The authors state that they have no conflicts of interest
Article first published online: 16 FEB 2009
Copyright © 2009 ASBMR
Journal of Bone and Mineral Research
Volume 24, Issue 7, pages 1150–1161, July 2009
How to Cite
Diamond, P., Labrinidis, A., Martin, S. K., Farrugia, A. N., Gronthos, S., To, L. B., Fujii, N., O'Loughlin, P. D., Evdokiou, A. and Zannettino, A. C. (2009), Targeted Disruption of the CXCL12/CXCR4 Axis Inhibits Osteolysis in a Murine Model of Myeloma-Associated Bone Loss. J Bone Miner Res, 24: 1150–1161. doi: 10.1359/jbmr.090210
Published online on February 16, 2009.
- Issue published online: 4 DEC 2009
- Article first published online: 16 FEB 2009
- Manuscript Accepted: 11 FEB 2009
- Manuscript Revised: 29 OCT 2008
- Manuscript Received: 21 AUG 2008
- multiple myeloma;
- stromal-derived factor-1α;
The plasma cell (PC) malignancy, multiple myeloma (MM), is unique among hematological malignancies in its capacity to cause osteoclast (OC)-mediated skeletal destruction. We have previously shown that elevated plasma levels of PC-derived CXCL12 are associated with presence of X-ray detectable osteolytic lesions in MM patients. To further investigate this relationship, plasma levels of CXCL12 and βCrossLaps, a marker of bone loss, were measured. A strong correlation between levels of CXCL12 and OC-mediated bone resorption was identified. To confirm the OC-activating potential of MM PC-derived CXCL12 in vivo, we established a model of MM-mediated focal osteolysis, wherein MM PC lines, such as RPMI-8226, were injected into the tibias of nude mice. Implanting RPMI-8226 gave rise to osteolytic lesions proximal to the tumor, resulting in a 5% decrease in bone volume (BV) compared with vehicle control. Importantly, bone loss was significantly inhibited with systemic administration of the CXCL12/CXCR4 antagonist T140. Furthermore, implanting CXCL12-overexpressing RPMI-8226 cells resulted in a 13% decrease in BV and was associated with increased OC recruitment proximal to the tumor, increased serum matrix metalloproteinase activity, and increased levels of collagen I degradation products. These findings confirm our hypothesis that MM PC-derived CXCL12 stimulates the recruitment and activity of OC, thereby contributing to the formation of MM osteolytic lesions.