Sulfated polysaccharides enhance the biological activities of bone morphogenetic proteins.
Bone morphogenetic proteins (BMPs), which have been shown to be heparin-binding proteins, induce osteoblast differentiation in mesenchymal cells. In the present study, we examined the effects of heparin on the BMP activities in C2C12 myoblasts. Heparin dose dependently enhanced the osteoblast differentiation induced by not only homodimers of BMP-2 or BMP-4 but also heterodimers of BMP-2/6 or BMP-2/7. However, the osteoblast differentiation induced by the constitutively active BMPR-IA, a functional BMP type I receptor, was not affected by heparin. Heparan sulfate and dextran sulfate also enhanced the BMP-2 activity, although the chemically desulfated heparin-derivatives have lost this stimulatory capacity. Heparin dose-dependently suppressed the accumulation of BMP-2 from the culture media into the cell layer or BMPR-IA, and retained a large amount of BMP-2 in the culture media. The biological activity of BMP-2, which was evaluated using a BMP-responsive reporter gene expression, was prolonged in the presence of heparin. Taken together, these results suggest that sulfated polysaccharides enhance the biological activity of both homodimers and heterodimers of BMPs by continuously serving the ligands to their signaling receptors expressed on cell membranes.
Takada
Takatora
T
Department of Biochemistry, Showa University, Tokyo 142-8555, Japan.
Katagiri
Takenobu
T
Ifuku
Michiyo
M
Morimura
Naoko
N
Kobayashi
Makoto
M
Hasegawa
Kohji
K
Ogamo
Akira
A
Kamijo
Ryutaro
R
D015153:Blotting, Western; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D055418:Bone Morphogenetic Protein 6; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D019070:Cell Lineage; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016264:Dextran Sulfate / Q000494:pharmacology; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D017930:Genes, Reporter; D006493:Heparin / Q000378:metabolism; D006497:Heparan Sulfate / Q000494:pharmacology; D006801:Humans; D010006:Osteoblasts / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011134:Polysaccharides / Q000378:metabolism*; D011233:Precipitin Tests; D015398:Signal Transduction; D013455:Sulfur / Q000378:metabolism; D016212:Transforming Growth Factor beta
D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D055418:Bone Morphogenetic Protein 6; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D017077:Culture Media, Conditioned; D016264:Dextran Sulfate; D006493:Heparin; D006497:Heparan Sulfate; D011134:Polysaccharides; D013455:Sulfur; D016212:Transforming Growth Factor beta; C525718:BMP2 protein, human; C525809:BMP4 protein, human; C525816:BMP6 protein, human; C525819:BMP7 protein, human