FOXO are required for intervertebral disk homeostasis during aging and their deficiency promotes disk degeneration
Intervertebral disk (IVD) degeneration is a prevalent age‐associated musculoskeletal disorder and a major cause of chronic low back pain. Aging is the main risk factor for the disease, but the molecular mechanisms regulating IVD homeostasis during aging are unknown. The aim of this study was to inve...
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| Veröffentlicht in: | Aging cell 2018-10, Vol.17 (5), p.e12800-n/a |
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| creator | Alvarez‐Garcia, Oscar Matsuzaki, Tokio Olmer, Merissa Miyata, Kohei Mokuda, Sho Sakai, Daisuke Masuda, Koichi Asahara, Hiroshi Lotz, Martin K. |
| description | Intervertebral disk (IVD) degeneration is a prevalent age‐associated musculoskeletal disorder and a major cause of chronic low back pain. Aging is the main risk factor for the disease, but the molecular mechanisms regulating IVD homeostasis during aging are unknown. The aim of this study was to investigate the function of FOXO, a family of transcription factors linked to aging and longevity, in IVD aging and age‐related degeneration. Conditional deletion of all FOXO isoforms (FOXO1, 3, and 4) in IVD using the Col2a1Cre and AcanCreER mouse resulted in spontaneous development of IVD degeneration that was driven by severe cell loss in the nucleus pulposus (NP) and cartilaginous endplates (EP). Conditional deletion of individual FOXO in mature mice showed that FOXO1 and FOXO3 are the dominant isoforms and have redundant functions in promoting IVD homeostasis. Gene expression analyses indicated impaired autophagy and reduced antioxidant defenses in the NP of FOXO‐deficient IVD. In primary human NP cells, FOXO directly regulated autophagy and adaptation to hypoxia and promoted resistance to oxidative and inflammatory stress. Our findings demonstrate that FOXO are critical regulators of IVD homeostasis during aging and suggest that maintaining or restoring FOXO expression can be a therapeutic strategy to promote healthy IVD aging and delay the onset of IVD degeneration. |
| doi_str_mv | 10.1111/acel.12800 |
| format | Article |
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Aging is the main risk factor for the disease, but the molecular mechanisms regulating IVD homeostasis during aging are unknown. The aim of this study was to investigate the function of FOXO, a family of transcription factors linked to aging and longevity, in IVD aging and age‐related degeneration. Conditional deletion of all FOXO isoforms (FOXO1, 3, and 4) in IVD using the Col2a1Cre and AcanCreER mouse resulted in spontaneous development of IVD degeneration that was driven by severe cell loss in the nucleus pulposus (NP) and cartilaginous endplates (EP). Conditional deletion of individual FOXO in mature mice showed that FOXO1 and FOXO3 are the dominant isoforms and have redundant functions in promoting IVD homeostasis. Gene expression analyses indicated impaired autophagy and reduced antioxidant defenses in the NP of FOXO‐deficient IVD. In primary human NP cells, FOXO directly regulated autophagy and adaptation to hypoxia and promoted resistance to oxidative and inflammatory stress. Our findings demonstrate that FOXO are critical regulators of IVD homeostasis during aging and suggest that maintaining or restoring FOXO expression can be a therapeutic strategy to promote healthy IVD aging and delay the onset of IVD degeneration.</description><identifier>ISSN: 1474-9718</identifier><identifier>EISSN: 1474-9726</identifier><identifier>DOI: 10.1111/acel.12800</identifier><identifier>PMID: 29963746</identifier><language>eng</language><publisher>England: John Wiley & Sons, Inc</publisher><subject>Aging ; Aging - metabolism ; Analysis ; Animals ; Antioxidants ; Autophagy ; Backache ; Cells, Cultured ; Clonal deletion ; Degeneration ; Forkhead Box Protein O1 - deficiency ; Forkhead Box Protein O1 - genetics ; Forkhead Box Protein O1 - metabolism ; Forkhead Box Protein O3 - deficiency ; Forkhead Box Protein O3 - genetics ; Forkhead Box Protein O3 - metabolism ; Forkhead protein ; FOXO ; FOXO1 protein ; FOXO3 protein ; Gene expression ; Homeostasis ; Humans ; Hypoxia ; Inflammation ; Intervertebral Disc - metabolism ; Intervertebral discs ; intervertebral disk ; Isoforms ; Low back pain ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Molecular modelling ; Musculoskeletal diseases ; Nucleus pulposus ; Original ; Pain ; Phagocytosis ; Physiological aspects ; Transcription factors</subject><ispartof>Aging cell, 2018-10, Vol.17 (5), p.e12800-n/a</ispartof><rights>2018 The Authors. published by the Anatomical Society and John Wiley & Sons Ltd.</rights><rights>2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.</rights><rights>COPYRIGHT 2018 John Wiley & Sons, Inc.</rights><rights>Copyright © 2018 The Anatomical Society and John Wiley & Sons Ltd.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5150-952a0ee24f34d38ae0a1fd9b0374dba4f0f62d2aa40a1bb33df5155b878898e83</citedby><cites>FETCH-LOGICAL-c5150-952a0ee24f34d38ae0a1fd9b0374dba4f0f62d2aa40a1bb33df5155b878898e83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156454/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156454/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,1417,11562,27924,27925,45574,45575,46052,46476,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29963746$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Alvarez‐Garcia, Oscar</creatorcontrib><creatorcontrib>Matsuzaki, Tokio</creatorcontrib><creatorcontrib>Olmer, Merissa</creatorcontrib><creatorcontrib>Miyata, Kohei</creatorcontrib><creatorcontrib>Mokuda, Sho</creatorcontrib><creatorcontrib>Sakai, Daisuke</creatorcontrib><creatorcontrib>Masuda, Koichi</creatorcontrib><creatorcontrib>Asahara, Hiroshi</creatorcontrib><creatorcontrib>Lotz, Martin K.</creatorcontrib><title>FOXO are required for intervertebral disk homeostasis during aging and their deficiency promotes disk degeneration</title><title>Aging cell</title><addtitle>Aging Cell</addtitle><description>Intervertebral disk (IVD) degeneration is a prevalent age‐associated musculoskeletal disorder and a major cause of chronic low back pain. Aging is the main risk factor for the disease, but the molecular mechanisms regulating IVD homeostasis during aging are unknown. The aim of this study was to investigate the function of FOXO, a family of transcription factors linked to aging and longevity, in IVD aging and age‐related degeneration. Conditional deletion of all FOXO isoforms (FOXO1, 3, and 4) in IVD using the Col2a1Cre and AcanCreER mouse resulted in spontaneous development of IVD degeneration that was driven by severe cell loss in the nucleus pulposus (NP) and cartilaginous endplates (EP). Conditional deletion of individual FOXO in mature mice showed that FOXO1 and FOXO3 are the dominant isoforms and have redundant functions in promoting IVD homeostasis. Gene expression analyses indicated impaired autophagy and reduced antioxidant defenses in the NP of FOXO‐deficient IVD. In primary human NP cells, FOXO directly regulated autophagy and adaptation to hypoxia and promoted resistance to oxidative and inflammatory stress. Our findings demonstrate that FOXO are critical regulators of IVD homeostasis during aging and suggest that maintaining or restoring FOXO expression can be a therapeutic strategy to promote healthy IVD aging and delay the onset of IVD degeneration.</description><subject>Aging</subject><subject>Aging - metabolism</subject><subject>Analysis</subject><subject>Animals</subject><subject>Antioxidants</subject><subject>Autophagy</subject><subject>Backache</subject><subject>Cells, Cultured</subject><subject>Clonal deletion</subject><subject>Degeneration</subject><subject>Forkhead Box Protein O1 - deficiency</subject><subject>Forkhead Box Protein O1 - genetics</subject><subject>Forkhead Box Protein O1 - metabolism</subject><subject>Forkhead Box Protein O3 - deficiency</subject><subject>Forkhead Box Protein O3 - genetics</subject><subject>Forkhead Box Protein O3 - metabolism</subject><subject>Forkhead protein</subject><subject>FOXO</subject><subject>FOXO1 protein</subject><subject>FOXO3 protein</subject><subject>Gene expression</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Hypoxia</subject><subject>Inflammation</subject><subject>Intervertebral Disc - metabolism</subject><subject>Intervertebral discs</subject><subject>intervertebral disk</subject><subject>Isoforms</subject><subject>Low back pain</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Mice, Transgenic</subject><subject>Molecular modelling</subject><subject>Musculoskeletal diseases</subject><subject>Nucleus pulposus</subject><subject>Original</subject><subject>Pain</subject><subject>Phagocytosis</subject><subject>Physiological aspects</subject><subject>Transcription factors</subject><issn>1474-9718</issn><issn>1474-9726</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>EIF</sourceid><recordid>eNp9Ul1rHCEUldLQpNu-9AcUoS-hsFt1nA9fCsuSpIWFfWmhb-KM11nTGd3oTML--7iZZNuUUAUVPedc7-Eg9IGSBU3ji2qgW1BWEfIKnVFe8rkoWfH6eKbVKXob4zUhtBQke4NOmRBFVvLiDIXLza8NVgFwgJvRBtDY-ICtGyDcQhigDqrD2sbfeOt78HFQ0Uasx2Bdi1X7sDqNhy3YgDUY21hwzR7vgu_9AHHiamjBQVCD9e4dOjGqi_D-cZ-hn5cXP1bf5uvN1ffVcj1vcpqTuciZIgCMm4zrrFJAFDVa1CR9XNeKG2IKpplSPD3UdZZpk3h5XZVVJSqoshn6OunuxroH3YAbUi9yF2yvwl56ZeXzF2e3svW3sqB5wXOeBM4fBYK_GSEOsrcxed0pB36MkpFkIuUsEwn66R_otR-DS-1JRikjTGQ5-YNqVQfSOuNT3eYgKpclKauclElthhYvoNLU0NvGu-Rxun9G-DwRmuBjDGCOPVIiDwmRh4TIh4Qk8Me_XTlCnyKRAHQC3KUy-_9IyeXqYj2J3gMpYsbr</recordid><startdate>201810</startdate><enddate>201810</enddate><creator>Alvarez‐Garcia, Oscar</creator><creator>Matsuzaki, Tokio</creator><creator>Olmer, Merissa</creator><creator>Miyata, Kohei</creator><creator>Mokuda, Sho</creator><creator>Sakai, Daisuke</creator><creator>Masuda, Koichi</creator><creator>Asahara, Hiroshi</creator><creator>Lotz, Martin K.</creator><general>John Wiley & Sons, Inc</general><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>WIN</scope><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>7TK</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>201810</creationdate><title>FOXO are required for intervertebral disk homeostasis during aging and their deficiency promotes disk degeneration</title><author>Alvarez‐Garcia, Oscar ; Matsuzaki, Tokio ; Olmer, Merissa ; Miyata, Kohei ; Mokuda, Sho ; Sakai, Daisuke ; Masuda, Koichi ; Asahara, Hiroshi ; Lotz, Martin K.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5150-952a0ee24f34d38ae0a1fd9b0374dba4f0f62d2aa40a1bb33df5155b878898e83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Aging</topic><topic>Aging - metabolism</topic><topic>Analysis</topic><topic>Animals</topic><topic>Antioxidants</topic><topic>Autophagy</topic><topic>Backache</topic><topic>Cells, Cultured</topic><topic>Clonal deletion</topic><topic>Degeneration</topic><topic>Forkhead Box Protein O1 - deficiency</topic><topic>Forkhead Box Protein O1 - genetics</topic><topic>Forkhead Box Protein O1 - metabolism</topic><topic>Forkhead Box Protein O3 - deficiency</topic><topic>Forkhead Box Protein O3 - genetics</topic><topic>Forkhead Box Protein O3 - metabolism</topic><topic>Forkhead protein</topic><topic>FOXO</topic><topic>FOXO1 protein</topic><topic>FOXO3 protein</topic><topic>Gene expression</topic><topic>Homeostasis</topic><topic>Humans</topic><topic>Hypoxia</topic><topic>Inflammation</topic><topic>Intervertebral Disc - metabolism</topic><topic>Intervertebral discs</topic><topic>intervertebral disk</topic><topic>Isoforms</topic><topic>Low back pain</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Mice, Transgenic</topic><topic>Molecular modelling</topic><topic>Musculoskeletal diseases</topic><topic>Nucleus pulposus</topic><topic>Original</topic><topic>Pain</topic><topic>Phagocytosis</topic><topic>Physiological aspects</topic><topic>Transcription factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Alvarez‐Garcia, Oscar</creatorcontrib><creatorcontrib>Matsuzaki, Tokio</creatorcontrib><creatorcontrib>Olmer, Merissa</creatorcontrib><creatorcontrib>Miyata, Kohei</creatorcontrib><creatorcontrib>Mokuda, Sho</creatorcontrib><creatorcontrib>Sakai, Daisuke</creatorcontrib><creatorcontrib>Masuda, Koichi</creatorcontrib><creatorcontrib>Asahara, Hiroshi</creatorcontrib><creatorcontrib>Lotz, Martin K.</creatorcontrib><collection>Wiley Online Library (Open Access Collection)</collection><collection>Wiley Online Library (Open Access Collection)</collection><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>Neurosciences Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Aging cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Alvarez‐Garcia, Oscar</au><au>Matsuzaki, Tokio</au><au>Olmer, Merissa</au><au>Miyata, Kohei</au><au>Mokuda, Sho</au><au>Sakai, Daisuke</au><au>Masuda, Koichi</au><au>Asahara, Hiroshi</au><au>Lotz, Martin K.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>FOXO are required for intervertebral disk homeostasis during aging and their deficiency promotes disk degeneration</atitle><jtitle>Aging cell</jtitle><addtitle>Aging Cell</addtitle><date>2018-10</date><risdate>2018</risdate><volume>17</volume><issue>5</issue><spage>e12800</spage><epage>n/a</epage><pages>e12800-n/a</pages><issn>1474-9718</issn><eissn>1474-9726</eissn><abstract>Intervertebral disk (IVD) degeneration is a prevalent age‐associated musculoskeletal disorder and a major cause of chronic low back pain. Aging is the main risk factor for the disease, but the molecular mechanisms regulating IVD homeostasis during aging are unknown. The aim of this study was to investigate the function of FOXO, a family of transcription factors linked to aging and longevity, in IVD aging and age‐related degeneration. Conditional deletion of all FOXO isoforms (FOXO1, 3, and 4) in IVD using the Col2a1Cre and AcanCreER mouse resulted in spontaneous development of IVD degeneration that was driven by severe cell loss in the nucleus pulposus (NP) and cartilaginous endplates (EP). Conditional deletion of individual FOXO in mature mice showed that FOXO1 and FOXO3 are the dominant isoforms and have redundant functions in promoting IVD homeostasis. Gene expression analyses indicated impaired autophagy and reduced antioxidant defenses in the NP of FOXO‐deficient IVD. In primary human NP cells, FOXO directly regulated autophagy and adaptation to hypoxia and promoted resistance to oxidative and inflammatory stress. Our findings demonstrate that FOXO are critical regulators of IVD homeostasis during aging and suggest that maintaining or restoring FOXO expression can be a therapeutic strategy to promote healthy IVD aging and delay the onset of IVD degeneration.</abstract><cop>England</cop><pub>John Wiley & Sons, Inc</pub><pmid>29963746</pmid><doi>10.1111/acel.12800</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Aging Aging - metabolism Analysis Animals Antioxidants Autophagy Backache Cells, Cultured Clonal deletion Degeneration Forkhead Box Protein O1 - deficiency Forkhead Box Protein O1 - genetics Forkhead Box Protein O1 - metabolism Forkhead Box Protein O3 - deficiency Forkhead Box Protein O3 - genetics Forkhead Box Protein O3 - metabolism Forkhead protein FOXO FOXO1 protein FOXO3 protein Gene expression Homeostasis Humans Hypoxia Inflammation Intervertebral Disc - metabolism Intervertebral discs intervertebral disk Isoforms Low back pain Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Molecular modelling Musculoskeletal diseases Nucleus pulposus Original Pain Phagocytosis Physiological aspects Transcription factors |
| title | FOXO are required for intervertebral disk homeostasis during aging and their deficiency promotes disk degeneration |
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