Vicious cycle between myeloma cell binding to bone marrow stromal cells via VLA-4-VCAM-1 adhesion and macrophage inflammatory protein-1alpha and MIP-1beta production

J Bone Miner Metab. 2009;27(1):16-23. doi: 10.1007/s00774-008-0012-z. Epub 2008 Dec 5.


Multiple myeloma (MM) cell adhesion to stromal cells via very late antigen (VLA)-4 and vascular cell adhesion molecule (VCAM)-1 interaction causes enhanced secretion of osteoclastogenic activity by MM cells. We have reported that MM cell-derived macrophage inflammatory protein (MIP)-1alpha and MIP-1beta are responsible for most of the osteoclastogenic activity in MM. Thus, adhesion-mediated osteoclastogenesis may be caused by enhanced production of MIP-1 via VLA-4-VCAM-1 interaction. The present study was undertaken to clarify whether MM cell-derived MIP-1 plays a role in VLA-4-VCAM-1 adhesion-mediated osteoclastogenesis. Adhesion of MM cells to VCAM-1 upregulated MIP-1alpha and MIP-1beta production from MM cells and enhanced production of osteoclastogenic activity by MM cells. Blockade of MIP-1alpha and MIP-1beta actions not only abrogated elaboration of osteoclastogenic activity, but also suppressed spontaneous MM cell adhesion to VCAM-1. These results demonstrate that MM cell adhesion to VCAM-1 upregulates MIP-1 production by MM cells to cause enhancement of osteoclastogenesis. In addition, the results suggest that the increased production of MIP-1 further enhances MM cell binding to stromal cells via stimulation of VLA-4-VCAM-1 adhesion, forming a "vicious cycle" between MM cell adhesion to stromal cells and MIP-1 production via VLA-4-VCAM-1 interaction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Cells / metabolism*
  • Cell Adhesion / physiology
  • Cell Line
  • Chemokine CCL3 / metabolism*
  • Chemokine CCL4 / metabolism*
  • Humans
  • Integrin alpha4beta1 / metabolism*
  • Mice
  • Multiple Myeloma / pathology*
  • Multiple Myeloma / physiopathology
  • Osteoclasts / cytology
  • Osteoclasts / physiology
  • Stromal Cells / metabolism*
  • Vascular Cell Adhesion Molecule-1 / metabolism*


  • Chemokine CCL3
  • Chemokine CCL4
  • Integrin alpha4beta1
  • Vascular Cell Adhesion Molecule-1