Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy
Identifieur interne : 000814 ( Main/Exploration ); précédent : 000813; suivant : 000815Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy
Auteurs : Uxía Nogueira-Recalde [Espagne] ; Irene Lorenzo-G Mez [Espagne] ; Francisco J. Blanco [Espagne] ; María I. Loza [Espagne] ; Diego Grassi [France] ; Valery Shirinsky [Russie] ; Ivan Shirinsky [Russie] ; Martin Lotz [États-Unis] ; Paul D. Robbins [États-Unis] ; Eduardo Domínguez [Espagne] ; Beatriz Caramés [Espagne]Source :
- EBioMedicine [ 2352-3964 ] ; 2019.
Abstract
Ageing-related failure of homeostasis mechanisms contributes to articular cartilage degeneration and osteoarthritis (OA), for which disease-modifying treatments are not available. Our objective was to identify molecules to prevent OA by regulating chondrocyte senescence and autophagy.
Human chondrocytes with IL-6 induced senescence and autophagy suppression and SA-β-gal as a reporter of senescence and LC3 as reporter of autophagic flux were used to screen the Prestwick Chemical Library of approved drugs. Preclinical cellular, tissue and blood from OA and blood from OA and ageing models were used to test the efficacy and relevance of activating PPARα related to cartilage degeneration.
Senotherapeutic molecules with pro-autophagic activity were identified. Fenofibrate (FN), a PPARα agonist used for dyslipidaemias in humans, reduced the number of senescent cells
These results demonstrate that FDA-approved fibrate drugs targeting lipid metabolism protect against cartilage degeneration seen with ageing and OA. Thus, these drugs could have immediate clinically utility for age-related cartilage degeneration and OA treatment.
This study was supported by Instituto de Salud Carlos III- Ministerio de Ciencia, Innovación y Universidades, Spain, Plan Estatal 2013–2016 and Fondo Europeo de Desarrollo Regional (FEDER),
Url:
DOI: 10.1016/j.ebiom.2019.06.049
PubMed: 31285188
PubMed Central: 6642320
Affiliations:
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Blanco and Beatriz Caramés, Grupo de Biología del Cartílago, Servicio de Reumatología, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complejo Hospitalario Universitario de A Coruña, Sergas, A Coruña</wicri:regionArea><wicri:noRegion>A Coruña</wicri:noRegion></affiliation></author><author><name sortKey="Lorenzo G Mez, Irene" sort="Lorenzo G Mez, Irene" uniqKey="Lorenzo G Mez I" first="Irene" last="Lorenzo-G Mez">Irene Lorenzo-G Mez</name><affiliation wicri:level="1"><nlm:aff id="af0005">Uxía Nogueira-Recalde, Irene Lorenzo Gómez, Francisco J. Blanco and Beatriz Caramés, Grupo de Biología del Cartílago, Servicio de Reumatología, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complejo Hospitalario Universitario de A Coruña, Sergas, A Coruña, Spain</nlm:aff><country xml:lang="fr">Espagne</country><wicri:regionArea>Uxía Nogueira-Recalde, Irene Lorenzo Gómez, Francisco J. 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Robbins</name><affiliation wicri:level="1"><nlm:aff id="af0030">Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN</wicri:regionArea><wicri:noRegion>MN</wicri:noRegion></affiliation></author><author><name sortKey="Dominguez, Eduardo" sort="Dominguez, Eduardo" uniqKey="Dominguez E" first="Eduardo" last="Domínguez">Eduardo Domínguez</name><affiliation wicri:level="1"><nlm:aff id="af0010">Eduardo Domínguez: Biofarma Research Group, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Universidad de Santiago de Compostela, Spain</nlm:aff><country xml:lang="fr">Espagne</country><wicri:regionArea>Eduardo Domínguez: Biofarma Research Group, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Universidad de Santiago de Compostela</wicri:regionArea><wicri:noRegion>Universidad de Santiago de Compostela</wicri:noRegion></affiliation></author><author><name sortKey="Carames, Beatriz" sort="Carames, Beatriz" uniqKey="Carames B" first="Beatriz" last="Caramés">Beatriz Caramés</name><affiliation wicri:level="1"><nlm:aff id="af0005">Uxía Nogueira-Recalde, Irene Lorenzo Gómez, Francisco J. Blanco and Beatriz Caramés, Grupo de Biología del Cartílago, Servicio de Reumatología, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complejo Hospitalario Universitario de A Coruña, Sergas, A Coruña, Spain</nlm:aff><country xml:lang="fr">Espagne</country><wicri:regionArea>Uxía Nogueira-Recalde, Irene Lorenzo Gómez, Francisco J. 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Blanco and Beatriz Caramés, Grupo de Biología del Cartílago, Servicio de Reumatología, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complejo Hospitalario Universitario de A Coruña, Sergas, A Coruña, Spain</nlm:aff><country xml:lang="fr">Espagne</country><wicri:regionArea>Uxía Nogueira-Recalde, Irene Lorenzo Gómez, Francisco J. Blanco and Beatriz Caramés, Grupo de Biología del Cartílago, Servicio de Reumatología, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complejo Hospitalario Universitario de A Coruña, Sergas, A Coruña</wicri:regionArea><wicri:noRegion>A Coruña</wicri:noRegion></affiliation></author><author><name sortKey="Lorenzo G Mez, Irene" sort="Lorenzo G Mez, Irene" uniqKey="Lorenzo G Mez I" first="Irene" last="Lorenzo-G Mez">Irene Lorenzo-G Mez</name><affiliation wicri:level="1"><nlm:aff id="af0005">Uxía Nogueira-Recalde, Irene Lorenzo Gómez, Francisco J. Blanco and Beatriz Caramés, Grupo de Biología del Cartílago, Servicio de Reumatología, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complejo Hospitalario Universitario de A Coruña, Sergas, A Coruña, Spain</nlm:aff><country xml:lang="fr">Espagne</country><wicri:regionArea>Uxía Nogueira-Recalde, Irene Lorenzo Gómez, Francisco J. Blanco and Beatriz Caramés, Grupo de Biología del Cartílago, Servicio de Reumatología, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complejo Hospitalario Universitario de A Coruña, Sergas, A Coruña</wicri:regionArea><wicri:noRegion>A Coruña</wicri:noRegion></affiliation></author><author><name sortKey="Blanco, Francisco J" sort="Blanco, Francisco J" uniqKey="Blanco F" first="Francisco J." last="Blanco">Francisco J. Blanco</name><affiliation wicri:level="1"><nlm:aff id="af0005">Uxía Nogueira-Recalde, Irene Lorenzo Gómez, Francisco J. Blanco and Beatriz Caramés, Grupo de Biología del Cartílago, Servicio de Reumatología, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complejo Hospitalario Universitario de A Coruña, Sergas, A Coruña, Spain</nlm:aff><country xml:lang="fr">Espagne</country><wicri:regionArea>Uxía Nogueira-Recalde, Irene Lorenzo Gómez, Francisco J. Blanco and Beatriz Caramés, Grupo de Biología del Cartílago, Servicio de Reumatología, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complejo Hospitalario Universitario de A Coruña, Sergas, A Coruña</wicri:regionArea><wicri:noRegion>A Coruña</wicri:noRegion></affiliation></author><author><name sortKey="Loza, Maria I" sort="Loza, Maria I" uniqKey="Loza M" first="María I." last="Loza">María I. Loza</name><affiliation wicri:level="1"><nlm:aff id="af0010">Eduardo Domínguez: Biofarma Research Group, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Universidad de Santiago de Compostela, Spain</nlm:aff><country xml:lang="fr">Espagne</country><wicri:regionArea>Eduardo Domínguez: Biofarma Research Group, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Universidad de Santiago de Compostela</wicri:regionArea><wicri:noRegion>Universidad de Santiago de Compostela</wicri:noRegion></affiliation></author><author><name sortKey="Grassi, Diego" sort="Grassi, Diego" uniqKey="Grassi D" first="Diego" last="Grassi">Diego Grassi</name><affiliation wicri:level="1"><nlm:aff id="af0015">Institute for Interdisciplinary Neuroscience (IINS), Bordeaux, Nouvelle-Aquitaine, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Institute for Interdisciplinary Neuroscience (IINS), Bordeaux, Nouvelle-Aquitaine</wicri:regionArea><wicri:noRegion>Nouvelle-Aquitaine</wicri:noRegion><wicri:noRegion>Nouvelle-Aquitaine</wicri:noRegion></affiliation></author><author><name sortKey="Shirinsky, Valery" sort="Shirinsky, Valery" uniqKey="Shirinsky V" first="Valery" last="Shirinsky">Valery Shirinsky</name><affiliation wicri:level="1"><nlm:aff id="af0020">Scientific Research Institute of Clinical immunology, Novosibirsk, Russia</nlm:aff><country xml:lang="fr">Russie</country><wicri:regionArea>Scientific Research Institute of Clinical immunology, Novosibirsk</wicri:regionArea><wicri:noRegion>Novosibirsk</wicri:noRegion></affiliation></author><author><name sortKey="Shirinsky, Ivan" sort="Shirinsky, Ivan" uniqKey="Shirinsky I" first="Ivan" last="Shirinsky">Ivan Shirinsky</name><affiliation wicri:level="1"><nlm:aff id="af0020">Scientific Research Institute of Clinical immunology, Novosibirsk, Russia</nlm:aff><country xml:lang="fr">Russie</country><wicri:regionArea>Scientific Research Institute of Clinical immunology, Novosibirsk</wicri:regionArea><wicri:noRegion>Novosibirsk</wicri:noRegion></affiliation></author><author><name sortKey="Lotz, Martin" sort="Lotz, Martin" uniqKey="Lotz M" first="Martin" last="Lotz">Martin Lotz</name><affiliation wicri:level="1"><nlm:aff id="af0025">Department of Molecular Medicine, Scripps Research, La Jolla, CA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Molecular Medicine, Scripps Research, La Jolla, CA</wicri:regionArea><wicri:noRegion>CA</wicri:noRegion></affiliation></author><author><name sortKey="Robbins, Paul D" sort="Robbins, Paul D" uniqKey="Robbins P" first="Paul D." last="Robbins">Paul D. Robbins</name><affiliation wicri:level="1"><nlm:aff id="af0030">Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN</wicri:regionArea><wicri:noRegion>MN</wicri:noRegion></affiliation></author><author><name sortKey="Dominguez, Eduardo" sort="Dominguez, Eduardo" uniqKey="Dominguez E" first="Eduardo" last="Domínguez">Eduardo Domínguez</name><affiliation wicri:level="1"><nlm:aff id="af0010">Eduardo Domínguez: Biofarma Research Group, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Universidad de Santiago de Compostela, Spain</nlm:aff><country xml:lang="fr">Espagne</country><wicri:regionArea>Eduardo Domínguez: Biofarma Research Group, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Universidad de Santiago de Compostela</wicri:regionArea><wicri:noRegion>Universidad de Santiago de Compostela</wicri:noRegion></affiliation></author><author><name sortKey="Carames, Beatriz" sort="Carames, Beatriz" uniqKey="Carames B" first="Beatriz" last="Caramés">Beatriz Caramés</name><affiliation wicri:level="1"><nlm:aff id="af0005">Uxía Nogueira-Recalde, Irene Lorenzo Gómez, Francisco J. Blanco and Beatriz Caramés, Grupo de Biología del Cartílago, Servicio de Reumatología, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complejo Hospitalario Universitario de A Coruña, Sergas, A Coruña, Spain</nlm:aff><country xml:lang="fr">Espagne</country><wicri:regionArea>Uxía Nogueira-Recalde, Irene Lorenzo Gómez, Francisco J. Blanco and Beatriz Caramés, Grupo de Biología del Cartílago, Servicio de Reumatología, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complejo Hospitalario Universitario de A Coruña, Sergas, A Coruña</wicri:regionArea><wicri:noRegion>A Coruña</wicri:noRegion></affiliation></author></analytic><series><title level="j">EBioMedicine</title><idno type="eISSN">2352-3964</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background</title><p>Ageing-related failure of homeostasis mechanisms contributes to articular cartilage degeneration and osteoarthritis (OA), for which disease-modifying treatments are not available. Our objective was to identify molecules to prevent OA by regulating chondrocyte senescence and autophagy.</p></sec><sec><title>Methods</title><p>Human chondrocytes with IL-6 induced senescence and autophagy suppression and SA-β-gal as a reporter of senescence and LC3 as reporter of autophagic flux were used to screen the Prestwick Chemical Library of approved drugs. Preclinical cellular, tissue and blood from OA and blood from OA and ageing models were used to test the efficacy and relevance of activating PPARα related to cartilage degeneration.</p></sec><sec><title>Findings</title><p>Senotherapeutic molecules with pro-autophagic activity were identified. Fenofibrate (FN), a PPARα agonist used for dyslipidaemias in humans, reduced the number of senescent cells <italic>via</italic> apoptosis, increased autophagic flux, and protected against cartilage degradation. FN reduced both senescence and inflammation and increased autophagy in both ageing human and OA chondrocytes whereas PPARα knockdown conferred the opposite effect. Moreover, PPARα expression was reduced through both ageing and OA in mice and also in blood and cartilage from knees of OA patients. Remarkably, in a retrospective study, fibrate treatment improved OA clinical conditions in human patients from the Osteoarthritis Initiative (OAI) Cohort.</p></sec><sec><title>Interpretation</title><p>These results demonstrate that FDA-approved fibrate drugs targeting lipid metabolism protect against cartilage degeneration seen with ageing and OA. Thus, these drugs could have immediate clinically utility for age-related cartilage degeneration and OA treatment.</p></sec><sec><title>Fund</title><p>This study was supported by Instituto de Salud Carlos III- Ministerio de Ciencia, Innovación y Universidades, Spain, Plan Estatal 2013–2016 and Fondo Europeo de Desarrollo Regional (FEDER), <italic>“Una manera de hacer Europa</italic>”, PI14/01324 and PI17/02059<italic>,</italic> by Innopharma Pharmacogenomics platform applied to the validation of targets and discovery of drugs candidates to preclinical phases, Ministerio de Economía y Competitividad, by grants of the National Instiutes of Health to PDR (P01 AG043376 and U19 AG056278). We thank FOREUM Foundation for Research in Rheumatology for their support.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Lopez Otin, C" uniqKey="Lopez Otin C">C. 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Blanco</name><name sortKey="Carames, Beatriz" sort="Carames, Beatriz" uniqKey="Carames B" first="Beatriz" last="Caramés">Beatriz Caramés</name><name sortKey="Dominguez, Eduardo" sort="Dominguez, Eduardo" uniqKey="Dominguez E" first="Eduardo" last="Domínguez">Eduardo Domínguez</name><name sortKey="Lorenzo G Mez, Irene" sort="Lorenzo G Mez, Irene" uniqKey="Lorenzo G Mez I" first="Irene" last="Lorenzo-G Mez">Irene Lorenzo-G Mez</name><name sortKey="Loza, Maria I" sort="Loza, Maria I" uniqKey="Loza M" first="María I." last="Loza">María I. Loza</name></country><country name="France"><noRegion><name sortKey="Grassi, Diego" sort="Grassi, Diego" uniqKey="Grassi D" first="Diego" last="Grassi">Diego Grassi</name></noRegion></country><country name="Russie"><noRegion><name sortKey="Shirinsky, Valery" sort="Shirinsky, Valery" uniqKey="Shirinsky V" first="Valery" last="Shirinsky">Valery Shirinsky</name></noRegion><name sortKey="Shirinsky, Ivan" sort="Shirinsky, Ivan" uniqKey="Shirinsky I" first="Ivan" last="Shirinsky">Ivan Shirinsky</name></country><country name="États-Unis"><noRegion><name sortKey="Lotz, Martin" sort="Lotz, Martin" uniqKey="Lotz M" first="Martin" last="Lotz">Martin Lotz</name></noRegion><name sortKey="Robbins, Paul D" sort="Robbins, Paul D" uniqKey="Robbins P" first="Paul D." last="Robbins">Paul D. Robbins</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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