Heparan sulfate is required for bone morphogenetic protein-7 signaling

Although genetic studies have suggested that heparan sulfate (HS) is involved in bone morphogenetic protein (BMP)-mediated embryonic morphogenesis, it is unclear whether HS is directly involved in BMP-mediated signaling. Here, we investigate the involvement of HS in BMP-7 signaling. We show that HS...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2003-09, Vol.308 (4), p.858-865
Main Authors: Irie, Atsushi, Habuchi, Hiroko, Kimata, Koji, Sanai, Yutaka
Format: Article
Language:English
Subjects:
Animals
Bone morphogenetic protein
Bone Morphogenetic Protein 7
Bone Morphogenetic Proteins - metabolism
Cell Membrane - enzymology
Cell Membrane - metabolism
Chlorine - pharmacology
Dose-Response Relationship, Drug
Enzyme-Linked Immunosorbent Assay
Glycosaminoglycan
Glycosaminoglycans - metabolism
Heparan sulfate
Heparin - metabolism
Heparitin Sulfate - metabolism
Immunoblotting
Models, Chemical
Osteoblasts
Phosphorylation
Polysaccharide-Lyases - metabolism
Protein Binding
Proteoglycan
Rats
Reverse Transcriptase Polymerase Chain Reaction
Sepharose - metabolism
Signal Transduction
Transforming Growth Factor beta
Tumor Cells, Cultured
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Summary:Although genetic studies have suggested that heparan sulfate (HS) is involved in bone morphogenetic protein (BMP)-mediated embryonic morphogenesis, it is unclear whether HS is directly involved in BMP-mediated signaling. Here, we investigate the involvement of HS in BMP-7 signaling. We show that HS and heparin chains specifically bind to BMP-7. Digestion of cell-surface HS with heparitinase interferes with BMP-7-mediated Smad phosphorylation in ROS 17/2.8 osteoblastic cells. Inhibiting sulfation of cell-surface HS with chlorate also causes interruption of Smad phosphorylation. Addition of exogenous heparin to ROS 17/2.8 cells prevents BMP-7-mediated Smad phosphorylation rather than enhances the BMP-7 signal, suggesting that HS should be anchored on the plasma membrane for BMP signaling. Moreover, BMP-7 binding to ROS 17/2.8 cells is inhibited by chlorate treatment and exogenous application of heparin. These results demonstrate that BMP-7 specifically binds to cell-surface HS and the BMP-7–HS interaction is required for BMP-7 signaling.
ISSN:0006-291X
1090-2104
DOI:10.1016/S0006-291X(03)01500-6