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Targeting MEK1/2 blocks osteoclast differentiation, function and cytokine secretion in multiple myeloma
Author(s) -
Breitkreutz Iris,
Raab Marc S.,
Vallet Sonia,
Hideshima Teru,
Raje Noopur,
Chauhan Dharminder,
Munshi Nikhil C.,
Richardson Paul G.,
Anderson Kenneth C.
Publication year - 2007
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2007.06747.x
Subject(s) - osteoclast , mapk/erk pathway , microbiology and biotechnology , bone resorption , cancer research , chemistry , osteoprotegerin , cellular differentiation , downregulation and upregulation , kinase , medicine , endocrinology , biology , biochemistry , receptor , activator (genetics) , gene
Summary 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 α V β 3‐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‐1 α ), 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.