FHL2 inhibits the activated osteoclast in a TRAF6-dependent manner.

Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 7802877 Publication Model: Print-Electronic Cited Medium: Print ISSN: 0021-9738 (Print) Linking ISSN: 00219738 NLM ISO Abbreviation: J Clin Invest Subsets: MEDLINE

Publication: 1999- : Ann Arbor, MI : American Society for Clinical Investigation
Original Publication: New Haven [etc.] American Society for Clinical Investigation.

Cell Differentiation/*physiology ; Homeodomain Proteins/*metabolism ; Muscle Proteins/*metabolism ; Osteoclasts/*metabolism ; Signal Transduction/*physiology ; TNF Receptor-Associated Factor 6/*metabolism ; Transcription Factors/*metabolism; Animals ; Arthritis/genetics ; Arthritis/metabolism ; Arthritis/pathology ; Bone Resorption/genetics ; Bone Resorption/metabolism ; Bone Resorption/pathology ; Carrier Proteins/metabolism ; Cell Line ; Cytoskeleton/genetics ; Cytoskeleton/metabolism ; Homeodomain Proteins/genetics ; LIM-Homeodomain Proteins ; Membrane Glycoproteins/metabolism ; Mice ; Mice, Knockout ; Muscle Proteins/genetics ; Osteoclasts/cytology ; RANK Ligand ; Receptor Activator of Nuclear Factor-kappa B ; Transcription Factors/genetics

TNF receptor-associated factor 6 (TRAF6) associates with the cytoplasmic domain of receptor activator of NF-kappaB (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-kappaB 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.

Bioessays. 2003 Nov;25(11):1096-105. (PMID: 14579250)
Mol Cell Biol. 2004 Dec;24(24):10689-702. (PMID: 15572674)
J Bone Miner Res. 2004 Jul;19(7):1059-66. (PMID: 15176987)
J Biol Chem. 2004 Jul 2;279(27):28641-52. (PMID: 15117962)
J Clin Invest. 2004 Jul;114(2):206-13. (PMID: 15254587)
J Immunol. 2004 Oct 15;173(8):4838-46. (PMID: 15470024)
Proc Natl Acad Sci U S A. 1987 Sep;84(18):6471-5. (PMID: 2442758)
Am J Pathol. 1996 Jul;149(1):37-44. (PMID: 8686760)
Nature. 1996 Oct 3;383(6599):443-6. (PMID: 8837778)
Cell. 1998 Apr 17;93(2):165-76. (PMID: 9568710)
Gene. 1998 Apr 14;210(2):345-50. (PMID: 9573400)
Trends Genet. 1998 Apr;14(4):156-62. (PMID: 9594664)
Genes Dev. 1998 Sep 15;12(18):2821-30. (PMID: 9744859)
Genes Dev. 1999 Apr 15;13(8):1015-24. (PMID: 10215628)
Genes Cells. 1999 Jun;4(6):353-62. (PMID: 10421844)
Genes Dev. 1999 Sep 15;13(18):2412-24. (PMID: 10500098)
Nat Rev Mol Cell Biol. 2004 Nov;5(11):920-31. (PMID: 15520811)
J Clin Invest. 2005 Jul;115(7):1848-54. (PMID: 15937549)
Exp Cell Res. 2000 Jan 10;254(1):14-24. (PMID: 10623461)
EMBO J. 2000 Feb 1;19(3):359-69. (PMID: 10654935)
J Clin Invest. 2000 Feb;105(4):433-40. (PMID: 10683372)
Mech Dev. 2000 Mar 1;91(1-2):5-17. (PMID: 10704826)
Biochem Biophys Res Commun. 2000 Jul 5;273(2):776-83. (PMID: 10873680)
Mech Dev. 2000 Jul;95(1-2):259-65. (PMID: 10906474)
Science. 2000 Sep 1;289(5484):1504-8. (PMID: 10968780)
Mol Cell Biol. 2000 Oct;20(20):7460-2. (PMID: 11003643)
Mol Cell Biol. 2000 Nov;20(22):8613-22. (PMID: 11046156)
EMBO J. 2001 Mar 15;20(6):1271-80. (PMID: 11250893)
J Clin Invest. 2001 Oct;108(7):971-9. (PMID: 11581298)
J Biol Chem. 2001 Oct 19;276(42):39295-302. (PMID: 11514537)
Oncogene. 2001 Oct 1;20(44):6482-91. (PMID: 11607847)
EMBO J. 2002 Feb 15;21(4):736-48. (PMID: 11847121)
Sci STKE. 1999 Oct 26;1999(5):RE1. (PMID: 11865184)
Proc Natl Acad Sci U S A. 2002 Apr 16;99(8):5585-90. (PMID: 11943846)
Nature. 2002 Jul 25;418(6896):443-7. (PMID: 12140561)
Nat Med. 2002 Sep;8(9):943-9. (PMID: 12161749)
J Biol Chem. 2002 Oct 4;277(40):37045-53. (PMID: 12145280)
J Biol Chem. 2002 Nov 15;277(46):44347-56. (PMID: 12185073)
J Biol Chem. 2003 Feb 14;278(7):5188-94. (PMID: 12466281)
J Clin Invest. 2003 Mar;111(5):749-58. (PMID: 12618529)
Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3977-82. (PMID: 12644711)
J Exp Med. 2003 Sep 1;198(5):771-81. (PMID: 12939342)
Curr Top Dev Biol. 2004;64:207-38. (PMID: 15563949)
J Biol Chem. 2004 Feb 13;279(7):6065-76. (PMID: 14645259)

AR32788 United States AR NIAMS NIH HHS; AR46852 United States AR NIAMS NIH HHS; R01 AR046523 United States AR NIAMS NIH HHS; R37 AR046523 United States AR NIAMS NIH HHS; P30 DK056341 United States DK NIDDK NIH HHS; R01 AR046852 United States AR NIAMS NIH HHS; AR48812 United States AR NIAMS NIH HHS; R01 AR032788 United States AR NIAMS NIH HHS; R01 AR048812 United States AR NIAMS NIH HHS; R01 AR048853 United States AR NIAMS NIH HHS; DK-56341 United States DK NIDDK NIH HHS; AR46523 United States AR NIAMS NIH HHS; AR48853 United States AR NIAMS NIH HHS

0 (Carrier Proteins)
0 (Fhl2 protein, mouse)
0 (Homeodomain Proteins)
0 (LIM-Homeodomain Proteins)
0 (Membrane Glycoproteins)
0 (Muscle Proteins)
0 (RANK Ligand)
0 (Receptor Activator of Nuclear Factor-kappa B)
0 (TNF Receptor-Associated Factor 6)
0 (Tnfrsf11a protein, mouse)
0 (Tnfsf11 protein, mouse)
0 (Transcription Factors)

Date Created: 20050927 Date Completed: 20051212 Latest Revision: 20181113

20231215

PMC1224296

10.1172/JCI24921

16184196