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J. Biol. Chem., Vol. 282, Issue 50, 36454-36462, December 14, 2007

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Osteocrin Is a Specific Ligand of the Natriuretic Peptide Clearance Receptor That Modulates Bone Growth^*

Pierre Moffatt^**12, Gethin Thomas^¶1, Karine Sellin^||, Marie-Claude Bessette^||, François Lafrenière^||, Omar Akhouayri, René St-Arnaud^**, and Christian Lanctôt^||

From the Shriners Hospital for Children, Montréal, Québec H3G 1A6, Canada, ^**Department of Human Genetics, McGill University, Montréal, Québec H3A 2T5, Canada, Enobia Pharma, Montréal, Québec H1W 4A4, Canada, ^¶Diamantina Institute for Cancer, Immunology, and Metabolic Medicine, The University of Queensland, Princess Alexandria Hospital, Brisbane, Australia, and ^||Phenogene Therapeutics, Montréal, Québec H3A 1L2, Canada

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 K_d of 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.

Received for publication, October 16, 2007

^* This work was supported in part by the Shriners of North America. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1-3.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: Shriners Hospital for Children, 1529 Cedar Ave., Montréal, Québec H3G 1A6, Canada. Tel.: 514-282-7161; Fax: 514-842-5581; E-mail: pmoffatt{at}shriners.mcgill.ca.

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