FHL2 inhibits the activated osteoclast in a TRAF6-dependent manner

Shuting Bai, Hideki Kitaura, Haibo Zhao, Ju Chen, Judith M. Müller, Roland Schüle, Bryant Darnay, Deborah V. Novack, F. Patrick Ross, Steven L. Teitelbaum

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Abstract

TNF receptor-associated factor 6 (TRAF6) associates with the cytoplasmic domain of receptor activator of NF-κB (RANK). This event is central to normal osteoclastogenesis. We discovered that TRAF6 also interacts with FHL2 (four and a half LIM domain 2), a LIM domain-only protein that functions as a transcriprional coactivator or corepressor in a cell-type-specific manner. FHL2 mRNA and protein are undetectable in marrow macrophages and increase pari passu with osteoclast differentiation in vitro. FHL2 inhibits TRAF6-induced NF-κB activity in wild-type osteoclast precursors and, in keeping with its role as a suppressor of TRAF6-mediated RANK signaling, TRAF6/RANK association is enhanced in FHL2-/- osteoclasts. FHL2 overexpression delays RANK ligand-induced (RANKL-induced) osteoclast formation and cytoskeletal organization. Interestingly, osteoclast-resicling FHL2 is not detectable in naive wild-type mice, in vivo, but is abundant in those treated with RANKL and following induction of inflammatory arthritis. Reflecting increased RANKL sensitivity, osteociasts generated from FHL2-/- mice reach maturation and optimally organize their cytoskeleton earlier than their wild-type counterparts. As a consequence, FHL2-/- osteoclasts are hyperresorptive, and mice lacking the protein undergo enhanced RANKL and inflammatory arthritis-stimulated bone loss. FHL2 is, therefore, an antiosteoclastogenic molecule exerting its effect by attenuating TRAF6-mediated RANK signaling.

Original languageEnglish
Pages (from-to)2742-2751
Number of pages10
JournalJournal of Clinical Investigation
Volume115
Issue number10
DOIs
Publication statusPublished - 2005 Oct

ASJC Scopus subject areas

  • Medicine(all)

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    Bai, S., Kitaura, H., Zhao, H., Chen, J., Müller, J. M., Schüle, R., Darnay, B., Novack, D. V., Ross, F. P., & Teitelbaum, S. L. (2005). FHL2 inhibits the activated osteoclast in a TRAF6-dependent manner. Journal of Clinical Investigation, 115(10), 2742-2751. https://doi.org/10.1172/JCI24921