title: Bone morphogenetic protein-4 inhibits proliferation and induces apoptosis of multiple myeloma cells.
abstract: Bone morphogenetic proteins (BMPs) can be isolated from organic bone matrix and are able to initiate de novo cartilage and bone formation. Here it is shown that BMP-4 inhibited DNA synthesis in a dose-dependent manner in 3 IL-6-dependent multiple myeloma (MM) cell lines (OH-2, IH-1, and ANBL-6). In contrast, no effect on DNA synthesis was observed in 3 IL-6-independent MM cell lines (JJN-3, U266, and RPMI 8226). BMP-4 induced cell cycle growth arrest in the G(0)/G(1) phase in OH-2 and ANBL-6 cells but not in IH-1 cells. BMP-4 induced apoptosis in OH-2 and IH-1 cells, but not significantly in ANBL-6 cells. Furthermore, BMP-4 induced apoptosis in freshly isolated MM cells from 4 of 13 patients. In the OH-2 and ANBL-6 cell lines and in a patient sample, immunoblotting showed that BMP-4 down-regulated IL-6-induced tyrosine phosphorylation of Stat3, suggesting a mechanism for the apparent antagonism between IL-6 and BMP-4. BMP-4 or analogues may be attractive therapeutic agents in MM because of possible beneficial effects on both tumor burden and bone disease.
authors.affiliation: Institute of Cancer Research and Molecular Biology, and the Section of Hematology, Institute of Environmental Medicine, Norwegian University of Science and Technology, Trondheim, Norway. oyvind.hjertner@medisin.ntnu.no
authors.forename: O
authors.initials: O
authors.lastname: Hjertner
authors.forename: H
authors.initials: H
authors.lastname: Hjorth-Hansen
authors.forename: M
authors.initials: M
authors.lastname: Börset
authors.forename: C
authors.initials: C
authors.lastname: Seidel
authors.forename: A
authors.initials: A
authors.lastname: Waage
authors.forename: A
authors.initials: A
authors.lastname: Sundan
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects*; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology* / Q000502:physiology*; D018929:Cell Culture Techniques; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D006801:Humans; D008875:Middle Aged; D009101:Multiple Myeloma / Q000473:pathology* / Q000503:physiopathology; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D019947:Receptors, Interleukin-6 / Q000502:physiology; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000093242:Interleukin-6 Inhibitors
chemical_list: D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; D000093242:Interleukin-6 Inhibitors; C525809:BMP4 protein, human; C494086:STAT3 protein, human