title: Thalidomide derivative CC-4047 inhibits osteoclast formation by down-regulation of PU.1.
abstract: CC-4047, an immunomodulatory analog of thalidomide, inhibits multiple myeloma with unknown effects on the human osteoclast lineage. Early osteoclast progenitors are of hematopoietic origin and differentiate into mature bone resorbing multinucleated osteoclasts. We investigated the effects of CC-4047 and thalidomide on human osteoclastogenesis, using in vitro receptor activator of NFkappa-B ligand/macrophage colony-stimulating factor-stimulated bone marrow cell cultures. Treating bone marrow cultures with CC-4047 for 3 weeks decreased osteoclast formation accompanied by complete inhibition of bone resorption. The inhibitory effect was similar when cultures were treated for 3 weeks or for only the first week (90% inhibition), indicating that CC-4047 inhibits early stages of osteoclast formation. Inhibition of osteoclastogenesis by CC-4047 was mediated by a shift of lineage commitment to granulocyte colony-forming units at the expense of granulocyte-macrophage colony-forming units. Further studies revealed that this shift in lineage commitment was mediated through down-regulation of PU.1. Treatment with thalidomide resulted in significantly less potent inhibition of osteoclast formation and bone resorption. These results provide evidence that CC-4047 blocks osteoclast differentiation during early phases of osteoclastogenesis. Therefore, CC-4047 might be a valuable drug for targeting both tumors and osteoclastic activity in patients with multiple myeloma and other diseases associated with osteolytic lesions.
authors.affiliation: University of Pittsburgh Cancer Institute, Division of Hematology/Oncology, Pittsburgh, PA 15232, USA.
authors.forename: Gülsüm
authors.initials: G
authors.lastname: Anderson
authors.forename: Margarete
authors.initials: M
authors.lastname: Gries
authors.forename: Noriyoshi
authors.initials: N
authors.lastname: Kurihara
authors.forename: Tadashi
authors.initials: T
authors.lastname: Honjo
authors.forename: Judy
authors.initials: J
authors.lastname: Anderson
authors.forename: Vera
authors.initials: V
authors.lastname: Donnenberg
authors.forename: Albert
authors.initials: A
authors.lastname: Donnenberg
authors.forename: Irene
authors.initials: I
authors.lastname: Ghobrial
authors.forename: Markus Y
authors.initials: MY
authors.lastname: Mapara
authors.forename: David
authors.initials: D
authors.lastname: Stirling
authors.forename: David
authors.initials: D
authors.lastname: Roodman
authors.forename: Suzanne
authors.initials: S
authors.lastname: Lentzsch
mesh_terms: D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D001862:Bone Resorption / Q000188:drug therapy / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D009101:Multiple Myeloma / Q000188:drug therapy; D023461:Myeloid Progenitor Cells / Q000166:cytology / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D013792:Thalidomide / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D015534:Trans-Activators / Q000096:biosynthesis*; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D020533:Angiogenesis Inhibitors; D016173:Macrophage Colony-Stimulating Factor; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D013792:Thalidomide; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C467566:pomalidomide