Severe osteopetrosis, defective interleukin‐1 signalling and lymph node organogenesis in <i>TRAF6</i>‐deficient mice

Naito, Asuka; Azuma, Sakura; Tanaka, Sakae; Miyazaki, Tsuyoshi; Takaki, Satoshi; Takatsu, Kiyoshi; Nakao, Kazuki; Nakamura, Kenji; Katsuki, Motoya; Yamamoto, Tadashi; Inoue, Jun‐ichiro

doi:10.1046/j.1365-2443.1999.00265.x

Cited by 600 publications

(479 citation statements)

References 44 publications

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“…Traf6 has been shown to bind directly to Troy, and this interaction, therefore, could take place in tooth germ epithelium (Naito et al, 2002). Traf6 mutant mice exhibit an HED skin and hair phenotype and die between 17 and 19 days postnatal (Naito et al, 1999(Naito et al, , 2002. To determine whether these mice had a tooth phenotype, we examined sections of teeth from newborn mutants.…”

Section: Tooth Phenotype In Traf6 Mutant Micementioning

confidence: 99%

“…Traf6 mutant mice were produced as described by Naito et al (1999). Crinkled mice were produced as described by Headon et al (2001).…”

Section: Experimental Procedures Preparation Of Mutant and Wild-type mentioning

confidence: 99%

“…Traf6-deficient mice suggest that TRAF6 is essential molecule for osteoclast function, B-cell differentiation, IL-1 signalling, lipopolysaccharide signaling, lymph node organogenesis, and neural tube closure (Lomaga et al, 1999(Lomaga et al, , 2000Naito et al, 1999;Kobayashi et al, 2001). Although Traf6 mutant mice also exhibit skin and hair phenotypes similar to HED, the role of Traf6 in tooth development is not known (Naito et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Traf6 is essential for murine tooth cusp morphogenesis

Ohazama

Courtney

Tucker

et al. 2003

Developmental Dynamics

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Ectodermal appendages such as skin, hair, teeth, and sweat glands are affected in patients with hypohidrotic (anhydrotic) ectodermal dysplasia (HED). It has been established that mutations in the tumor necrosis factor (TNF) superfamily of molecules, i.e., ectodysplasin (EDA), EDA receptor (EDAR), and EDAR-associated death domain (EDARADD; the intracellular adaptor for EDAR), are responsible for several forms of HED in humans and mice. We show here by in situ hybridisation that another TNF family (orphan) receptor, TROY (also known TAJ, TAJ-␣, TRADE, and TNFRSF19), is strongly coexpressed with Edar in the epithelial enamel knot signalling centres that are believe to regulate cuspal morphogenesis during murine tooth development. Traf6 is known to function as an intracellular adaptor protein for Troy and examination of Traf6 mutant mice revealed abnormalities in molar teeth that are similar but more severe than those produced by mutations in Eda signalling molecules. This finding suggests that, in additional to ectodysplasin, another TNF pathway involving Troy/Traf6 is involved in molar tooth cusp formation and identifies an essential role for a Traf in tooth development. Developmental Dynamics 229:131-135, 2004.

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Section: Tooth Phenotype In Traf6 Mutant Micementioning

confidence: 99%

“…Traf6 mutant mice were produced as described by Naito et al (1999). Crinkled mice were produced as described by Headon et al (2001).…”

Section: Experimental Procedures Preparation Of Mutant and Wild-type mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Traf6 is essential for murine tooth cusp morphogenesis

Ohazama

Courtney

Tucker

et al. 2003

Developmental Dynamics

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“…(4,5) Numerous studies have shown that the receptor activator of NF-kB (RANK) signaling pathway is crucial for the differentiation and activation of osteoclasts. (6)(7)(8) Therefore, the amount of RANK ligand (RANKL) on the osteoblastic cell surface, where RANKL binds to RANK through cell-to-cell contact and triggers downstream signaling in osteoclast precursors, is considered to determine the magnitude of the signal input and the degree of osteoclastogenesis. (9,10) Previously, we have shown that most of the newly synthesized RANKL is transferred from the Golgi apparatus to the lysosomal storage compartment via the route involving vacuolar protein sorting 33a (Vps33a) in osteoblastic cells.…”

Section: Introductionmentioning

confidence: 99%

Function of OPG as a traffic regulator for RANKL is crucial for controlled osteoclastogenesis

Aoki

Honma

Kariya

et al. 2010

Journal of Bone and Mineral Research

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The amount of the receptor activator of NF-kB ligand (RANKL) on the osteoblastic cell surface is considered to determine the magnitude of the signal input to osteoclast precursors and the degree of osteoclastogenesis. Previously, we have shown that RANKL is localized predominantly in lysosomal organelles, but little is found on the osteoblastic cell surface, and consequently, the regulated subcellular trafficking of RANKL in osteoblastic cells is important for controlled osteoclastogenesis. Here we have examined the involvement of osteoprotegerin (OPG), which is currently recognized as a decoy receptor for RANKL, in the regulation of RANKL behavior. It was suggested that OPG already makes a complex with RANKL in the Golgi apparatus and that the complex formation is necessary for RANKL sorting to the secretory lysosomes. It was also shown that each structural domain of OPG is indispensable for exerting OPG function as a traffic regulator. In particular, the latter domains of OPG, whose physiologic functions have been unclear, were indicated to sort RANKL molecules to lysosomes from the Golgi apparatus. In addition, the overexpression of RANK-OPG chimeric protein, which retained OPG function as a decoy receptor but lost the function as a traffic regulator, inhibited endogenous OPG function as a traffic regulator selectively in osteoblastic cells and resulted in the upregulation of osteoclastogenic ability despite the increased number of decoy receptor molecules. Conclusively, OPG function as a traffic regulator for RANKL is crucial for regulating osteoclastogenesis at least as well as that as a decoy receptor. ß

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“…(5) Numerous studies, including detailed in vitro analyses and in vivo genetic investigations, have revealed that the receptor activator of the NF-kB (RANK) signaling is crucial for differentiation and activation of osteoclasts. (6)(7)(8) Most previous studies have focused on the total amount of RANK ligand (RANKL) expressed in whole osteoblastic cells, including studies focused on transcriptional regulation of RANKL. (9)(10)(11) However, only RANKL molecules expressed at the cell surface actually can bind to RANK, which is located at the cell surface of osteoclast precursor cells.…”

Section: Introductionmentioning

confidence: 99%

Rab27a and Rab27b are involved in stimulation-dependent RANKL release from secretory lysosomes in osteoblastic cells

Kariya

Honma

Hanamura

et al. 2010

Journal of Bone and Mineral Research

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The quantity of the receptor activator of NF-kB ligand (RANKL) expressed at the cell surface of osteoblastic cells is an important factor regulating osteoclast activation. Previously, RANKL was found to be localized to secretory lysosomes in osteoblastic cells and to translocate to the cell surface in response to stimulation with RANK-Fc-conjugated beads. However, the in vivo significance of stimulation-dependent RANKL release has not been elucidated. In this study we show that small GTPases Rab27a and Rab27b are involved in the stimulation-dependent RANKL release pathway in osteoblastic cells. Suppression of either Rab27a or Rab27b resulted in a marked reduction in RANKL release after stimulation. Slp4-a, Slp5, and Munc13-4 acted as effector molecules that coordinated Rab27a/b activity in this pathway. Suppression of Rab27a/b or these effector molecules did not inhibit accumulation of RANKL in lysosomal vesicles around the stimulated sites but did inhibit the fusion of these vesicles to the plasma membrane. In osteoblastic cells, suppression of the effector molecules resulted in reduced osteoclastogenic ability. Furthermore, Jinx mice, which lack a functional Munc13-4 gene, exhibited a phenotype characterized by increased bone volume near the tibial metaphysis caused by low bone resorptive activity. In conclusion, stimulation-dependent RANKL release is mediated by Rab27a/b and their effector molecules, and this mechanism may be important for osteoclast activation in vivo. ß

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Severe osteopetrosis, defective interleukin‐1 signalling and lymph node organogenesis in TRAF6‐deficient mice

Cited by 600 publications

References 44 publications

Traf6 is essential for murine tooth cusp morphogenesis

Traf6 is essential for murine tooth cusp morphogenesis

Function of OPG as a traffic regulator for RANKL is crucial for controlled osteoclastogenesis

Rab27a and Rab27b are involved in stimulation-dependent RANKL release from secretory lysosomes in osteoblastic cells

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