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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Research Article Bone biology

FHL2 inhibits the activated osteoclast in a TRAF6-dependent manner

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 11

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FHL2 is expressed only in activated osteoclasts. (A) WT mice were admini...
FHL2 is expressed only in activated osteoclasts. (A) WT mice were administered PBS or RANKL (100 μg/day) for 7 days. On day 9, histological sections of tibiae were stained for TRAP activity (red reaction product) or immunostained using an anti-FHL2 mAb. Osteoclasts in the RANKL-treated, but not PBS-treated, mice stained positive for the brown reaction product. (B) Serum transfer inflammatory arthritis was induced in WT mice. After 7 days, histological sections of the inflamed joints were immunostained for FHL-2, which is present in osteoclasts. (C) WT and FHL2–/– mice were administered arthrogenic serum to induce inflammatory arthritis or PBS as control. Serum TRACP 5b levels were measured at days 0, 7, and 14. *P < 0.05 vs. WT serum. Magnification: ×400.