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First published online May 28, 2004
doi: 10.1242/10.1242/jcs.01133

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Targeted expression of a dominant-negative N-cadherin in vivo delays peak bone mass and increases adipogenesis

Charlles H. M. Castro^1,3,*, Chan Soo Shin^1,4,*, Joseph P. Stains¹, Su-Li Cheng¹, Sharmin Sheikh¹, Gabriel Mbalaviele^1,5, Vera Lucia Szejnfeld³ and Roberto Civitelli^1,2,

¹ Division of Bone and Mineral Diseases, Department of Internal Medicine, Washington University School of Medicine, 216 S. Kingshighway Blvd, St Louis, MO 63110, USA
² Department of Cell Biology and Physiology, Washington University School of Medicine, 216 S. Kingshighway Blvd, St Louis, MO 63110, USA
³ Universidade Federal de São Paulo-Escola Paulista de Medicina, Rua Botucatu 740, São Paulo-SP, Brasil
⁴ Department of Internal Medicine, Seoul National University College of Medicine, 28 Yongon-Dong, Chongno-Gu, Seoul 110-774, Republic of Korea
⁵ Pfizer Incorporated, 700 Chesterfield Parkway West, Chesterfield, MO 63107, USA

Author for correspondence (e-mail: rcivitel{at}im.wustl.edu)

Accepted 2 February 2004

We studied the function of osteoblast cadherins in vivo by transgenic expression of a truncated N-cadherin with dominant-negative action, driven by an osteoblast-specific promoter (OG2-NcadC). During the first 3 months of life, bone mineral density was reduced, whereas percent body fat was increased in transgenic animals compared with wild-type littermates, with associated decreased bone formation rate and osteoblast number, but normal osteoclast number. Osteoblast differentiation was delayed in calvaria cells isolated from transgenic mice. Likewise, the number of osteoblast precursors in bone marrow stromal cells from OG2-NcadC mice was decreased compared with wild-type cultures, whereas the number of adipogenic precursors was increased. In vitro, a transcriptionally active ß-catenin mutant reversed the delay in osteoblast differentiation and the exuberant adipogenesis. Thus, in vivo disruption of cadherin function hinders osteoblast differentiation and favors, indirectly, bone marrow progenitor cell commitment to the alternative adipogenic lineage via interference with ß-catenin signaling. This results in decreased bone formation, delayed acquisition of peak bone mass and increased body fat.

Key words: Cell-cell adhesion, Mesenchymal differentiation, Cadherins, Adipogenesis, Transgenic mice

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