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Published online 9 February 2004. doi:10.1083/jcb.200308155
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 164, Number 4, 613-623
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Article

Mice lacking JunB are osteopenic due to cell-autonomous osteoblast and osteoclast defects



Lukas Kenner1, Astrid Hoebertz1, Timo Beil2, Niamh Keon3, Florian Karreth1, Robert Eferl1, Harald Scheuch1, Agnieszka Szremska1, Michael Amling2, Marina Schorpp-Kistner3, Peter Angel3, and Erwin F. Wagner1

1 Research Institute of Molecular Pathology (IMP), A-1030 Vienna, Austria
2 Department of Trauma, Hand, and Reconstructive Surgery, Hamburg University School of Medicine, D-20246 Hamburg, Germany
3 Department of Signal Transduction and Growth Control, Deutsches Krebsforschungszentrum (DKFZ), D-69120 Heidelberg, Germany

Address correspondence to Erwin F. Wagner, Research Institute of Molecular Pathology, Dr. Bohr-Gasse 7, A-1030 Vienna, Austria. Tel.: 43-1-797-30-888. Fax: 43-1-798-71-53. email: wagner{at}imp.univie.ac.at

Because JunB is an essential gene for placentation, it was conditionally deleted in the embryo proper. JunB{Delta}/{Delta} mice are born viable, but develop severe low turnover osteopenia caused by apparent cell-autonomous osteoblast and osteoclast defects before a chronic myeloid leukemia-like disease. Although JunB was reported to be a negative regulator of cell proliferation, junB{Delta}/{Delta} osteoclast precursors and osteoblasts show reduced proliferation along with a differentiation defect in vivo and in vitro. Mutant osteoblasts express elevated p16INK4a levels, but exhibit decreased cyclin D1 and cyclin A expression. Runx2 is transiently increased during osteoblast differentiation in vitro, whereas mature osteoblast markers such as osteocalcin and bone sialoprotein are strongly reduced. To support a cell-autonomous function of JunB in osteoclasts, junB was inactivated specifically in the macrophage–osteoclast lineage. Mutant mice develop an osteopetrosis-like phenotype with increased bone mass and reduced numbers of osteoclasts. Thus, these data reveal a novel function of JunB as a positive regulator controlling primarily osteoblast as well as osteoclast activity.

Key Words: AP-1; conditional gene targeting; osteoblasts; osteopenia; osteopetrosis

L. Kenner and A. Hoebertz contributed equally to this paper.

Abbreviations used in this paper: AP-1, activator protein-1; CML, chronic myeloid leukemia; ES, embryonic stem; M-CSF, macrophage colony–stimulating factor; MMP-9, matrix metalloproteinase-9; RANKL, receptor activator of NF{kappa}B ligand; TRAP, tartrate-resistant acid phosphatase.


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