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Molecular and Cellular Biology, September 2002, p. 6222-6233, Vol. 22, No. 17
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.17.6222-6233.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

High Bone Resorption in Adult Aging Transgenic Mice Overexpressing Cbfa1/Runx2 in Cells of the Osteoblastic Lineage

Valérie Geoffroy,1,{dagger} Michaela Kneissel,2 Brigitte Fournier,2 Alan Boyde,3 and Patrick Matthias1*

Friedrich-Miescher Institute for Biomedical Research, Zweigniederlassung Novartis Forschungsstiftung,1 Novartis Pharma,Basel, Switzerland,2 University College, London, United Kingdom3

Received 26 November 2001/ Returned for modification 25 January 2002/ Accepted 22 May 2002

The runt family transcription factor core-binding factor {alpha}1 (Cbfa1) is essential for bone formation during development. Surprisingly, transgenic mice overexpressing Cbfa1 under the control of the 2.3-kb collagen type I promoter developed severe osteopenia that increased progressively with age and presented multiple fractures. Analysis of skeletally mature transgenic mice showed that osteoblast maturation was affected and that specifically in cortical bone, bone resorption as well as bone formation was increased, inducing high bone turnover rates and a decreased degree of mineralization. To understand the origin of the increased bone resorption, we developed bone marrow stromal cell cultures and reciprocal coculture of primary osteoblasts and spleen cells from wild-type or transgenic mice. We showed that transgenic cells of the osteoblastic lineage induced an increased number of tartrate-resistant acid phosphatase-positive multinucleated cells, suggesting that primary osteoblasts as well as bone marrow stromal cells from transgenic mice have stronger osteoclastogenic properties than cells derived from wild-type animals. We investigated the candidate genes whose altered expression could trigger this increase in bone resorption, and we found that the expression of receptor activator of NF-{kappa}B ligand (RANKL) and collagenase 3, two factors involved in bone formation-resorption coupling, was markedly increased in transgenic cells. Our data thus suggest that overexpression of Cbfa1 in cells of the osteoblastic lineage does not necessarily induce a substantial increase in bone formation in the adult skeleton but has a positive effect on osteoclast differentiation in vitro and can also dramatically enhance bone resorption in vivo, possibly through increased RANKL expression.

* Corresponding author. Mailing address: Friedrich Miescher Institute, Maulbeerstr. 66, CH-4058 Basle, Switzerland. Phone: 41 61 697 66 61. Fax: 41 61 697 39 76. E-mail address: matthias{at}fmi.ch.

{dagger} Present address: INSERM U349 Hôpital Lariboisière, Paris, France.

Molecular and Cellular Biology, September 2002, p. 6222-6233, Vol. 22, No. 17
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.17.6222-6233.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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