Disruption of CXCR4 enhances osteoclastogenesis and tumor growth in bone.
CXCR4 regulates hematopoietic and tumor cell homing to bone, but its role during osteoclast (OC) development is unknown. We investigated the role of CXCR4 in osteoclastogenesis and in a model of bone metastasis. Compared with controls, mice reconstituted with CXCR4 null hematopoietic cells exhibited elevated markers of bone resorption, increased OC perimeter along bone, and increased bone loss. CXCR4-/- OCs demonstrated accelerated differentiation and enhanced bone resorption in vitro. Furthermore, tumor growth specifically in bone was significantly increased in mice reconstituted with CXCR4-/- hematopoietic cells. Finally, enhancement of bone tumor growth in the absence of CXCR4 was abrogated with the OC inhibitor, zoledronic acid. These data demonstrate that disruption of CXCR4 enhances osteoclastogenesis and suggest that inhibition of CXCR4 may enhance established skeletal tumor burden by increasing OC activity.
Hirbe
Angela C
AC
Department of Medicine, Division of Oncology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Rubin
Jessica
J
Uluçkan
Ozge
O
Morgan
Elizabeth A
EA
Eagleton
Mark C
MC
Prior
Julie L
JL
Piwnica-Worms
David
D
Weilbaecher
Katherine N
KN
D000818:Animals; D050071:Bone Density Conservation Agents / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000235:genetics / Q000473:pathology*; D001862:Bone Resorption; D002455:Cell Division; D004164:Diphosphonates / Q000627:therapeutic use; D007093:Imidazoles / Q000627:therapeutic use; D007700:Kinetics; D008264:Macrophages / Q000473:pathology / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D010010:Osteoclasts / Q000473:pathology; D019718:Receptors, CXCR4 / Q000172:deficiency / Q000235:genetics*; D000077211:Zoledronic Acid
D050071:Bone Density Conservation Agents; C514936:CXCR4 protein, mouse; D004164:Diphosphonates; D007093:Imidazoles; D019718:Receptors, CXCR4; D000077211:Zoledronic Acid
Blood. 2005 Nov 1;106(9):3020-7
16037394
J Exp Med. 1997 Jan 6;185(1):111-20
8996247
J Bone Miner Res. 2005 Dec;20(12):2116-23
16294265
Immunol Rev. 2005 Dec;208:88-105
16313343
Nature. 2006 Mar 30;440(7084):692-6
16572175
Ann N Y Acad Sci. 2006 Apr;1068:165-72
16831915
J Exp Med. 2006 Sep 4;203(9):2201-13
16940167
Clin Cancer Res. 2006 Oct 15;12(20 Pt 2):6309s-6314s
17062720
Biochem Biophys Res Commun. 2006 Dec 8;351(1):99-105
17052691
Nat Med. 2007 Jan;13(1):62-9
17159986
Nature. 2007 Feb 22;445(7130):E19; discussion E19-20
17314931
Blood. 2007 Apr 15;109(8):3424-31
17192391
Blood. 2007 Apr 1;109(7):2708-17
17119115
Cell Mol Immunol. 2004 Apr;1(2):95-104
16212895
J Clin Invest. 1999 Nov;104(9):1199-211
10545519
Cancer. 2000 Jun 15;88(12 Suppl):2892-8
10898330
J Biol Chem. 2001 Oct 19;276(42):39295-302
11514537
Cancer Res. 2002 Mar 15;62(6):1832-7
11912162
J Biol Chem. 2002 Apr 19;277(16):14221-6
11827970
J Clin Oncol. 2002 Aug 1;20(15):3219-24
12149294
Nat Rev Cancer. 2002 Aug;2(8):584-93
12154351
Leukemia. 2002 Oct;16(10):1992-2003
12357350
J Immunol. 2002 Nov 15;169(10):5546-54
12421931
Traffic. 2003 Feb;4(2):113-25
12559037
Anticancer Res. 2003 Mar-Apr;23(2A):1027-9
12820342
Cancer Cell. 2003 Jun;3(6):537-49
12842083
Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13513-8
14595012
Histochem Cell Biol. 2003 Nov;120(5):391-400
14600836
Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14205-10
14612570
Nature. 1996 Aug 15;382(6592):635-8
8757135
Clin Exp Metastasis. 1992 Nov;10(6):411-8
1451351
Nature. 1998 Jun 11;393(6685):591-4
9634237
Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9448-53
9689100
Cancer Res. 2004 Dec 1;64(23):8604-12
15574767
J Bone Miner Res. 2005 Feb;20(2):318-29
15647826
J Biol Chem. 2005 Mar 25;280(12):11395-403
15647289
Bone. 2005 May;36(5):840-53
15794931
IUBMB Life. 2005 Jun;57(6):389-95
16012047
J Mammary Gland Biol Neoplasia. 2005 Apr;10(2):169-80
16025223
Blood. 2005 Sep 1;106(5):1867-74
15890685
J Biol Chem. 2005 Oct 21;280(42):35760-6
16107333
Stem Cells. 2004;22(1):109-18
14688397
N Engl J Med. 2004 Apr 15;350(16):1655-64
15084698
Trends Immunol. 2004 Jun;25(6):306-14
15145320
J Mol Histol. 2004 Mar;35(3):233-45
15339043
J Bone Miner Res. 1987 Dec;2(6):595-610
3455637
Arthritis Res Ther. 2005;7(6):R1208-20
16277673