Vps33a Mediates RANKL Storage in Secretory Lysosomes in Osteoblastic Cells

Kariya, Yutaka; Honma, Masashi; Aoki, Shigeki; Chiba, Atsushi; Suzuki, Hiroshi

doi:10.1359/jbmr.090409

Cited by 29 publications

(56 citation statements)

References 46 publications

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“…We also ORIGINAL ARTICLE J JBMR have shown that the suppression of Vps33a disrupted this regulated behavior of RANKL, resulting in the accumulation of RANKL in the Golgi apparatus and thus in upregulation of the cell surface RANKL leaked via the minor pathway in osteoblastic cells. (11) These findings indicate that regulation of RANKL at the protein trafficking level has an impact on osteoclastogenesis physiologically, and Vps33a-mediated transport of RANKL plays a key role.…”

Section: Introductionmentioning

confidence: 81%

“…(11) In addition, we have shown that the stimulation of osteoblastic cells with RANK extracellular domain conjugated beads, which mimics contact with osteoclasts, induces translocation of RANKL from the lysosomal storage to the bead interface. (11) Recruitment of RANKL to the bead interface requires only binding of the RANK extracellular domain to the small amount of RANKL already localized at the cell surface, which might be supplied via the minor pathway. We also ORIGINAL ARTICLE J JBMR have shown that the suppression of Vps33a disrupted this regulated behavior of RANKL, resulting in the accumulation of RANKL in the Golgi apparatus and thus in upregulation of the cell surface RANKL leaked via the minor pathway in osteoblastic cells.…”

Section: Introductionmentioning

confidence: 94%

“…(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. (11) There also exists the minor pathway transporting RANKL from the Golgi apparatus to the plasma membrane. (11) In addition, we have shown that the stimulation of osteoblastic cells with RANK extracellular domain conjugated beads, which mimics contact with osteoclasts, induces translocation of RANKL from the lysosomal storage to the bead interface.…”

Section: Introductionmentioning

confidence: 99%

“…(11) There also exists the minor pathway transporting RANKL from the Golgi apparatus to the plasma membrane. (11) In addition, we have shown that the stimulation of osteoblastic cells with RANK extracellular domain conjugated beads, which mimics contact with osteoclasts, induces translocation of RANKL from the lysosomal storage to the bead interface. (11) Recruitment of RANKL to the bead interface requires only binding of the RANK extracellular domain to the small amount of RANKL already localized at the cell surface, which might be supplied via the minor pathway.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Introductionmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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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“…Further study may be necessary regarding the reverse signals using ST‐2 cells since the RANKL expressions are very low on ST‐2 cells in the steady state. Kariya et al 34 have already shown that RANKL is predominantly localized in lysosomes in the steady state and is translocated into the plasma membranes after stimulation with RANKL using RANK‐Fc‐conjugated beads in ST‐2 cells. Our preliminary experiment also showed that GFP‐RANKL, which was transfected in ST‐2 cells, is translocated from lysosomes to the plasma membrane within 2 hours after the stimulation with the RANKL‐binding peptide, W9 (data not shown).…”

Section: Discussionmentioning

confidence: 97%

Peptide drugs accelerate BMP‐2‐induced calvarial bone regeneration and stimulate osteoblast differentiation through mTORC1 signaling

et al. 2016

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Both W9 and OP3‐4 were known to bind the receptor activator of NF‐κB ligand (RANKL), inhibiting osteoclastogenesis. Recently, both peptides were shown to stimulate osteoblast differentiation; however, the mechanism underlying the activity of these peptides remains to be clarified. A primary osteoblast culture showed that rapamycin, an mTORC1 inhibitor, which was recently demonstrated to be an important serine/threonine kinase for bone formation, inhibited the peptide‐induced alkaline phosphatase activity. Furthermore, both peptides promoted the phosphorylation of Akt and S6K1, an upstream molecule of mTORC1 and the effector molecule of mTORC1, respectively. In the in vivo calvarial defect model, W9 and OP3‐4 accelerated BMP‐2‐induced bone formation to a similar extent, which was confirmed by histomorphometric analyses using fluorescence images of undecalcified sections. Our data suggest that these RANKL‐binding peptides could stimulate the mTORC1 activity, which might play a role in the acceleration of BMP‐2‐induced bone regeneration by the RANKL‐binding peptides.

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RANKL subcellular trafficking and regulatory mechanisms in osteocytes

Honma

Ikebuchi

Kariya

et al. 2013

Journal of Bone and Mineral Research

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The receptor activator of the NF-kB ligand (RANKL) is the central player in the regulation of osteoclastogenesis, and the quantity of RANKL presented to osteoclast precursors is an important factor determining the magnitude of osteoclast formation. Because osteoblastic cells are thought to be a major source of RANKL, the regulatory mechanisms of RANKL subcellular trafficking have been studied in osteoblastic cells. However, recent reports showed that osteocytes are a major source of RANKL presentation to osteoclast precursors, prompting a need to reinvestigate RANKL subcellular trafficking in osteocytes. Investigation of molecular mechanisms in detail needs well-designed in vitro experimental systems. Thus, we developed a novel co-culture system of osteoclast precursors and osteocytes embedded in collagen gel. Experiments using this model revealed that osteocytic RANKL is provided as a membrane-bound form to osteoclast precursors through osteocyte dendritic processes and that the contribution of soluble RANKL to the osteoclastogenesis supported by osteocytes is minor. Moreover, the regulation of RANKL subcellular trafficking, such as OPG-mediated transport of newly synthesized RANKL molecules to lysosomal storage compartments, and the release of RANKL to the cell surface upon stimulation with RANK are confirmed to be functional in osteocytes. These results provide a novel understanding of the regulation of osteoclastogenesis.

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Vps33a Mediates RANKL Storage in Secretory Lysosomes in Osteoblastic Cells

Cited by 29 publications

References 46 publications

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

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

Peptide drugs accelerate BMP‐2‐induced calvarial bone regeneration and stimulate osteoblast differentiation through mTORC1 signaling

RANKL subcellular trafficking and regulatory mechanisms in osteocytes

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