Osteocrin is a specific ligand of the natriuretic Peptide clearance receptor that modulates bone growth.
Osteocrin (Ostn) is a recently discovered secreted protein produced by cells of the osteoblast lineage that shows a well conserved homology with members of the natriuretic peptide (NP) family. We hypothesized that Ostn could interact with the NP receptors, thereby modulating NP actions on the skeleton. Ostn binds specifically and saturably to the NP peptide receptor-C (NPR-C) receptor with a Kd of approximately 5 nM with no binding to the GC-A or GC-B receptors. Deletion of several of the residues deemed important for NP binding to NPR-C led to abolition of Ostn binding, confirming the presence of a "natriuretic motif." Functionally, Ostn was able to augment C-type natriuretic peptide-stimulated cGMP production in both pre-chondrocytic (ATDC5) and osteoblastic (UMR106) cells, suggesting increased NP levels due to attenuation of NPR-C associated NP clearance. Ostn-transgenic mice displayed elongated bones and a marked kyphosis associated with elevated bone cGMP levels, suggesting that elevated natriuretic peptide activity contributed to the increased bone length possibly through an increase in growth plate chondrocyte proliferation. Thus, we have demonstrated that Ostn is a naturally occurring ligand of the NPR-C clearance receptor and may act to locally modulate the actions of the natriuretic system in bone by blocking the clearance action of NPR-C, thus locally elevating levels of C-type natriuretic peptide.
Moffatt
Pierre
P
Shriners Hospital for Children, and Department of Human Genetics, McGill University, Montréal, Québec H3A 2T5, Canada. pmoffatt@shriners.mcgill.ca
Thomas
Gethin
G
Sellin
Karine
K
Bessette
Marie-Claude
MC
Lafrenière
François
F
Akhouayri
Omar
O
St-Arnaud
René
R
Lanctôt
Christian
C
D020816:Amino Acid Motifs / Q000235:genetics; D000818:Animals; D030801:Animals, Genetically Modified; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019902:Chondrocytes / Q000378:metabolism*; D006152:Cyclic GMP / Q000235:genetics / Q000378:metabolism; D006132:Growth Plate / Q000254:growth & development* / Q000378:metabolism; D006801:Humans; D007738:Kyphosis / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D020098:Natriuretic Peptide, C-Type / Q000378:metabolism*; D010006:Osteoblasts / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D051381:Rats; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
D008024:Ligands; D009124:Muscle Proteins; C480236:OSTN protein, human; C498449:Ostn protein, mouse; C498450:Ostn protein, rat; D014157:Transcription Factors; D020098:Natriuretic Peptide, C-Type; D017461:Receptors, Atrial Natriuretic Factor; C073616:atrial natriuretic factor receptor C; D006152:Cyclic GMP