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RANKL subcellular trafficking and regulatory mechanisms in osteocytes
ABSTRACT The receptor activator of the NF‐κB 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...
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| Published in: | Journal of bone and mineral research 2013-09, Vol.28 (9), p.1936-1949 |
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| Main Authors: | , , , , , , |
| Format: | Article |
| Language: | English |
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| cited_by | cdi_FETCH-LOGICAL-c4871-e83b63ff5b6bb16112e2e5e9ccfdaa3d6df7fc7fea2f1b2a7fa66e6e48e12bcd3 |
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| cites | cdi_FETCH-LOGICAL-c4871-e83b63ff5b6bb16112e2e5e9ccfdaa3d6df7fc7fea2f1b2a7fa66e6e48e12bcd3 |
| container_end_page | 1949 |
| container_issue | 9 |
| container_start_page | 1936 |
| container_title | Journal of bone and mineral research |
| container_volume | 28 |
| creator | Honma, Masashi Ikebuchi, Yuki Kariya, Yoshiaki Hayashi, Madoka Hayashi, Naoki Aoki, Shigeki Suzuki, Hiroshi |
| description | ABSTRACT
The receptor activator of the NF‐κB 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. |
| doi_str_mv | 10.1002/jbmr.1941 |
| format | article |
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The receptor activator of the NF‐κB 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.</description><identifier>ISSN: 0884-0431</identifier><identifier>EISSN: 1523-4681</identifier><identifier>DOI: 10.1002/jbmr.1941</identifier><identifier>PMID: 23529793</identifier><identifier>CODEN: JBMREJ</identifier><language>eng</language><publisher>United States: Wiley Subscription Services, Inc</publisher><subject>Animals ; Bone Marrow Cells - cytology ; Bone Marrow Cells - drug effects ; Bone Marrow Cells - metabolism ; Cell Communication - drug effects ; Cell Culture Techniques ; Cell Membrane - drug effects ; Cell Membrane - metabolism ; Collagen - pharmacology ; Dendrites - drug effects ; Dendrites - metabolism ; Immune system ; Lysosomes - drug effects ; Lysosomes - metabolism ; Macrophages - cytology ; Macrophages - drug effects ; Mice ; Mice, Inbred C57BL ; Models, Biological ; OPG ; OSTEOCLASTOGENESIS ; Osteoclasts - cytology ; Osteoclasts - drug effects ; Osteoclasts - metabolism ; OSTEOCYTE ; Osteocytes - cytology ; Osteocytes - drug effects ; Osteocytes - metabolism ; Osteogenesis - drug effects ; Osteoprotegerin - metabolism ; Porosity ; Protein Transport - drug effects ; RANK Ligand - metabolism ; RANKL ; Regulation ; Rodents ; Subcellular Fractions - drug effects ; Subcellular Fractions - metabolism ; SUBCELLULAR TRAFFIC</subject><ispartof>Journal of bone and mineral research, 2013-09, Vol.28 (9), p.1936-1949</ispartof><rights>2013 American Society for Bone and Mineral Research</rights><rights>2013 American Society for Bone and Mineral Research.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4871-e83b63ff5b6bb16112e2e5e9ccfdaa3d6df7fc7fea2f1b2a7fa66e6e48e12bcd3</citedby><cites>FETCH-LOGICAL-c4871-e83b63ff5b6bb16112e2e5e9ccfdaa3d6df7fc7fea2f1b2a7fa66e6e48e12bcd3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fjbmr.1941$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fjbmr.1941$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>315,786,790,27957,27958,50923,51032</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23529793$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Honma, Masashi</creatorcontrib><creatorcontrib>Ikebuchi, Yuki</creatorcontrib><creatorcontrib>Kariya, Yoshiaki</creatorcontrib><creatorcontrib>Hayashi, Madoka</creatorcontrib><creatorcontrib>Hayashi, Naoki</creatorcontrib><creatorcontrib>Aoki, Shigeki</creatorcontrib><creatorcontrib>Suzuki, Hiroshi</creatorcontrib><title>RANKL subcellular trafficking and regulatory mechanisms in osteocytes</title><title>Journal of bone and mineral research</title><addtitle>J Bone Miner Res</addtitle><description>ABSTRACT
The receptor activator of the NF‐κB 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.</description><subject>Animals</subject><subject>Bone Marrow Cells - cytology</subject><subject>Bone Marrow Cells - drug effects</subject><subject>Bone Marrow Cells - metabolism</subject><subject>Cell Communication - drug effects</subject><subject>Cell Culture Techniques</subject><subject>Cell Membrane - drug effects</subject><subject>Cell Membrane - metabolism</subject><subject>Collagen - pharmacology</subject><subject>Dendrites - drug effects</subject><subject>Dendrites - metabolism</subject><subject>Immune system</subject><subject>Lysosomes - drug effects</subject><subject>Lysosomes - metabolism</subject><subject>Macrophages - cytology</subject><subject>Macrophages - drug effects</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Models, Biological</subject><subject>OPG</subject><subject>OSTEOCLASTOGENESIS</subject><subject>Osteoclasts - cytology</subject><subject>Osteoclasts - drug effects</subject><subject>Osteoclasts - metabolism</subject><subject>OSTEOCYTE</subject><subject>Osteocytes - cytology</subject><subject>Osteocytes - drug effects</subject><subject>Osteocytes - metabolism</subject><subject>Osteogenesis - drug effects</subject><subject>Osteoprotegerin - metabolism</subject><subject>Porosity</subject><subject>Protein Transport - drug effects</subject><subject>RANK Ligand - metabolism</subject><subject>RANKL</subject><subject>Regulation</subject><subject>Rodents</subject><subject>Subcellular Fractions - drug effects</subject><subject>Subcellular Fractions - metabolism</subject><subject>SUBCELLULAR TRAFFIC</subject><issn>0884-0431</issn><issn>1523-4681</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><recordid>eNqN0ctKxDAUBuAgio6XhS8gBTe6qJOTtGm71MH7qDDoOiTpiXbsZUxapG9vx1EXguAqcPj4OSc_IftAT4BSNp7ryp1AFsEaGUHMeBiJFNbJiKZpFNKIwxbZ9n5OKRWxEJtki_GYZUnGR-R8dnp_Ow18pw2WZVcqF7ROWVuY16J-DlSdBw6fh3nbuD6o0LyouvCVD4o6aHyLjelb9Ltkw6rS497Xu0OeLs4fJ1fh9OHyenI6DU2UJhBiyrXg1sZaaA0CgCHDGDNjbK4Uz0VuE2sSi4pZ0EwlVgmBAqMUgWmT8x1ytMpduOatQ9_KqvDLxVWNTeclRDxjkIKI_0GZSGIQjA308BedN52rh0M-FbAUEj6o45UyrvHeoZULV1TK9RKoXNYglzXIZQ2DPfhK7HSF-Y_8_vcBjFfgvSix_ztJ3pzdzT4jPwBudZJh</recordid><startdate>201309</startdate><enddate>201309</enddate><creator>Honma, Masashi</creator><creator>Ikebuchi, Yuki</creator><creator>Kariya, Yoshiaki</creator><creator>Hayashi, Madoka</creator><creator>Hayashi, Naoki</creator><creator>Aoki, Shigeki</creator><creator>Suzuki, Hiroshi</creator><general>Wiley Subscription Services, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7TS</scope><scope>K9.</scope><scope>7X8</scope></search><sort><creationdate>201309</creationdate><title>RANKL subcellular trafficking and regulatory mechanisms in osteocytes</title><author>Honma, Masashi ; Ikebuchi, Yuki ; Kariya, Yoshiaki ; Hayashi, Madoka ; Hayashi, Naoki ; Aoki, Shigeki ; Suzuki, Hiroshi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4871-e83b63ff5b6bb16112e2e5e9ccfdaa3d6df7fc7fea2f1b2a7fa66e6e48e12bcd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animals</topic><topic>Bone Marrow Cells - cytology</topic><topic>Bone Marrow Cells - drug effects</topic><topic>Bone Marrow Cells - metabolism</topic><topic>Cell Communication - drug effects</topic><topic>Cell Culture Techniques</topic><topic>Cell Membrane - drug effects</topic><topic>Cell Membrane - metabolism</topic><topic>Collagen - pharmacology</topic><topic>Dendrites - drug effects</topic><topic>Dendrites - metabolism</topic><topic>Immune system</topic><topic>Lysosomes - drug effects</topic><topic>Lysosomes - metabolism</topic><topic>Macrophages - cytology</topic><topic>Macrophages - drug effects</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Models, Biological</topic><topic>OPG</topic><topic>OSTEOCLASTOGENESIS</topic><topic>Osteoclasts - cytology</topic><topic>Osteoclasts - drug effects</topic><topic>Osteoclasts - metabolism</topic><topic>OSTEOCYTE</topic><topic>Osteocytes - cytology</topic><topic>Osteocytes - drug effects</topic><topic>Osteocytes - metabolism</topic><topic>Osteogenesis - drug effects</topic><topic>Osteoprotegerin - metabolism</topic><topic>Porosity</topic><topic>Protein Transport - drug effects</topic><topic>RANK Ligand - metabolism</topic><topic>RANKL</topic><topic>Regulation</topic><topic>Rodents</topic><topic>Subcellular Fractions - drug effects</topic><topic>Subcellular Fractions - metabolism</topic><topic>SUBCELLULAR TRAFFIC</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Honma, Masashi</creatorcontrib><creatorcontrib>Ikebuchi, Yuki</creatorcontrib><creatorcontrib>Kariya, Yoshiaki</creatorcontrib><creatorcontrib>Hayashi, Madoka</creatorcontrib><creatorcontrib>Hayashi, Naoki</creatorcontrib><creatorcontrib>Aoki, Shigeki</creatorcontrib><creatorcontrib>Suzuki, Hiroshi</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Physical Education Index</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of bone and mineral research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Honma, Masashi</au><au>Ikebuchi, Yuki</au><au>Kariya, Yoshiaki</au><au>Hayashi, Madoka</au><au>Hayashi, Naoki</au><au>Aoki, Shigeki</au><au>Suzuki, Hiroshi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>RANKL subcellular trafficking and regulatory mechanisms in osteocytes</atitle><jtitle>Journal of bone and mineral research</jtitle><addtitle>J Bone Miner Res</addtitle><date>2013-09</date><risdate>2013</risdate><volume>28</volume><issue>9</issue><spage>1936</spage><epage>1949</epage><pages>1936-1949</pages><issn>0884-0431</issn><eissn>1523-4681</eissn><coden>JBMREJ</coden><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><notes>ObjectType-Article-2</notes><notes>ObjectType-Feature-1</notes><abstract>ABSTRACT
The receptor activator of the NF‐κB 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.</abstract><cop>United States</cop><pub>Wiley Subscription Services, Inc</pub><pmid>23529793</pmid><doi>10.1002/jbmr.1941</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| source | Wiley |
| subjects | Animals Bone Marrow Cells - cytology Bone Marrow Cells - drug effects Bone Marrow Cells - metabolism Cell Communication - drug effects Cell Culture Techniques Cell Membrane - drug effects Cell Membrane - metabolism Collagen - pharmacology Dendrites - drug effects Dendrites - metabolism Immune system Lysosomes - drug effects Lysosomes - metabolism Macrophages - cytology Macrophages - drug effects Mice Mice, Inbred C57BL Models, Biological OPG OSTEOCLASTOGENESIS Osteoclasts - cytology Osteoclasts - drug effects Osteoclasts - metabolism OSTEOCYTE Osteocytes - cytology Osteocytes - drug effects Osteocytes - metabolism Osteogenesis - drug effects Osteoprotegerin - metabolism Porosity Protein Transport - drug effects RANK Ligand - metabolism RANKL Regulation Rodents Subcellular Fractions - drug effects Subcellular Fractions - metabolism SUBCELLULAR TRAFFIC |
| title | RANKL subcellular trafficking and regulatory mechanisms in osteocytes |
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