Heterodimeric bone morphogenetic proteins show enhanced activity in vitro and in vivo

Growth Factors. 1996;13(3-4):291-300. doi: 10.3109/08977199609003229.


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.

MeSH terms

  • Alkaline Phosphatase / metabolism
  • Animals
  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Protein 7
  • Bone Morphogenetic Proteins / genetics
  • Bone Morphogenetic Proteins / pharmacology*
  • Bone and Bones / drug effects
  • Bone and Bones / enzymology
  • CHO Cells
  • Cattle
  • Cell Line
  • Cricetinae
  • Mice
  • Recombinant Proteins / pharmacology
  • Transforming Growth Factor beta / pharmacology


  • Bmp2 protein, mouse
  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Protein 7
  • Bone Morphogenetic Proteins
  • Recombinant Proteins
  • Transforming Growth Factor beta
  • Alkaline Phosphatase