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J. Biol. Chem., Vol. 283, Issue 26, 17991-18001, June 27, 2008

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Periostin, a Member of a Novel Family of Vitamin K-dependent Proteins, Is Expressed by Mesenchymal Stromal Cells^*

Daniel L. Coutu¹, Jian Hui Wu, Anne Monette^¶2, Georges-Étienne Rivard^||, Mark D. Blostein^**, and Jacques Galipeau, An FRSQ Chercheur Boursier Sénior^**3

From the Division of Experimental Medicine, McGill University, Montreal, Quebec H3A 1A3, Canada, Lady Davis Institute for Medical Research, ^¶HIV-1 RNA Trafficking Laboratory, ^||Service d'Hématologie-Oncologie, Centre Hospitalier Universitaire Ste-Justine, Université de Montréal, Montreal, Quebec H3T 1C5, Canada and the ^**Division of Hematology, Jewish General Hospital, McGill University, Montreal, Quebec H3T 1E2, Canada

The modification of glutamic acid residues to -carboxyglutamic acid (Gla) is a post-translational modification catalyzed by the vitamin K-dependent enzyme -glutamylcarboxylase. Despite ubiquitous expression of the -carboxylation machinery in mammalian tissues, only 12 Gla-containing proteins have so far been identified in humans. Because bone tissue is the second most abundant source of Gla-containing proteins after the liver, we sought to identify Gla proteins secreted by bone marrow-derived mesenchymal stromal cells (MSCs). We used a proteomics approach to screen the secretome of MSCs with a combination of two-dimensional gel electrophoresis and tandem mass spectrometry. The most abundant Gla-containing protein secreted by MSCs was identified as periostin, a previously unrecognized -carboxylated protein. In silico amino acid sequence analysis of periostin demonstrated the presence of four consensus -carboxylase recognition sites embedded within fasciclin-like protein domains. The carboxylation of periostin was confirmed by immunoprecipitation and purification of the recombinant protein. Carboxylation of periostin could be inhibited by warfarin in MSCs, demonstrating its dependence on the presence of vitamin K. We were able to demonstrate localization of carboxylated periostin to bone nodules formed by MSCs in vitro, suggesting a role in extracellular matrix mineralization. Our data also show that another fasciclin I-like protein, βig-h3, contains Gla. In conclusion, periostin is a member of a novel vitamin K-dependent -carboxylated protein family characterized by the presence of fasciclin domains. Furthermore, carboxylated periostin is produced by bone-derived cells of mesenchymal lineage and is abundantly found in mineralized bone nodules in vitro.

Received for publication, September 25, 2007 , and in revised form, April 29, 2008.

^* This work was supported in part by the Fonds de la Recherche en Santédu Québec (FRSQ) hemovigilance program. 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.

¹ Recipient of studentships from the Canadian Stem Cell Network and the FRSQ.

² Supported by a Canadian Institutes of Health Research studentship and CIHR Grant MOP-56974 and Canadian Foundation for Innovation Project 6484 (to Andrew Mouland).

³ To whom correspondence should be addressed: SMBD-Jewish General Hospital (McGill University), 3755 Cote Ste-Catherine Rd., Montreal, Québec H3T 1E2, Canada. Tel.: 514-340-8214; Fax: 514-340-8281; E-mail: jacques.galipeau{at}mcgill.ca.

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