MIP-1α utilizes both CCR1 and CCR5 to induce osteoclast formation and increase adhesion of myeloma cells to marrow stromal cells

Yasuo Oba, Jun Won Lee, Lori A. Ehrlich, Ho Yeon Chung, Diane F Jelinek, Natalie S. Callander, Richard Horuk, Sun Jin Choi, G. David Roodman

Research output: Contribution to journalArticle

112 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)272-278
Number of pages7
JournalExperimental Hematology
Volume33
Issue number3
DOIs
StatePublished - Mar 2005

Fingerprint

Macrophage Inflammatory Proteins
Osteoclasts
Stromal Cells
Cell Adhesion
Bone Marrow
Multiple Myeloma
Neutralizing Antibodies
Chemokine CCL7
Polymerase Chain Reaction
Chemokine Receptors
Tumor Burden
Integrins
Interleukin-6
Up-Regulation
Bone and Bones
Cell Line
Messenger RNA

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Genetics
  • Hematology
  • Oncology
  • Transplantation

Cite this

MIP-1α utilizes both CCR1 and CCR5 to induce osteoclast formation and increase adhesion of myeloma cells to marrow stromal cells. / Oba, Yasuo; Lee, Jun Won; Ehrlich, Lori A.; Chung, Ho Yeon; Jelinek, Diane F; Callander, Natalie S.; Horuk, Richard; Choi, Sun Jin; Roodman, G. David.

In: Experimental Hematology, Vol. 33, No. 3, 03.2005, p. 272-278.

Research output: Contribution to journalArticle

Oba, Yasuo ; Lee, Jun Won ; Ehrlich, Lori A. ; Chung, Ho Yeon ; Jelinek, Diane F ; Callander, Natalie S. ; Horuk, Richard ; Choi, Sun Jin ; Roodman, G. David. / MIP-1α utilizes both CCR1 and CCR5 to induce osteoclast formation and increase adhesion of myeloma cells to marrow stromal cells. In: Experimental Hematology. 2005 ; Vol. 33, No. 3. pp. 272-278.
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abstract = "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.",
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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

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.

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