Mechanosensory responses of osteocytes to physiological forces occur along processes and not cell body and require αVβ₃ integrin
Osteocytes in the lacunar–canalicular system of the bone are thought to be the cells that sense mechanical loading and transduce mechanical strain into biomechanical responses. The goal of this study was to evaluate the extent to which focal mechanical stimulation of osteocyte cell body and process...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2013-12, Vol.110 (52), p.21012-21017 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | Thi, Mia M. Suadicani, Sylvia O. Schaffler, Mitchell B. Weinbaum, Sheldon Spray, David C. |
| description | Osteocytes in the lacunar–canalicular system of the bone are thought to be the cells that sense mechanical loading and transduce mechanical strain into biomechanical responses. The goal of this study was to evaluate the extent to which focal mechanical stimulation of osteocyte cell body and process led to activation of the cells, and determine whether integrin attachments play a role in osteocyte activation. We use a novel Stokesian fluid stimulus probe to hydrodynamically load osteocyte processes vs. cell bodies in murine long bone osteocyte Y4 (MLO-Y4) cells with physiological-level forces |
| doi_str_mv | 10.1073/pnas.1321210110 |
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The goal of this study was to evaluate the extent to which focal mechanical stimulation of osteocyte cell body and process led to activation of the cells, and determine whether integrin attachments play a role in osteocyte activation. We use a novel Stokesian fluid stimulus probe to hydrodynamically load osteocyte processes vs. cell bodies in murine long bone osteocyte Y4 (MLO-Y4) cells with physiological-level forces <10 pN without probe contact, and measured intracellular Ca ²⁺ responses. Our results indicate that osteocyte processes are extremely responsive to piconewton-level mechanical loading, whereas the osteocyte cell body and processes with no local attachment sites are not. Ca ²⁺ signals generated at stimulated sites spread within the processes with average velocity of 5.6 μm/s. Using the near-infrared fluorescence probe IntegriSense 750, we demonstrated that inhibition of α Vβ ₃ integrin attachment sites compromises the response to probe stimulation. Moreover, using apyrase, an extracellular ATP scavenger, we showed that Ca ²⁺ signaling from the osteocyte process to the cell body was greatly diminished, and thus dependent on ATP-mediated autocrine signaling. These findings are consistent with the hypothesis that osteocytes in situ are highly polarized cells, where mechanotransduction occurs at substrate attachment sites along the processes at force levels predicted to occur at integrin attachment sites in vivo. We also demonstrate the essential role of α Vβ ₃ integrin in osteocyte-polarized mechanosensing and mechanotransduction.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1321210110</identifier><identifier>PMID: 24324138</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>adenosine triphosphate ; Animals ; apyrase ; autocrine signaling ; Biological Sciences ; Biomechanical Phenomena ; biomechanics ; Bone and Bones - cytology ; Bones ; Calcium ; Calcium - metabolism ; Cell membranes ; Cell physiology ; Cell Surface Extensions - physiology ; Fluid flow ; Fluid mechanics ; Fluorescence ; Hydrodynamics ; Image Processing, Computer-Assisted ; Imaging ; Integrin alphaVbeta3 - metabolism ; Integrins ; mechanical stress ; mechanotransduction ; Mechanotransduction, Cellular - physiology ; Mice ; Osteocytes ; Osteocytes - cytology ; Osteocytes - physiology ; Physical Sciences ; Physiological stimulation</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2013-12, Vol.110 (52), p.21012-21017</ispartof><rights>copyright © 1993–2008 National Academy of Sciences of the United States of America</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/110/52.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/23761847$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/23761847$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24324138$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Thi, Mia M.</creatorcontrib><creatorcontrib>Suadicani, Sylvia O.</creatorcontrib><creatorcontrib>Schaffler, Mitchell B.</creatorcontrib><creatorcontrib>Weinbaum, Sheldon</creatorcontrib><creatorcontrib>Spray, David C.</creatorcontrib><title>Mechanosensory responses of osteocytes to physiological forces occur along processes and not cell body and require αVβ₃ integrin</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Osteocytes in the lacunar–canalicular system of the bone are thought to be the cells that sense mechanical loading and transduce mechanical strain into biomechanical responses. The goal of this study was to evaluate the extent to which focal mechanical stimulation of osteocyte cell body and process led to activation of the cells, and determine whether integrin attachments play a role in osteocyte activation. We use a novel Stokesian fluid stimulus probe to hydrodynamically load osteocyte processes vs. cell bodies in murine long bone osteocyte Y4 (MLO-Y4) cells with physiological-level forces <10 pN without probe contact, and measured intracellular Ca ²⁺ responses. Our results indicate that osteocyte processes are extremely responsive to piconewton-level mechanical loading, whereas the osteocyte cell body and processes with no local attachment sites are not. Ca ²⁺ signals generated at stimulated sites spread within the processes with average velocity of 5.6 μm/s. Using the near-infrared fluorescence probe IntegriSense 750, we demonstrated that inhibition of α Vβ ₃ integrin attachment sites compromises the response to probe stimulation. Moreover, using apyrase, an extracellular ATP scavenger, we showed that Ca ²⁺ signaling from the osteocyte process to the cell body was greatly diminished, and thus dependent on ATP-mediated autocrine signaling. These findings are consistent with the hypothesis that osteocytes in situ are highly polarized cells, where mechanotransduction occurs at substrate attachment sites along the processes at force levels predicted to occur at integrin attachment sites in vivo. We also demonstrate the essential role of α Vβ ₃ integrin in osteocyte-polarized mechanosensing and mechanotransduction.</description><subject>adenosine triphosphate</subject><subject>Animals</subject><subject>apyrase</subject><subject>autocrine signaling</subject><subject>Biological Sciences</subject><subject>Biomechanical Phenomena</subject><subject>biomechanics</subject><subject>Bone and Bones - cytology</subject><subject>Bones</subject><subject>Calcium</subject><subject>Calcium - metabolism</subject><subject>Cell membranes</subject><subject>Cell physiology</subject><subject>Cell Surface Extensions - physiology</subject><subject>Fluid flow</subject><subject>Fluid mechanics</subject><subject>Fluorescence</subject><subject>Hydrodynamics</subject><subject>Image Processing, Computer-Assisted</subject><subject>Imaging</subject><subject>Integrin alphaVbeta3 - metabolism</subject><subject>Integrins</subject><subject>mechanical stress</subject><subject>mechanotransduction</subject><subject>Mechanotransduction, Cellular - physiology</subject><subject>Mice</subject><subject>Osteocytes</subject><subject>Osteocytes - cytology</subject><subject>Osteocytes - physiology</subject><subject>Physical Sciences</subject><subject>Physiological stimulation</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc1u1DAUhSMEokNhzQrwkk3K9U9sZ4NUVfxJRSygbC3HuZlJlbFTO0GaLfBC8CB9CJ4EhxkKrFhZvufz0bk-RfGQwgkFxZ-N3qYTyhllFCiFW8WKQk1LKWq4XawAmCq1YOKouJfSJQDUlYa7xRETnAnK9ar4-hbdxvqQ0KcQdyRiGoNPmEjoSEgTBreb8m0KZNzsUh-GsO6dHUgXolso5-ZI7BD8mowx5NHy1vqW-DARh8NAmtDufk0iXs19RHL97eP19x-fv5DeT7iOvb9f3OnskPDB4TwuLl6--HD2ujx_9-rN2el52TFdTaWFjirtGnRQq7rBiikthaxVJ5y1oBttOa8Adde06JC3TAlZMUspyhYY8uPi-d53nJsttg79FO1gxthvbdyZYHvzr-L7jVmHT4ZrJVnFssHTg0EMVzOmyWz7tCxpPYY5GaqBU8YU1_9Hc0VKVEzKjD7-O9ZNnt8tZYAcgFz3jZz7NhUzS_NLskd75DJNIf6x4EpSLVTWn-z1zgZj86cnc_GeAZUAVFDBKP8JS4y31A</recordid><startdate>20131224</startdate><enddate>20131224</enddate><creator>Thi, Mia M.</creator><creator>Suadicani, Sylvia O.</creator><creator>Schaffler, Mitchell B.</creator><creator>Weinbaum, Sheldon</creator><creator>Spray, David C.</creator><general>National Academy of Sciences</general><general>NATIONAL ACADEMY OF SCIENCES</general><general>National Acad Sciences</general><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope><scope>7S9</scope><scope>L.6</scope><scope>5PM</scope></search><sort><creationdate>20131224</creationdate><title>Mechanosensory responses of osteocytes to physiological forces occur along processes and not cell body and require αVβ₃ integrin</title><author>Thi, Mia M. ; Suadicani, Sylvia O. ; Schaffler, Mitchell B. ; Weinbaum, Sheldon ; Spray, David C.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-f285t-a0f178cbec0979be527864697f4caa08b8a3350e8fbdece3d274652a11e6d02e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>adenosine triphosphate</topic><topic>Animals</topic><topic>apyrase</topic><topic>autocrine signaling</topic><topic>Biological Sciences</topic><topic>Biomechanical Phenomena</topic><topic>biomechanics</topic><topic>Bone and Bones - cytology</topic><topic>Bones</topic><topic>Calcium</topic><topic>Calcium - metabolism</topic><topic>Cell membranes</topic><topic>Cell physiology</topic><topic>Cell Surface Extensions - physiology</topic><topic>Fluid flow</topic><topic>Fluid mechanics</topic><topic>Fluorescence</topic><topic>Hydrodynamics</topic><topic>Image Processing, Computer-Assisted</topic><topic>Imaging</topic><topic>Integrin alphaVbeta3 - metabolism</topic><topic>Integrins</topic><topic>mechanical stress</topic><topic>mechanotransduction</topic><topic>Mechanotransduction, Cellular - physiology</topic><topic>Mice</topic><topic>Osteocytes</topic><topic>Osteocytes - cytology</topic><topic>Osteocytes - physiology</topic><topic>Physical Sciences</topic><topic>Physiological stimulation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Thi, Mia M.</creatorcontrib><creatorcontrib>Suadicani, Sylvia O.</creatorcontrib><creatorcontrib>Schaffler, Mitchell B.</creatorcontrib><creatorcontrib>Weinbaum, Sheldon</creatorcontrib><creatorcontrib>Spray, David C.</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><collection>AGRICOLA</collection><collection>AGRICOLA - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Thi, Mia M.</au><au>Suadicani, Sylvia O.</au><au>Schaffler, Mitchell B.</au><au>Weinbaum, Sheldon</au><au>Spray, David C.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mechanosensory responses of osteocytes to physiological forces occur along processes and not cell body and require αVβ₃ integrin</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2013-12-24</date><risdate>2013</risdate><volume>110</volume><issue>52</issue><spage>21012</spage><epage>21017</epage><pages>21012-21017</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>Osteocytes in the lacunar–canalicular system of the bone are thought to be the cells that sense mechanical loading and transduce mechanical strain into biomechanical responses. The goal of this study was to evaluate the extent to which focal mechanical stimulation of osteocyte cell body and process led to activation of the cells, and determine whether integrin attachments play a role in osteocyte activation. We use a novel Stokesian fluid stimulus probe to hydrodynamically load osteocyte processes vs. cell bodies in murine long bone osteocyte Y4 (MLO-Y4) cells with physiological-level forces <10 pN without probe contact, and measured intracellular Ca ²⁺ responses. Our results indicate that osteocyte processes are extremely responsive to piconewton-level mechanical loading, whereas the osteocyte cell body and processes with no local attachment sites are not. Ca ²⁺ signals generated at stimulated sites spread within the processes with average velocity of 5.6 μm/s. Using the near-infrared fluorescence probe IntegriSense 750, we demonstrated that inhibition of α Vβ ₃ integrin attachment sites compromises the response to probe stimulation. Moreover, using apyrase, an extracellular ATP scavenger, we showed that Ca ²⁺ signaling from the osteocyte process to the cell body was greatly diminished, and thus dependent on ATP-mediated autocrine signaling. These findings are consistent with the hypothesis that osteocytes in situ are highly polarized cells, where mechanotransduction occurs at substrate attachment sites along the processes at force levels predicted to occur at integrin attachment sites in vivo. We also demonstrate the essential role of α Vβ ₃ integrin in osteocyte-polarized mechanosensing and mechanotransduction.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>24324138</pmid><doi>10.1073/pnas.1321210110</doi><tpages>6</tpages></addata></record> |
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| subjects | adenosine triphosphate Animals apyrase autocrine signaling Biological Sciences Biomechanical Phenomena biomechanics Bone and Bones - cytology Bones Calcium Calcium - metabolism Cell membranes Cell physiology Cell Surface Extensions - physiology Fluid flow Fluid mechanics Fluorescence Hydrodynamics Image Processing, Computer-Assisted Imaging Integrin alphaVbeta3 - metabolism Integrins mechanical stress mechanotransduction Mechanotransduction, Cellular - physiology Mice Osteocytes Osteocytes - cytology Osteocytes - physiology Physical Sciences Physiological stimulation |
| title | Mechanosensory responses of osteocytes to physiological forces occur along processes and not cell body and require αVβ₃ integrin |
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