title: Osteoclast-gene expression profiling reveals osteoclast-derived CCR2 chemokines promoting myeloma cell migration.
abstract: Multiple myeloma is characterized by the clonal expansion of malignant plasma cells (multiple myeloma cells [MMCs]), in the bone marrow. Osteolytic bone lesions are detected in 80% of patients because of increased osteoclastic bone resorption and reduced osteoblastic bone formation. MMCs are found closely associated with sites of increased bone resorption. Osteoclasts strongly support MMC survival in vitro. To further elucidate the mechanisms involved in osteoclast/MMC interaction, we have identified 552 genes overexpressed in osteoclasts compared with other bone marrow cell subpopulations. Osteoclasts express specifically genes coding for 4 CCR2-targeting chemokines and genes coding for MMC growth factors. An anti-CCR2 monoclonal antibody blocked osteoclast chemoattractant activity for MMC, and CCR2 chemokines are also MMC growth factors, promoting mitogen-activated protein kinase activation in MMC. An anti-insulin growth factor-1 receptor monoclonal antibody completely blocked the osteoclast-induced survival of MMC suppressing both osteoclast and MMC survival. Specific a proliferation-inducing ligand or IL-6 inhibitors partially blocked osteoclast-induced MMC survival. These data may explain why newly diagnosed patients whose MMC express high levels of CCR2 present numerous bone lesions. This study displays additional mechanisms involved in osteoclast/MMC interaction and suggests using CCR2 and/or insulin growth factor-1 targeting strategies to block this interaction and prevent drug resistance.
authors.affiliation: Centre Hospitalier Universitaire Montpellier, Institute of Research in Biotherapy, Av. Augustin Fliche, Montpellier cedex, France.
authors.forename: Jerome
authors.initials: J
authors.lastname: Moreaux
authors.forename: Dirk
authors.initials: D
authors.lastname: Hose
authors.forename: Alboukadel
authors.initials: A
authors.lastname: Kassambara
authors.forename: Thierry
authors.initials: T
authors.lastname: Reme
authors.forename: Philippe
authors.initials: P
authors.lastname: Moine
authors.forename: Guilhem
authors.initials: G
authors.lastname: Requirand
authors.forename: Hartmut
authors.initials: H
authors.lastname: Goldschmidt
authors.forename: Bernard
authors.initials: B
authors.lastname: Klein
mesh_terms: D000368:Aged; D001862:Bone Resorption / Q000378:metabolism / Q000473:pathology; D002450:Cell Communication / Q000235:genetics / Q000502:physiology; D002465:Cell Movement / Q000235:genetics*; D002478:Cells, Cultured; D002630:Chemotactic Factors / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D020869:Gene Expression Profiling; D006801:Humans; D046228:Microarray Analysis; D008875:Middle Aged; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009362:Neoplasm Metastasis; D010010:Osteoclasts / Q000378:metabolism* / Q000502:physiology; D054390:Receptors, CCR2 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*
chemical_list: C515334:CCR2 protein, human; D002630:Chemotactic Factors; D054390:Receptors, CCR2