Osteocyte Wnt/beta-catenin signaling is required for normal bone homeostasis.
Beta-Catenin-dependent canonical Wnt signaling plays an important role in bone metabolism by controlling differentiation of bone-forming osteoblasts and bone-resorbing osteoclasts. To investigate its function in osteocytes, the cell type constituting the majority of bone cells, we generated osteocyte-specific beta-catenin-deficient mice (Ctnnb1(loxP/loxP); Dmp1-Cre). Homozygous mutants were born at normal Mendelian frequency with no obvious morphological abnormalities or detectable differences in size or body weight, but bone mass accrual was strongly impaired due to early-onset, progressive bone loss in the appendicular and axial skeleton with mild growth retardation and premature lethality. Cancellous bone mass was almost completely absent, and cortical bone thickness was dramatically reduced. The low-bone-mass phenotype was associated with increased osteoclast number and activity, whereas osteoblast function and osteocyte density were normal. Cortical bone Wnt/beta-catenin target gene expression was reduced, and of the known regulators of osteoclast differentiation, osteoprotegerin (OPG) expression was significantly downregulated in osteocyte bone fractions of mutant mice. Moreover, the OPG levels expressed by osteocytes were higher than or comparable to the levels expressed by osteoblasts during skeletal growth and at maturity, suggesting that the reduction in osteocytic OPG and the concomitant increase in osteocytic RANKL/OPG ratio contribute to the increased number of osteoclasts and resorption in osteocyte-specific beta-catenin mutants. Together, these results reveal a crucial novel function for osteocyte beta-catenin signaling in controlling bone homeostasis.
Kramer
Ina
I
Musculoskeletal Disease Area, Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland.
Halleux
Christine
C
Keller
Hansjoerg
H
Pegurri
Marco
M
Gooi
Jonathan H
JH
Weber
Patricia Brander
PB
Feng
Jian Q
JQ
Bonewald
Lynda F
LF
Kneissel
Michaela
M
D000818:Animals; D000831:Animals, Newborn; D001862:Bone Resorption / Q000378:metabolism; D001842:Bone and Bones / Q000378:metabolism* / Q000473:pathology; D002452:Cell Count; D020964:Embryo Loss / Q000378:metabolism / Q000473:pathology; D005269:Femur / Q000002:abnormalities / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D006706:Homeostasis; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D010011:Osteocytes / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D013997:Time Factors; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
D051153:Wnt Proteins; D051176:beta Catenin
Am J Physiol Cell Physiol. 2003 Apr;284(4):C934-43
12477665
J Biol Chem. 2003 Nov 28;278(48):48137-45
12972427
J Bone Miner Res. 2006 Apr;21(4):605-15
16598381
J Biol Chem. 2008 Feb 29;283(9):5866-75
18089564
Mol Endocrinol. 2007 Nov;21(11):2605-14
17622581
Crit Rev Eukaryot Gene Expr. 2009;19(1):73-88
19191758
Bonekey Osteovision. 2006 Oct;3(10):7-15
17415409
Genes Dev. 1998 May 1;12(9):1260-8
9573043
J Bone Miner Res. 2001 Nov;16(11):2017-26
11697797
PLoS One. 2009;4(5):e5438
19412553
J Cell Sci. 2009 Oct 1;122(Pt 19):3566-78
19737815
J Bone Miner Res. 2002 Nov;17(11):2068-79
12412815
J Bone Miner Res. 2008 Jun;23(6):860-9
18269310
J Musculoskelet Neuronal Interact. 2005 Oct-Dec;5(4):321-4
16340122
Arch Biochem Biophys. 2008 May 15;473(2):112-6
18364235
J Bone Miner Res. 2002 May;17(5):907-14
12009022
Bone. 2007 Mar;40(3):627-37
17157571
Cell Tissue Res. 2006 Feb;323(2):263-71
16175387
Ann N Y Acad Sci. 2007 Nov;1116:423-31
17646262
Bone. 2009 Oct;45(4):682-92
19539797
J Bone Miner Res. 1999 Mar;14(3):396-405
10027904
Biochem Biophys Res Commun. 1998 Jun 29;247(3):610-5
9647741
Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3324-9
17360646
J Biomech. 1994 Mar;27(3):339-60
8051194
EMBO J. 2003 Dec 1;22(23):6267-76
14633986
Bone. 2000 Jan;26(1):71-8
10617159
Bone. 2008 Jan;42(1):172-9
17997378
Bone. 2001 Mar;28(3):237-50
11248653
Bone. 2008 Apr;42(4):606-15
18280232
Cell Signal. 2008 Jun;20(6):999-1009
18164181
J Biol Chem. 2007 Sep 14;282(37):27298-27305
17623658
Dev Cell. 2005 May;8(5):739-50
15866164
J Biol Chem. 2006 Aug 18;281(33):23698-711
16790443
Bone. 2001 Feb;28(2):145-9
11182371
Bone. 2009 Jun;44(6):1026-33
19345750
J Bone Miner Res. 1987 Dec;2(6):595-610
3455637
J Biol Chem. 2007 Jul 13;282(28):20715-27
17491024
J Bone Miner Res. 2008 May;23(5):610-20
18251703
Dev Cell. 2005 May;8(5):751-64
15866165
J Bone Miner Res. 2006 Apr;21(4):616-25
16598382
J Clin Invest. 2001 Oct;108(7):971-9
11581298
J Bone Miner Res. 2003 Jun;18(6):960-74
12817748
J Cell Biol. 2002 Apr 15;157(2):303-14
11956231
FASEB J. 2003 Sep;17(12):1751-3
12958198
Mol Cell Biol. 2002 Feb;22(4):1184-93
11809809
Proc Natl Acad Sci U S A. 2008 Dec 30;105(52):20764-9
19075223
J Biol Chem. 2002 Jun 14;277(24):21657-65
11940574
J Dent Res. 2007 Apr;86(4):320-5
17384025
J Bone Miner Res. 2000 May;15(5):863-71
10804015
Arch Biochem Biophys. 2008 May 15;473(2):139-46
18395508
J Bone Miner Res. 2007 Dec;22(12):1924-32
17708715
Biorheology. 2003;40(6):577-90
14610309
Bone. 2004 Mar;34(3):499-509
15003797
J Biol Chem. 2006 Oct 20;281(42):31720-8
16908522
Bone. 2005 Aug;37(2):148-58
15946907
Arch Biochem Biophys. 2008 May 15;473(2):132-8
18424258
J Exp Med. 2004 Mar 15;199(6):805-14
15024046
Development. 2001 Apr;128(8):1253-64
11262227
Cell Metab. 2007 Jun;5(6):464-75
17550781
J Bone Miner Res. 2006 Aug;21(8):1297-306
16869728
Dev Cell. 2005 May;8(5):727-38
15866163
Mol Endocrinol. 2004 May;18(5):1222-37
14976225
J Bone Miner Res. 2009 Apr;24(4):597-605
19049324
J Bone Miner Res. 2009 Oct;24(10):1651-61
19419300
Ann N Y Acad Sci. 2007 Nov;1116:281-90
17646259
J Biol Chem. 2005 Jun 3;280(22):21162-8
15802266
Exp Cell Res. 2004 Apr 1;294(2):458-68
15023534
Development. 2005 Jan;132(1):49-60
15576404
Mol Cell Biol. 2002 Feb;22(4):1172-83
11809808
J Bone Miner Res. 2006 Dec;21(12):1821-7
17002562
Biochem Biophys Res Commun. 2005 Oct 7;335(4):1095-101
16111656