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J. Biol. Chem., Vol. 282, Issue 27, 19762-19772, July 6, 2007

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Nephroblastoma Overexpressed (Nov) Inhibits Osteoblastogenesis and Causes Osteopenia^*

Sheila Rydziel, Lisa Stadmeyer, Stefano Zanotti, Deena Durant, Anna Smerdel-Ramoya, and Ernesto Canalis¹

From the Department of Research, Saint Francis Hospital and Medical Center, Hartford, Connecticut 06105 and University of Connecticut School of Medicine, Farmington, Connecticut 06030

Nephroblastoma overexpressed (Nov), a member of the Cyr 61, connective tissue growth factor, Nov (CCN) family of proteins, is expressed by osteoblasts, but its function in cells of the osteoblastic lineage is not known. We investigated the effects of Nov overexpression by transducing murine ST-2 stromal and MC3T3 osteoblastic cells with a retroviral vector where Nov is under the control of the cytomegalovirus promoter. We also examined the skeletal phenotype of transgenic mice expressing Nov under the control of the human osteocalcin promoter. Overexpression of Nov in ST-2 cells inhibited the appearance of mineralized nodules and decreased alkaline phosphatase activity and osteocalcin mRNA levels. Nov overexpression inhibited the effect of bone morphogenetic protein (BMP)-2 on the phosphorylation of Smad 1/5/8; on the transactivation of 12xSBE-Oc-pGL3, a BMP/Smad signaling reporter construct, and of Wnt 3 on cytoplasmic β-catenin levels; and on the transactivation of the Wnt/β-catenin signaling reporter construct 16xTCF-Luc. Nov overexpression did not activate Notch or transforming growth factor β signaling. Glutathione S-transferase pulldown assays demonstrated direct Nov-BMP interactions. Nov transgenic mice exhibited osteopenia. In conclusion, Nov binds BMP-2 and antagonizes BMP-2 and Wnt activity, and its overexpression inhibits osteoblastogenesis and causes osteopenia.

Received for publication, January 8, 2007 , and in revised form, April 11, 2007.

^* This work was supported by NIAMS Grant AR21707 and NIDDK Grant DK45227 from the National Institutes of Health. 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 To whom correspondence and reprint requests should be addressed: Dept. of Research, Saint Francis Hospital and Medical Center, 114 Woodland St., Hartford, CT 06105-1299. Tel.: 860-714-4068; Fax: 860-714-8053; E-mail: ecanalis{at}stfranciscare.org.

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