Noggin and sclerostin bone morphogenetic protein antagonists form a mutually inhibitory complex.
Noggin and sclerostin are bone morphogenetic protein (BMP) antagonists that modulate mitogenic activity through sequestering BMPs. Little is known of the interactions among this class of proteins. We show that recombinant sclerostin and noggin bound to each other with high affinity (K(D) = 2.92 nm). This observation has been extended to naturally expressed noggin and sclerostin from the rat osteosarcoma cell line, ROS 17/2.8, supporting a role for the complex in natural systems. The noggin-sclerostin complex was competitive with BMP binding and mutually attenuated the activity of each BMP antagonist. Collectively, the data demonstrate a novel and exquisite paradigm for the regulation of BMP activity through direct neutralization of the BMP and activation by co-localized BMP antagonist expression. The pleiotrophic nature of noggin and sclerostin represents a novel mechanism for the fine-tuning of BMP activity in bone homeostasis.
Winkler
David G
DG
Department of Gene Function and Target Validation, Celltech R&D, Inc., Bothell, WA 98021, USA.
Yu
Changpu
C
Geoghegan
James C
JC
Ojala
Ethan W
EW
Skonier
John E
JE
Shpektor
Diana
D
Sutherland
May K
MK
Latham
John A
JA
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001667:Binding, Competitive; D015153:Blotting, Western; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D001842:Bone and Bones / Q000378:metabolism; D002352:Carrier Proteins; D002460:Cell Line; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004306:Dose-Response Relationship, Immunologic; D004797:Enzyme-Linked Immunosorbent Assay; D005819:Genetic Markers; D006023:Glycoproteins; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007700:Kinetics; D051379:Mice; D008809:Mice, Inbred C3H; D012516:Osteosarcoma / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051785:Smad Proteins; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D000099176:Noggin Protein
D048868:Adaptor Proteins, Signal Transducing; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D017077:Culture Media, Conditioned; D004268:DNA-Binding Proteins; D005819:Genetic Markers; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D011994:Recombinant Proteins; D051785:Smad Proteins; D015534:Trans-Activators; D000099176:Noggin Protein; C525816:BMP6 protein, human; C525817:Bmp6 protein, mouse; C525818:Bmp6 protein, rat; C422903:SOST protein, human; C486030:Sost protein, mouse