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PMID: 10215628 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling.

Genes & development ·Vol. 13 ·No. 8 ·1999-04-15 ·Pages 1015-24

Lomaga MA, Yeh WC, Sarosi I, Duncan GS, Furlonger C, Ho A, Morony S, Capparelli C, Van G, Kaufman S, van der Heiden A, Itie A, Wakeham A, Khoo W, Sasaki T, Cao Z, Penninger JM, Paige CJ, Lacey DL, Dunstan CR, Boyle WJ, Goeddel DV, Mak TW

Abstract

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.

MeSH Terms
Animals B-Lymphocytes/metabolism CD40 Antigens/metabolism Calcium-Calmodulin-Dependent Protein Kinases/metabolism Cell Division Enzyme Activation Female Interleukin-1/metabolism JNK Mitogen-Activated Protein Kinases Lipopolysaccharides/metabolism,pharmacology Macrophages/enzymology Mice Mice, Knockout Mitogen-Activated Protein Kinases NF-kappa B/metabolism Nitric Oxide Synthase/metabolism Nitric Oxide Synthase Type II Osteopetrosis/physiopathology Proteins/genetics,physiology Signal Transduction TNF Receptor-Associated Factor 6
Chemicals
CD40 Antigens Interleukin-1 Lipopolysaccharides NF-kappa B Proteins TNF Receptor-Associated Factor 6 Nitric Oxide Synthase Nitric Oxide Synthase Type II Nos2 protein, mouse Calcium-Calmodulin-Dependent Protein Kinases JNK Mitogen-Activated Protein Kinases Mitogen-Activated Protein Kinases
Authors & Affiliations
23 authors, click to expand affiliations / ORCID
Lomaga M A
Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada M5S 2S2.
Yeh W C
Sarosi I
Duncan G S
Furlonger C
Ho A
Morony S
Capparelli C
Van G
Kaufman S
van der Heiden A
Itie A
Wakeham A
Khoo W
Sasaki T
Cao Z
Penninger J M
Paige C J
Lacey D L
Dunstan C R
Boyle W J
Goeddel D V
Mak T W
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Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
0890-9369
DOI
10.1101/gad.13.8.1015
Published
1999-04-15
Pages
1015-24
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC316636
Subset
IM
External Links
PubMed source DOI: 10.1101/gad.13.8.1015 PMC Full Text View journal details
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