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doi: 10.1242/10.1242/jcs.00082

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Journal of Cell Science 115, 4317-4325 (2002)
doi: 10.1242/jcs.00082

Research Article

JNK1 modulates osteoclastogenesis through both c-Jun phosphorylation-dependent and -independent mechanisms

Jean-Pierre David1, Kanaga Sabapathy1,*, Oskar Hoffmann2, Maria H. Idarraga1 and Erwin F. Wagner1,{ddagger}

1 Research Institute of Molecular Pathology (IMP), Dr Bohr-Gasse 7, A-1030 Vienna, Austria
2 Institute fur Pharmakologie und Toxikologie, Pharmazie-Zentrum, Althanstrasse 14, A-1090 Vienna, Austria
* Present address: National Cancer Center, Division of Cellular and Molecular Research, 11 Hospital Drive, 169610 Singapore, Singapore

{ddagger} Author for correspondence (e-mail: Wagner{at}nt.imp.univie.ac.at)

Accepted 25 July 2002

Phosphorylation of the N-terminal domain of Jun by the Jun kinases (JNKs) modulates the transcriptional activity of AP-1, a dimeric transcription factor typically composed of c-Jun and c-Fos, the latter being essential for osteoclast differentiation. Using mice lacking JNK1 or JNK2, we demonstrate that JNK1, but not JNK2, is specifically activated by the osteoclast-differentiating factor RANKL. Activation of JNK1, but not JNK2, is required for efficient osteoclastogenesis from bone marrow monocytes (BMMs). JNK1 protects BMMs from RANKL-induced apoptosis during differentiation. In addition, BMMs from mice carrying a mutant of c-Jun phosphorylation sites (JunAA/JunAA), as well as cells lacking either c-Jun or JunD, which is another JNK substrate, revealed that c-Jun phosphorylation and c-Jun itself, but not JunD, are essential for efficient osteoclastogenesis. Moreover, JNK1-dependent c-Jun phosphorylation in response to RANKL is not involved in the anti-apoptotic function of JNK1. Thus, these data provide genetic evidence that JNK1 activation modulates osteoclastogenesis through both c-Jun-phosphorylation-dependent and -independent mechanisms.

Key words: Jun-N-terminal kinase, c-Jun, Osteoclasts, RANKL, Apoptosis




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