Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy

Uxía Nogueira-Recalde; Irene Lorenzo-Gómez; Francisco J. Blanco; María I. Loza; Diego Grassi; Valery Shirinsky; Ivan Shirinsky; Martin Lotz; Paul D. Robbins; Eduardo Domínguez; Beatriz Caramés

doi:10.1016/j.ebiom.2019.06.049

Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy

Uxía Nogueira-Recalde, Irene Lorenzo-Gómez, Francisco J. Blanco, María I. Loza, Diego Grassi, Valery Shirinsky, Ivan Shirinsky, Martin Lotz, Paul D. Robbins, Eduardo Domínguez, Beatriz Caramés

Research output: Contribution to journal › Article › peer-review

100 Scopus citations

Abstract

Background: 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. Methods: 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. Findings: Senotherapeutic molecules with pro-autophagic activity were identified. Fenofibrate (FN), a PPARα agonist used for dyslipidaemias in humans, reduced the number of senescent cells via 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. Interpretation: 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. Fund: 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), “Una manera de hacer Europa”, PI14/01324 and PI17/02059, 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.

Original language	English (US)
Pages (from-to)	588-605
Number of pages	18
Journal	EBioMedicine
Volume	45
DOIs	https://doi.org/10.1016/j.ebiom.2019.06.049
State	Published - Jul 2019

Bibliographical note

Funding Information:
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), “ Una manera de hacer Europa ”, PI14/01324 and PI17/02059 , 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 Institutes of Health to PDR ( P01 AG043376 and U19 AG056278 ). We thank the FOREUM Foundation for Research in Rheumatology for their support. UNR was supported by Programa Operativo FSE Galicia 2014–2020, Xunta de Galicia , Spain, BC was supported by Miguel Servet Type II Program - CPII16/00045-A , Instituto de Salud Carlos III , Ministerio de Ciencia, Innovación y Universidades , Spain. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Funding Information:
We thank the staff of the Orthopedic Department of the Complejo Hospitalario Universitario A Coru?a for providing the cartilage samples. Furthermore, we thank Tamara Hermida and Merissa Olmer for technical assistance and Richard Roberts for editing the revised manuscript in British English. The OAI is a public-private partnership comprising five contracts (N01-AR-2-2258; N01-AR-2-2259; N01-AR-2-2260; N01-AR-2-2261; N01-AR-2-2262) funded by the National Institutes of Health, a branch of the Department of Health and Human Services, and conducted by the OAI Study Investigators. Private funding partners include Merck Research Laboratories, Novartis Pharmaceuticals Corporation, GlaxoSmithKline and Pfizer, Inc. Private sector funding for the OAI is managed by the Foundation for the National Institutes of Health. This manuscript was prepared using an OAI public use data set and does not necessarily reflect the opinions or views of the OAI investigators, the NIH or the private funding partners. This study was supported by Instituto de Salud Carlos III- Ministerio de Ciencia, Innovaci?n y Universidades, Spain, Plan Estatal 2013-2016 and Fondo Europeo de Desarrollo Regional (FEDER), ?Una manera de hacer Europa?, PI14/01324 and PI17/02059, by Innopharma Pharmacogenomics platform applied to the validation of targets and discovery of drugs candidates to preclinical phases, Ministerio de Econom?a y Competitividad, by grants of the National Institutes of Health to PDR (P01 AG043376 and U19 AG056278). We thank the FOREUM Foundation for Research in Rheumatology for their support. UNR was supported by Programa Operativo FSE Galicia 2014?2020, Xunta de Galicia, Spain, BC was supported by Miguel Servet Type II Program-CPII16/00045-A, Instituto de Salud Carlos III, Ministerio de Ciencia, Innovaci?n y Universidades, Spain. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have declared no potential conflicts of interest. All authors approved the final version to be published. Concept and design: Dom?nguez, Caram?s. Performed the experiments: Nogueira-Recalde, Lorenzo-G?mez, Grassi, Dom?nguez, Caram?s. Data analysis and interpretation: Nogueira-Recalde, Dom?nguez, Caram?s. Writing and review of Manuscript: Nogueira-Recalde, Blanco, Loza, Shirinsky, Lotz, Robbins, Dom?nguez and Caram?s.

Funding Information:
The OAI is a public-private partnership comprising five contracts (N01-AR-2-2258; N01-AR-2-2259; N01-AR-2-2260; N01-AR-2-2261; N01-AR-2-2262) funded by the National Institutes of Health, a branch of the Department of Health and Human Services, and conducted by the OAI Study Investigators. Private funding partners include Merck Research Laboratories, Novartis Pharmaceuticals Corporation, GlaxoSmithKline and Pfizer, Inc. Private sector funding for the OAI is managed by the Foundation for the National Institutes of Health. This manuscript was prepared using an OAI public use data set and does not necessarily reflect the opinions or views of the OAI investigators, the NIH or the private funding partners.

Publisher Copyright:
© 2019 The Authors

Keywords

Ageing
Autophagy
Osteoarthritis
Screening
Senescence
Therapeutics

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10.1016/j.ebiom.2019.06.049

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@article{74fbae1f97924b66836c75a28bedacbe,

title = "Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy",

abstract = "Background: 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. Methods: 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. Findings: Senotherapeutic molecules with pro-autophagic activity were identified. Fenofibrate (FN), a PPARα agonist used for dyslipidaemias in humans, reduced the number of senescent cells via 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. Interpretation: 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. Fund: This study was supported by Instituto de Salud Carlos III- Ministerio de Ciencia, Innovaci{\'o}n y Universidades, Spain, Plan Estatal 2013–2016 and Fondo Europeo de Desarrollo Regional (FEDER), “Una manera de hacer Europa”, PI14/01324 and PI17/02059, by Innopharma Pharmacogenomics platform applied to the validation of targets and discovery of drugs candidates to preclinical phases, Ministerio de Econom{\'i}a 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.",

keywords = "Ageing, Autophagy, Osteoarthritis, Screening, Senescence, Therapeutics",

author = "Ux{\'i}a Nogueira-Recalde and Irene Lorenzo-G{\'o}mez and Blanco, {Francisco J.} and Loza, {Mar{\'i}a I.} and Diego Grassi and Valery Shirinsky and Ivan Shirinsky and Martin Lotz and Robbins, {Paul D.} and Eduardo Dom{\'i}nguez and Beatriz Caram{\'e}s",

note = "Funding Information: This study was supported by Instituto de Salud Carlos III - Ministerio de Ciencia, Innovaci{\'o}n y Universidades , Spain, Plan Estatal 2013-2016 and Fondo Europeo de Desarrollo Regional (FEDER), “ Una manera de hacer Europa ”, PI14/01324 and PI17/02059 , by Innopharma Pharmacogenomics platform applied to the validation of targets and discovery of drugs candidates to preclinical phases, Ministerio de Econom{\'i}a y Competitividad , by grants of the National Institutes of Health to PDR ( P01 AG043376 and U19 AG056278 ). We thank the FOREUM Foundation for Research in Rheumatology for their support. UNR was supported by Programa Operativo FSE Galicia 2014–2020, Xunta de Galicia , Spain, BC was supported by Miguel Servet Type II Program - CPII16/00045-A , Instituto de Salud Carlos III , Ministerio de Ciencia, Innovaci{\'o}n y Universidades , Spain. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Funding Information: We thank the staff of the Orthopedic Department of the Complejo Hospitalario Universitario A Coru?a for providing the cartilage samples. Furthermore, we thank Tamara Hermida and Merissa Olmer for technical assistance and Richard Roberts for editing the revised manuscript in British English. The OAI is a public-private partnership comprising five contracts (N01-AR-2-2258; N01-AR-2-2259; N01-AR-2-2260; N01-AR-2-2261; N01-AR-2-2262) funded by the National Institutes of Health, a branch of the Department of Health and Human Services, and conducted by the OAI Study Investigators. Private funding partners include Merck Research Laboratories, Novartis Pharmaceuticals Corporation, GlaxoSmithKline and Pfizer, Inc. Private sector funding for the OAI is managed by the Foundation for the National Institutes of Health. This manuscript was prepared using an OAI public use data set and does not necessarily reflect the opinions or views of the OAI investigators, the NIH or the private funding partners. This study was supported by Instituto de Salud Carlos III- Ministerio de Ciencia, Innovaci?n y Universidades, Spain, Plan Estatal 2013-2016 and Fondo Europeo de Desarrollo Regional (FEDER), ?Una manera de hacer Europa?, PI14/01324 and PI17/02059, by Innopharma Pharmacogenomics platform applied to the validation of targets and discovery of drugs candidates to preclinical phases, Ministerio de Econom?a y Competitividad, by grants of the National Institutes of Health to PDR (P01 AG043376 and U19 AG056278). We thank the FOREUM Foundation for Research in Rheumatology for their support. UNR was supported by Programa Operativo FSE Galicia 2014?2020, Xunta de Galicia, Spain, BC was supported by Miguel Servet Type II Program-CPII16/00045-A, Instituto de Salud Carlos III, Ministerio de Ciencia, Innovaci?n y Universidades, Spain. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have declared no potential conflicts of interest. All authors approved the final version to be published. Concept and design: Dom?nguez, Caram?s. Performed the experiments: Nogueira-Recalde, Lorenzo-G?mez, Grassi, Dom?nguez, Caram?s. Data analysis and interpretation: Nogueira-Recalde, Dom?nguez, Caram?s. Writing and review of Manuscript: Nogueira-Recalde, Blanco, Loza, Shirinsky, Lotz, Robbins, Dom?nguez and Caram?s. Funding Information: The OAI is a public-private partnership comprising five contracts (N01-AR-2-2258; N01-AR-2-2259; N01-AR-2-2260; N01-AR-2-2261; N01-AR-2-2262) funded by the National Institutes of Health, a branch of the Department of Health and Human Services, and conducted by the OAI Study Investigators. Private funding partners include Merck Research Laboratories, Novartis Pharmaceuticals Corporation, GlaxoSmithKline and Pfizer, Inc. Private sector funding for the OAI is managed by the Foundation for the National Institutes of Health. This manuscript was prepared using an OAI public use data set and does not necessarily reflect the opinions or views of the OAI investigators, the NIH or the private funding partners. Publisher Copyright: {\textcopyright} 2019 The Authors",

year = "2019",

month = jul,

doi = "10.1016/j.ebiom.2019.06.049",

language = "English (US)",

volume = "45",

pages = "588--605",

journal = "EBioMedicine",

issn = "2352-3964",

publisher = "Elsevier B.V.",

}

TY - JOUR

T1 - Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy

AU - Nogueira-Recalde, Uxía

AU - Lorenzo-Gómez, Irene

AU - Blanco, Francisco J.

AU - Loza, María I.

AU - Grassi, Diego

AU - Shirinsky, Valery

AU - Shirinsky, Ivan

AU - Lotz, Martin

AU - Robbins, Paul D.

AU - Domínguez, Eduardo

AU - Caramés, Beatriz

N1 - Funding Information: 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), “ Una manera de hacer Europa ”, PI14/01324 and PI17/02059 , 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 Institutes of Health to PDR ( P01 AG043376 and U19 AG056278 ). We thank the FOREUM Foundation for Research in Rheumatology for their support. UNR was supported by Programa Operativo FSE Galicia 2014–2020, Xunta de Galicia , Spain, BC was supported by Miguel Servet Type II Program - CPII16/00045-A , Instituto de Salud Carlos III , Ministerio de Ciencia, Innovación y Universidades , Spain. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Funding Information: We thank the staff of the Orthopedic Department of the Complejo Hospitalario Universitario A Coru?a for providing the cartilage samples. Furthermore, we thank Tamara Hermida and Merissa Olmer for technical assistance and Richard Roberts for editing the revised manuscript in British English. The OAI is a public-private partnership comprising five contracts (N01-AR-2-2258; N01-AR-2-2259; N01-AR-2-2260; N01-AR-2-2261; N01-AR-2-2262) funded by the National Institutes of Health, a branch of the Department of Health and Human Services, and conducted by the OAI Study Investigators. Private funding partners include Merck Research Laboratories, Novartis Pharmaceuticals Corporation, GlaxoSmithKline and Pfizer, Inc. Private sector funding for the OAI is managed by the Foundation for the National Institutes of Health. This manuscript was prepared using an OAI public use data set and does not necessarily reflect the opinions or views of the OAI investigators, the NIH or the private funding partners. This study was supported by Instituto de Salud Carlos III- Ministerio de Ciencia, Innovaci?n y Universidades, Spain, Plan Estatal 2013-2016 and Fondo Europeo de Desarrollo Regional (FEDER), ?Una manera de hacer Europa?, PI14/01324 and PI17/02059, by Innopharma Pharmacogenomics platform applied to the validation of targets and discovery of drugs candidates to preclinical phases, Ministerio de Econom?a y Competitividad, by grants of the National Institutes of Health to PDR (P01 AG043376 and U19 AG056278). We thank the FOREUM Foundation for Research in Rheumatology for their support. UNR was supported by Programa Operativo FSE Galicia 2014?2020, Xunta de Galicia, Spain, BC was supported by Miguel Servet Type II Program-CPII16/00045-A, Instituto de Salud Carlos III, Ministerio de Ciencia, Innovaci?n y Universidades, Spain. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have declared no potential conflicts of interest. All authors approved the final version to be published. Concept and design: Dom?nguez, Caram?s. Performed the experiments: Nogueira-Recalde, Lorenzo-G?mez, Grassi, Dom?nguez, Caram?s. Data analysis and interpretation: Nogueira-Recalde, Dom?nguez, Caram?s. Writing and review of Manuscript: Nogueira-Recalde, Blanco, Loza, Shirinsky, Lotz, Robbins, Dom?nguez and Caram?s. Funding Information: The OAI is a public-private partnership comprising five contracts (N01-AR-2-2258; N01-AR-2-2259; N01-AR-2-2260; N01-AR-2-2261; N01-AR-2-2262) funded by the National Institutes of Health, a branch of the Department of Health and Human Services, and conducted by the OAI Study Investigators. Private funding partners include Merck Research Laboratories, Novartis Pharmaceuticals Corporation, GlaxoSmithKline and Pfizer, Inc. Private sector funding for the OAI is managed by the Foundation for the National Institutes of Health. This manuscript was prepared using an OAI public use data set and does not necessarily reflect the opinions or views of the OAI investigators, the NIH or the private funding partners. Publisher Copyright: © 2019 The Authors

PY - 2019/7

Y1 - 2019/7

N2 - Background: 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. Methods: 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. Findings: Senotherapeutic molecules with pro-autophagic activity were identified. Fenofibrate (FN), a PPARα agonist used for dyslipidaemias in humans, reduced the number of senescent cells via 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. Interpretation: 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. Fund: 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), “Una manera de hacer Europa”, PI14/01324 and PI17/02059, 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.

AB - Background: 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. Methods: 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. Findings: Senotherapeutic molecules with pro-autophagic activity were identified. Fenofibrate (FN), a PPARα agonist used for dyslipidaemias in humans, reduced the number of senescent cells via 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. Interpretation: 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. Fund: 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), “Una manera de hacer Europa”, PI14/01324 and PI17/02059, 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.

KW - Ageing

KW - Autophagy

KW - Osteoarthritis

KW - Screening

KW - Senescence

KW - Therapeutics

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Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy

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