TY - JOUR
T1 - MIP-1α utilizes both CCR1 and CCR5 to induce osteoclast formation and increase adhesion of myeloma cells to marrow stromal cells
AU - Oba, Yasuo
AU - Lee, Jun Won
AU - Ehrlich, Lori A.
AU - Chung, Ho Yeon
AU - Jelinek, Diane F.
AU - Callander, Natalie S.
AU - Horuk, Richard
AU - Choi, Sun Jin
AU - Roodman, G. David
N1 - Funding Information:
This study was supported by research funds from a Veterans Administration Merit Review Grant, the Multiple Myeloma Research Foundation, and the International Myeloma Foundation. The authors wish to acknowledge the General Clinic Research Center at the University of Pittsburgh for their support of these studies. We also thank Donna Gaspich and Theresa Casciato for preparation of the manuscript.
PY - 2005/3
Y1 - 2005/3
N2 - Objectives. Macrophage inflammatory protein-1α (MIP-1α), an osteoclast (OCL) stimulatory factor produced by primary multiple myeloma (MM) cells, increases bone destruction and tumor burden in murine models of MM. Several chemokine receptors (CCR1, CCR5, and CCR9) mediate the effects of MIP-1α. In this study, we determined which of these mediates the effects of MIP-1α on human OCL formation and myeloma cells. Methods. We employed RT-PCR analysis, neutralizing antibodies to CCR1 and CCR5 as well as a CCR1-specific antagonist and OCL formation assays to identify the MIP-1α receptors involved in MIP-1α's effects on myeloma cells and OCL formation. Results. RT-PCR analysis demonstrated that both CCR1 and CCR5 were expressed by highly purified human OCL precursors, myeloma cell lines, and purified marrow plasma cells from MM patients. Neutralizing antibodies to CCR1 or CCR5 inhibited MIP-1α-induced OCL formation. Furthermore, monocyte chemotactic protein-3 (MCP-3), which binds CCR1 but not CCR5 and the CCR1-specific antagonist, BX471, markedly inhibited OCL formation stimulated with MIP-1α. Anti-CCR1, anti-CCR5, or BX471 also inhibited the upregulation of β1 integrin mRNA in myeloma cells induced by MIP-1α, as well as the adherence of myeloma cells to stromal cells and IL-6 production by stromal cells in response to myeloma cells. Conclusion. These data demonstrate that MIP-1α utilizes either CCR1 or CCR5 for its effects on OCL formation and myeloma cells, and that blocking either CCR1 or CCR5 inhibits OCL formation and myeloma cell adhesion to stromal cells.
AB - Objectives. Macrophage inflammatory protein-1α (MIP-1α), an osteoclast (OCL) stimulatory factor produced by primary multiple myeloma (MM) cells, increases bone destruction and tumor burden in murine models of MM. Several chemokine receptors (CCR1, CCR5, and CCR9) mediate the effects of MIP-1α. In this study, we determined which of these mediates the effects of MIP-1α on human OCL formation and myeloma cells. Methods. We employed RT-PCR analysis, neutralizing antibodies to CCR1 and CCR5 as well as a CCR1-specific antagonist and OCL formation assays to identify the MIP-1α receptors involved in MIP-1α's effects on myeloma cells and OCL formation. Results. RT-PCR analysis demonstrated that both CCR1 and CCR5 were expressed by highly purified human OCL precursors, myeloma cell lines, and purified marrow plasma cells from MM patients. Neutralizing antibodies to CCR1 or CCR5 inhibited MIP-1α-induced OCL formation. Furthermore, monocyte chemotactic protein-3 (MCP-3), which binds CCR1 but not CCR5 and the CCR1-specific antagonist, BX471, markedly inhibited OCL formation stimulated with MIP-1α. Anti-CCR1, anti-CCR5, or BX471 also inhibited the upregulation of β1 integrin mRNA in myeloma cells induced by MIP-1α, as well as the adherence of myeloma cells to stromal cells and IL-6 production by stromal cells in response to myeloma cells. Conclusion. These data demonstrate that MIP-1α utilizes either CCR1 or CCR5 for its effects on OCL formation and myeloma cells, and that blocking either CCR1 or CCR5 inhibits OCL formation and myeloma cell adhesion to stromal cells.
UR - http://www.scopus.com/inward/record.url?scp=13844317079&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=13844317079&partnerID=8YFLogxK
U2 - 10.1016/j.exphem.2004.11.015
DO - 10.1016/j.exphem.2004.11.015
M3 - Article
C2 - 15730850
AN - SCOPUS:13844317079
SN - 0301-472X
VL - 33
SP - 272
EP - 278
JO - Experimental Hematology
JF - Experimental Hematology
IS - 3
ER -