Potent ectopic bone-inducing activity of bone morphogenetic protein-4/7 heterodimer.
We have purified and characterized recombinant Xenopus bone morphogenetic proteins (xBMPs): homodimers of xBMP-4, 7 and heterodimers (xBMP-4/7) produced by a baculovirus expression system. Highly purified xBMPs had homogeneous NH2-termini predicted from a consensus motif, Arg-X-X-Arg, while they possessed diverse sugar chains. Implantation of xBMPs together with pure collagen carrier in rats induced new bone formation in a dose-dependent manner. The xBMP-4/7 heterodimer showed the strongest activity, with an effective dose of 1-30 micrograms, while more than 10 micrograms of xBMP-4 or 7 homodimer was required for a significant effect. Histological examination revealed that xBMP-4/7 implants showed intramembranous ossification without chondrogenesis. In primary cultures of rat bone marrow stromal cells, xBMP-4/7 induced alkaline phosphatase 3-fold more strongly than xBMP-7 and 20-fold more than xBMP-4. These results suggest that the heterodimeric form of BMP would generate the strongest signal triggering osteogenic differentiation of osteoprogenitor cells in adult tissues.
Aono
A
A
Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan.
Hazama
M
M
Notoya
K
K
Taketomi
S
S
Yamasaki
H
H
Tsukuda
R
R
Sasaki
S
S
Fujisawa
Y
Y
D000469:Alkaline Phosphatase / Q000096:biosynthesis; D000595:Amino Acid Sequence; D000818:Animals; D001846:Bone Development / Q000187:drug effects*; D001854:Bone Marrow Cells; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D016384:Consensus Sequence; D004790:Enzyme Induction; D006133:Growth Substances / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D008969:Molecular Sequence Data; D010006:Osteoblasts / Q000166:cytology* / Q000187:drug effects; D014176:Protein Biosynthesis; D055503:Protein Multimerization; D011506:Proteins / Q000302:isolation & purification / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000302:isolation & purification / Q000494:pharmacology; D018411:Spodoptera; D014162:Transfection; D016212:Transforming Growth Factor beta; D014981:Xenopus; D029867:Xenopus Proteins
C525821:Bmp7 protein, rat; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D006133:Growth Substances; D011506:Proteins; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D029867:Xenopus Proteins; C525822:bmp7.1 protein, Xenopus; D000469:Alkaline Phosphatase