Regulation of osteoblastogenesis and bone mass by Wnt10b.
Wnts comprise a family of secreted signaling proteins that regulate diverse developmental processes. Activation of Wnt signaling by Wnt10b inhibits differentiation of preadipocytes and blocks adipose tissue development; however, the effect of Wnt10b on other mesenchymal lineages has not been defined. To explore the physiological role of Wnt signaling in bone development, we analyzed FABP4-Wnt10b mice, which express the Wnt10b transgene in marrow. Femurs from FABP4-Wnt10b mice have almost four times as much bone in the distal metaphyses and are mechanically stronger. These mice maintain elevated bone mass at least through 23 months of age. In addition, FABP4-Wnt10b mice are protected from the bone loss characteristic of estrogen deficiency. We used pharmacological and genetic approaches to demonstrate that canonical Wnt signaling stimulates osteoblastogenesis and inhibits adipogenesis of bipotential mesenchymal precursors. Wnt10b shifts cell fate toward the osteoblast lineage by induction of the osteoblastogenic transcription factors Runx2, Dlx5, and osterix and suppression of the adipogenic transcription factors C/EBPalpha and PPARgamma. One mechanism whereby Wnt10b promotes osteoblastogenesis is suppression of PPARgamma expression. Finally, Wnt10b-/- mice have decreased trabecular bone and serum osteocalcin, confirming that Wnt10b is an endogenous regulator of bone formation.
Bennett
Christina N
CN
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109-0622, USA.
Longo
Kenneth A
KA
Wright
Wendy S
WS
Suva
Larry J
LJ
Lane
Timothy F
TF
Hankenson
Kurt D
KD
MacDougald
Ormond A
OA
D000375:Aging / Q000502:physiology; D000818:Animals; D015519:Bone Density / Q000502:physiology*; D002455:Cell Division / Q000502:physiology*; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology*; D010052:Ovariectomy; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D051153:Wnt Proteins
D011518:Proto-Oncogene Proteins; D051153:Wnt Proteins; C102068:Wnt10b protein, mouse
Osteoarthritis Cartilage. 2003 Jan;11(1):36-43
12505485
Cell. 2002 Nov 1;111(3):305-17
12419242
Cancer Res. 2003 Apr 15;63(8):1906-13
12702582
J Bone Miner Res. 2003 Jun;18(6):960-74
12817748
J Biol Chem. 2003 Jun 27;278(26):23270-7
12704187
Mol Cell Biol. 2003 Aug;23(15):5366-75
12861022
J Bone Miner Res. 2003 Oct;18(10):1842-53
14584895
J Biol Chem. 2003 Nov 14;278(46):45969-77
12925529
Biochem J. 2003 Dec 15;376(Pt 3):607-13
12954078
Endocrinology. 2004 Jan;145(1):401-6
14500573
Dev Cell. 2004 Mar;6(3):423-35
15030764
J Clin Invest. 2004 Mar;113(6):846-55
15067317
Mol Endocrinol. 2004 May;18(5):1222-37
14976225
Curr Opin Pharmacol. 2004 Jun;4(3):290-4
15140422
Differentiation. 2004 Jun;72(5):209-23
15270777
J Biol Chem. 2004 Aug 6;279(32):34015-22
15175325
J Biol Chem. 2004 Aug 20;279(34):35503-9
15190075
EMBO Rep. 2004 Oct;5(10):1007-12
15359271
Johns Hopkins Med J. 1974 Apr;128(4):194-207
4132675
J Biol Chem. 1997 Oct 10;272(41):25913-9
9325324
J Bone Miner Res. 1997 Nov;12(11):1772-9
9383681
J Cell Biochem. 1999 Sep 1;74(3):357-71
10412038
Mol Cell Biol. 2005 Feb;25(4):1272-82
15684380
Cell. 2000 Jan 21;100(2):197-207
10660043
J Bone Miner Res. 2000 May;15(5):851-62
10804014
Genes Dev. 2000 Jun 1;14(11):1293-307
10837022
Bone. 2000 Aug;27(2):177-84
10913909
Immunity. 2000 Jul;13(1):15-24
10933391
Science. 2000 Aug 11;289(5481):950-3
10937998
Annu Rev Nutr. 2000;20:535-59
10940345
J Biol Chem. 2001 May 11;276(19):16348-55
11340085
Cell. 2001 Nov 16;107(4):513-23
11719191
Genes Dev. 2002 Jan 1;16(1):22-6
11782441
J Bone Miner Res. 2002 Mar;17(3):415-25
11874233
J Cell Biol. 2002 Apr 15;157(2):303-14
11956231
N Engl J Med. 2002 May 16;346(20):1513-21
12015390
Endocrinology. 2002 Jun;143(6):2376-84
12021203
J Bone Miner Res. 2002 Jun;17(6):1008-14
12054155
J Biol Chem. 2002 Aug 23;277(34):30998-1004
12055200
J Biol Chem. 2002 Oct 11;277(41):38239-44
12154096
Biochem Biophys Res Commun. 2003 Jan 31;301(1):84-91
12535644