title: Bone morphogenetic protein-5, -6 and -7 inhibit growth and induce apoptosis in human myeloma cells.
abstract: Previously, bone morphogenetic protein (BMP)-2 and -4 have been shown to inhibit proliferation and induce apoptosis in human myeloma cells. BMP-2 and -4 belong to a subgroup of BMPs using the BMP receptors Alk-3 or -6. In this study, we examined the effects on human myeloma cells of BMP-6 and -7, members of a different BMP subgroup, which mainly utilize Alk-2 as their receptor. All cell lines examined expressed mRNA for the BMP-6 and -7 receptor Alk-2. We did not detect transcripts for the BMP-2 and -4 receptors Alk-3 or Alk-6 in INA-6 and RPMI-8226 cells by RT-PCR. Accordingly, the intracellular signalling molecules Smad-1, -5 and -8 were not phosphorylated by BMP-4 in INA-6 and RPMI-8226 cells. The expression patterns of various BMP receptors in the myeloma cell lines explained the differences in responses to the various BMPs. Alk-2-expressing cell lines responded with growth inhibition and apoptosis to BMP-6 and -7, whereas cell lines lacking both Alk-3 and -6 were resistant to BMP-4. Soluble Alk-3 and -6 were able to neutralize the BMP-4 effects in BMP-4-responsive cell lines. All BMPs reduced viability in more than 70% of purified primary myeloma cell samples. BMPs have intriguing antitumor effects in vitro. Importantly, myeloma cells not responsive to BMP-2 and -4 may still be sensitive to BMP-6 or -7. It is possible that therapeutic use of BMP or BMP analogues could have an impact on both myeloma bone disease and myeloma cell growth.
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim N-7489, Norway. torstein.ro@medisin.ntnu.no
authors.forename: Torstein Baade
authors.initials: TB
authors.lastname: Ro
authors.forename: Randi Utne
authors.initials: RU
authors.lastname: Holt
authors.forename: Anne-Tove
authors.initials: AT
authors.lastname: Brenne
authors.forename: Henrik
authors.initials: H
authors.lastname: Hjorth-Hansen
authors.forename: Anders
authors.initials: A
authors.lastname: Waage
authors.forename: Oyvind
authors.initials: O
authors.lastname: Hjertner
authors.forename: Anders
authors.initials: A
authors.lastname: Sundan
authors.forename: Magne
authors.initials: M
authors.lastname: Borset
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D055396:Bone Morphogenetic Protein 2; D055417:Bone Morphogenetic Protein 5; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D017931:DNA Primers; D006801:Humans; D009101:Multiple Myeloma / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: C525718:BMP2 protein, human; C525814:BMP5 protein, human; C525819:BMP7 protein, human; D055396:Bone Morphogenetic Protein 2; D055417:Bone Morphogenetic Protein 5; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D017931:DNA Primers; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta