Targeting MEK1/2 blocks osteoclast differentiation, function and cytokine secretion in multiple myeloma

Iris Breitkreutz, Marc S Raab, Sonia Vallet, Teru Hideshima, Noopur Raje, Dharminder Chauhan, Nikhil C Munshi, Paul G Richardson, Kenneth C Anderson

Research output: Journal article (peer-reviewed)Journal article

38 Citations (Scopus)

Abstract

Osteolytic bone disease in multiple myeloma (MM) is associated with upregulation of osteoclast (OCL) activity and constitutive inhibition of osteoblast function. The extracellular signal-regulated kinase 1/2 (ERK1/2) pathway mediates OCL differentiation and maturation. We hypothesized that inhibition of ERK1/2 could prevent OCL differentiation and downregulate OCL function. It was found that AZD6244, a mitogen-activated or extracellular signal-regulated protein kinase (MEK) inhibitor, blocked OCL differentiation and formation in a dose-dependent manner, evidenced by decreased alphaVbeta3-integrin expression and tartrate-resistant acid phosphatase positive (TRAP+) cells. Functional dentine disc cultures showed inhibition of OCL-induced bone resorption by AZD6244. Major MM growth and survival factors produced by OCLs including B-cell activation factor (BAFF) and a proliferation-inducing ligand (APRIL), as well as macrophage inflammatory protein (MIP-1alpha), which mediates OCL differentiation and MM, were also significantly inhibited by AZD6244. In addition to ERK inhibition, NFATc1 (nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1) and c-fos were both downregulated, suggesting that AZD6244 targets a later stage of OCL differentiation. These results indicate that AZD6244 inhibits OCL differentiation, formation and bone resorption, thereby abrogating paracrine MM cell survival in the bone marrow microenvironment. The present study therefore provides a preclinical rationale for the evaluation of AZD6244 as a potential new therapy for patients with MM.

Original languageEnglish
Pages (from-to)55-63
Number of pages9
JournalBritish Journal of Haematology
Volume139
Issue number1
Publication statusPublished - Oct 2007
Externally publishedYes

Keywords

  • Acid Phosphatase/metabolism
  • Benzimidazoles/therapeutic use
  • Biomarkers/analysis
  • Blotting, Western/methods
  • Bone Resorption/drug therapy
  • Cell Differentiation/drug effects
  • Chemokine CCL3
  • Chemokine CCL4
  • Cytokines/metabolism
  • Depression, Chemical
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors/therapeutic use
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Gene Expression/drug effects
  • Humans
  • Integrin alphaVbeta3/metabolism
  • Isoenzymes/metabolism
  • Macrophage Colony-Stimulating Factor/metabolism
  • Macrophage Inflammatory Proteins/metabolism
  • Mitogen-Activated Protein Kinases/antagonists & inhibitors
  • Multiple Myeloma/drug therapy
  • Osteoclasts/drug effects
  • RANK Ligand/metabolism
  • Tartrate-Resistant Acid Phosphatase
  • Transcription Factors/metabolism
  • Tumor Cells, Cultured

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