FHL2 inhibits the activated osteoclast in a TRAF6-dependent manner

J Clin Invest. 2005 Oct;115(10):2742-51. doi: 10.1172/JCI24921. Epub 2005 Sep 22.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

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


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