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FHL2 inhibits the activated osteoclast in a TRAF6-dependent manner
Shuting Bai, … , F. Patrick Ross, Steven L. Teitelbaum
Shuting Bai, … , F. Patrick Ross, Steven L. Teitelbaum
Published October 3, 2005
Citation Information: J Clin Invest. 2005;115(10):2742-2751. https://doi.org/10.1172/JCI24921.
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Categories: Research Article Bone biology

FHL2 inhibits the activated osteoclast in a TRAF6-dependent manner

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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 transcriptional 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-residing 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, osteoclasts 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.

Authors

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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Figure 8

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FHL2 overexpression attenuates osteoclast differentiation and spreading....
FHL2 overexpression attenuates osteoclast differentiation and spreading. BMMs were retrovirally transduced with empty vector or vector expressing FHL2 and selected with blasticidin S, hydrochloride for 3 days. Selected cells were stimulated with M-CSF and increasing doses of RANKL for 4 days after which the cultures were stained for TRAP activity. Arrows point to nonspread osteoclasts. Magnification: ×400.
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