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https://hdl.handle.net/2440/52537
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Type: | Journal article |
Title: | Targeted disruption of the CXCL12/CXCR4 axis inhibits osteolysis in a murine model of myeloma-associated bone loss |
Author: | Diamond, P. Labrinidis, A. Martin, S. Farrugia, A. Gronthos, S. To, L. Fujii, N. O'Loughlin, P. Evdokiou, A. Zannettino, A. |
Citation: | Journal of Bone and Mineral Research, 2009; 24(7):1150-1161 |
Publisher: | Amer Soc Bone & Mineral Res |
Issue Date: | 2009 |
ISSN: | 0884-0431 1523-4681 |
Statement of Responsibility: | Peter Diamond, Agatha Labrinidis, Sally K Martin, Amanda N Farrugia, Stan Gronthos, L Bik To, Nobutaka Fujii, Peter D O'Loughlin, Andreas Evdokiou and Andrew CW Zannettino |
Abstract: | 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. |
Keywords: | multiple myeloma stromal-derived factor-1α CXCL12 osteolysis |
DOI: | 10.1359/JBMR.090210 |
Published version: | http://dx.doi.org/10.1359/jbmr.090210 |
Appears in Collections: | Aurora harvest Medicine publications |
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