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J. Biol. Chem., Vol. 278, Issue 50, 50563-50571, December 12, 2003

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Osteocrin, a Novel Bone-specific Secreted Protein That Modulates the Osteoblast Phenotype^*

Gethin Thomas¶, Pierre Moffatt¶, Patrick Salois¶, Marie-Hélène Gaumond¶, Rock Gingras¶, Éric Godin¶, Dengshun Miao||, David Goltzman||, and Christian Lanctôt¶

From the ^¶Phenogene Therapeutics Inc., 416 de Maisonneuve West, Suite 1020, Montreal, Quebec H3A 1L2, Canada, and the ^||Calcium Research Laboratory, McGill University Health Centre, McGill University, Montreal, Quebec H3A 1A1, Canada

Although a number of secreted factors have been demonstrated to be bone regulators, none of these are unique to bone. Using a viral-based signal-trap strategy we have identified a novel gene we have termed "osteocrin." A 1280-bp mRNA encodes osteocrin producing a mature protein of 103 amino acids with a molecular mass of 11.4 kDa. Osteocrin shows no homology with any known gene except for two conserved sequence motifs reminiscent of dibasic cleavage sites found in peptide hormone precursors. Immunofluorescence and Western blot analysis confirmed the secretory nature of osteocrin. Two protein species were identified in the medium of cells overexpressing osteocrin, a full-length 11.4 kDa species and a processed 5 kDa species. Mutation of the ⁷⁶KKKR⁷⁹ dibasic cleavage site abolished the appearance of this smaller osteocrin fragment. By in situ hybridization in mouse embryos, osteocrin was expressed specifically in Cbfa-1-positive, osteocalcin-negative osteoblasts. Immunohistochemistry on adult mouse bone showed osteocrin localization in osteoblasts and young osteocytes. By Northern blot analysis, osteocrin expression was only detected in bone, expression peaking just after birth and decreasing markedly with age. In primary osteoblastic cell cultures osteocrin expression coincided with matrix formation then decreased in very mature cultures. Treatment of cultures with 1,25-dihydroxyvitamin D₃ resulted in a rapid dose-dependent down-regulation of osteocrin expression, suggesting direct regulation. Chronic treatment of primary cultures with osteocrin-conditioned media inhibited mineralization and reduced osteocalcin and alkaline phosphatase expression. These results suggest that osteocrin represents a novel, unique vitamin D-regulated bone-specific protein that appears to act as a soluble osteoblast regulator.

Received for publication, July 8, 2003 , and in revised form, September 27, 2003.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY395730, AY398681, AY398682, and AY398683.

^* 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.

These authors contributed equally to this work.

To whom correspondence should be addressed: Phenogene Therapeutics Inc., 416 de Maisonneuve West, Suite 1020, Montreal, Quebec, H3A 1L2, Canada. Tel.: 514-288-9099; Fax: 514-288-1111; E-mail: gthomas{at}phenogene.com.

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