TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling.
Bone resorption and remodeling is an intricately controlled, physiological process that requires the function of osteoclasts. The processes governing both the differentiation and activation of osteoclasts involve signals induced by osteoprotegerin ligand (OPGL), a member of tumor necrosis factor (TNF) superfamily, and its cognate receptor RANK. The molecular mechanisms of the intracellular signal transduction remain to be elucidated. Here we report that mice deficient in TNF receptor-associated factor 6 (TRAF6) are osteopetrotic with defects in bone remodeling and tooth eruption due to impaired osteoclast function. Using in vitro assays, we demonstrate that TRAF6 is crucial not only in IL-1 and CD40 signaling but also, surprisingly, in LPS signaling. Furthermore, like TRAF2 and TRAF3, TRAF6 is essential for perinatal and postnatal survival. These findings establish unexpectedly diverse and critical roles for TRAF6 in perinatal and postnatal survival, bone metabolism, LPS, and cytokine signaling.
Lomaga
M A
MA
Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada M5S 2S2.
Yeh
W C
WC
Sarosi
I
I
Duncan
G S
GS
Furlonger
C
C
Ho
A
A
Morony
S
S
Capparelli
C
C
Van
G
G
Kaufman
S
S
van der Heiden
A
A
Itie
A
A
Wakeham
A
A
Khoo
W
W
Sasaki
T
T
Cao
Z
Z
Penninger
J M
JM
Paige
C J
CJ
Lacey
D L
DL
Dunstan
C R
CR
Boyle
W J
WJ
Goeddel
D V
DV
Mak
T W
TW
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D019013:CD40 Antigens / Q000378:metabolism*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002455:Cell Division; D004789:Enzyme Activation; D005260:Female; D007375:Interleukin-1 / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases; D008070:Lipopolysaccharides / Q000378:metabolism* / Q000494:pharmacology; D008264:Macrophages / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010022:Osteopetrosis / Q000503:physiopathology*; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6
D019013:CD40 Antigens; D007375:Interleukin-1; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011506:Proteins; D048029:TNF Receptor-Associated Factor 6; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases