521
references: Cancer Res. 2007 Jun 1;67(11):5371-9
references: 17545618
references: Curr Top Dev Biol. 2006;76:103-27
references: 17118265
references: Nat Med. 2012 Feb 19;18(3):405-12
references: 22344299
references: Blood. 2007 Mar 1;109(5):2106-11
references: 17068150
references: Cell. 2008 Nov 28;135(5):825-37
references: 19041748
references: Dev Cell. 2005 May;8(5):751-64
references: 15866165
references: Am J Hum Genet. 2002 Jan;70(1):11-9
references: 11741193
references: Nat Rev Genet. 2003 Aug;4(8):638-49
references: 12897775
references: J Immunol. 2012 Mar 15;188(6):2612-21
references: 22312126
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 Bone Miner Res. 2011 Apr;26(4):704-17
references: 20939024
references: Bone. 2006 Oct;39(4):754-66
references: 16730481
references: J Cell Biol. 2002 Apr 15;157(2):303-14
references: 11956231
references: Nat Rev Drug Discov. 2006 Dec;5(12):993-6
references: 17139284
references: Cell. 2012 Jun 8;149(6):1192-205
references: 22682243
references: Pharmacol Ther. 2012 Jun;134(3):338-44
references: 22401778
references: Blood. 2008 Jul 15;112(2):374-82
references: 18344425