The LIM protein, Limd1, regulates AP-1 activation through an interaction with Traf6 to influence osteoclast development.
Increasingly a number of proteins important in the regulation of bone osteoclast development have been shown primarily influence osteoclastogenesis under conditions of physiologic or pathologic stress. Why basal osteoclastogenesis is normal and how these proteins regulate stress osteoclastogenic responses, as opposed to basal osteoclastogenesis, is unclear. LIM proteins of the Ajuba/Zyxin family localize to cellular sites of cell adhesion where they contribute to the regulation of cell adhesion and migration, translocate into the nucleus where they can affect cell fate, but are also found in the cytoplasm where their function is largely unknown. We show that one member of this LIM protein family, Limd1, is uniquely up-regulated during osteoclast differentiation and interacts with Traf6, a critical cytosolic regulator of RANK-L-regulated osteoclast development. Limd1 positively affects the capacity of Traf6 to activate AP-1, and Limd1(-/-) osteoclast precursor cells are defective in the activation of AP-1 and thus induction of NFAT2. Limd1(-/-) mice, although having normal basal bone osteoclast numbers and bone density, are resistant to physiological and pathologic osteoclastogenic stimuli. These results implicate Limd1 as a potentially important regulator of osteoclast development under conditions of stress.
Feng
Yunfeng
Y
Department of Medicine, Washington University, St. Louis, Missouri 63110, USA.
Zhao
Haibo
H
Luderer
Hilary F
HF
Epple
Holly
H
Faccio
Roberta
R
Ross
F Patrick
FP
Teitelbaum
Steven L
SL
Longmore
Gregory D
GD
D021581:Active Transport, Cell Nucleus; D000818:Animals; D001842:Bone and Bones / Q000378:metabolism; D002448:Cell Adhesion; D002465:Cell Movement; D003593:Cytoplasm / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism / Q000502:physiology*; D060588:LIM Domain Proteins; D008297:Male; D051379:Mice; D010006:Osteoblasts / Q000378:metabolism*; D011485:Protein Binding; D048029:TNF Receptor-Associated Factor 6 / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000378:metabolism*
D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; C509775:Limd1 protein, mouse; D048029:TNF Receptor-Associated Factor 6; D018808:Transcription Factor AP-1