title: Heterodimeric bone morphogenetic proteins show enhanced activity in vitro and in vivo.
abstract: The bone morphogenetic proteins (BMPs), a subgroup of the TGF-beta gene super-family, are dimeric molecules involved in the growth, differentiation and repair of a wide variety of tissues. Based on the observation that several of the BMPs co-purify when isolated from bovine bone and that a pattern of co-localization exists during mouse embryogenesis, we co-expressed various combinations of BMPs in Chinese hamster ovary cells to test for possible heterodimer formation and activity. Transient co-expression of BMP-2 with either BMP-5, BMP-6 or BMP-7, or BMP-4 transiently co-expressed with BMP-7, resulted in more BMP activity than expression of any single BMP. Stable cell lines were then made in order to purify and characterize co-expressed BMPs in more detail. Co-expression of BMP-2 with BMP-7 yielded heterodimeric BMP-2/7 with a specific activity about 20-fold higher than BMP homodimers in an in vitro alkaline phosphatase induction assay. These heterodimers were also 5- to 10-fold more potent than BMP-2 in inducing cartilage and bone in an in vivo assay. Similar results were obtained with BMP-2/6 heterodimer. These experiments demonstrate the increased potency of several BMP heterodimers relative to BMP homodimers and support the hypothesis that such heterodimeric forms are likely to have natural biological functions.
authors.affiliation: Genetics Institute, Cambridge, MA 02140, USA.
authors.forename: D I
authors.initials: DI
authors.lastname: Israel
authors.forename: J
authors.initials: J
authors.lastname: Nove
authors.forename: K M
authors.initials: KM
authors.lastname: Kerns
authors.forename: R J
authors.initials: RJ
authors.lastname: Kaufman
authors.forename: V
authors.initials: V
authors.lastname: Rosen
authors.forename: K A
authors.initials: KA
authors.lastname: Cox
authors.forename: J M
authors.initials: JM
authors.lastname: Wozney
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D055396:Bone Morphogenetic Protein 2; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000494:pharmacology*; D001842:Bone and Bones / Q000187:drug effects / Q000201:enzymology; D016466:CHO Cells; D002417:Cattle; D002460:Cell Line; D006224:Cricetinae; D051379:Mice; D011994:Recombinant Proteins / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D000469:Alkaline Phosphatase