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J. Biol. Chem., Vol. 278, Issue 23, 21058-21069, June 6, 2003

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Inactivation of Menin, the Product of the Multiple Endocrine Neoplasia Type 1 Gene, Inhibits the Commitment of Multipotential Mesenchymal Stem Cells into the Osteoblast Lineage^*

Hideaki Sowa, Hiroshi Kaji, Lucie Canaff  , Geoffrey N. Hendy , Tatsuo Tsukamoto, Toru Yamaguchi, Kohei Miyazono ¶ ||, Toshitsugu Sugimoto ** and Kazuo Chihara

From the Division of Endocrinology/Metabolism, Neurology, and Hematology/Oncology, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-Cho, Chuo-ku, Kobe 650-0017, Japan the Departments of Medicine, Physiology, and Human Genetics, McGill University and Royal Victoria Hospital, Montreal, Quebec H3A 1A1, Canada, the ^¶Department of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research, 1-37-1, Kami-ikebukuro, Toshima-ku, Tokyo 170-8455, Japan, and the ^||Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

The physiological roles of menin, the product of the multiple endocrine neoplasia type 1 gene, are not known. Homozygous menin knockout mice exhibit cranial and facial hypoplasia. We, therefore, investigated the role of menin in the regulation of osteoblastic differentiation. Menin antisense oligonucleotides (AS-oligo) reduced endogenous menin expression in the C3H10T1/2 (10T1/2) mouse mesenchymal stem cells and antagonized alkaline phosphatase (ALP) activity and the expression of type I collagen, Runx2/cbfa1 (Runx2), and osteocalcin (OCN) induced by bone morphogenetic protein 2 (BMP-2). AS-oligo did not affect adipogenic markers (Oil red staining and PPAR expression) and chondrogenic markers (Alcian blue staining and type IX collagen) induced by BMP-2 in 10T1/2 cells. Menin co-immunoprecipitated with Smad1 and Smad5, and inactivation of menin antagonized BMP-2-induced transcriptional activity of Smad1/5. In osteoblastic MC3T3-E1 cells, AS-oligo affected neither BMP-2-stimulated ALP activity nor the expression of Runx2 and OCN. Stable inactivation of menin in MC3T3-E1 cells increased ALP activity, mineralization, and the expression of type I collagen and OCN. In 21-day cultures of MC3T3-E1 cells and BMP-2-treated 10T1/2 cells, endogenous menin expression increased up to day 14 and declined thereafter. These data indicate that menin inactivation specifically inhibits the commitment of pluripotent mesenchymal stem cells to the osteoblast lineage, mediated by menin and Smad1/5 interactions. Menin is important for both early differentiation of osteoblasts and inhibition of their later differentiation, and it might be crucial for intramembranous ossification.

Received for publication, February 26, 2003

^* This work was supported in part by grants from the Uehara Memorial Foundation (to H. K.) and Canadian Institutes of Health Research Grant MOP-9315 (to G. N. H.). 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.

Recipient of a National Cancer Institute of Canada research studentship.

^** To whom correspondence should be addressed: Division of Endocrinology/Metabolism, Neurology, and Hematology/Oncology, Dept. of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-Cho, Chuo-ku, Kobe 650-0017, Japan. Tel.: 81-78-382-5885; Fax: 81-78-382-5899; E-mail: sugimot{at}med.kobe-u.ac.jp.

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