Regulated in Development and DNA Damage Response 1 Deficiency Impairs Autophagy and Mitochondrial Biogenesis in Articular Cartilage and Increases the Severity of Experimental Osteoarthritis
Objective Regulated in development and DNA damage response 1 (REDD1) is an endogenous inhibitor of mechanistic target of rapamycin (mTOR) that regulates cellular stress responses. REDD1 expression is decreased in aged and osteoarthritic (OA) cartilage, and it regulates mTOR signaling and autophagy i...
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| Veröffentlicht in: | Arthritis & rheumatology (Hoboken, N.J.) N.J.), 2017-07, Vol.69 (7), p.1418-1428 |
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| creator | Alvarez‐Garcia, Oscar Matsuzaki, Tokio Olmer, Merissa Plate, Lars Kelly, Jeffery W. Lotz, Martin K. |
| description | Objective
Regulated in development and DNA damage response 1 (REDD1) is an endogenous inhibitor of mechanistic target of rapamycin (mTOR) that regulates cellular stress responses. REDD1 expression is decreased in aged and osteoarthritic (OA) cartilage, and it regulates mTOR signaling and autophagy in articular chondrocytes in vitro. This study was undertaken to investigate the effects of REDD1 deletion in vivo using a mouse model of experimental OA.
Methods
OA severity was histologically assessed in 4‐month‐old wild‐type and REDD1−/− mice subjected to surgical destabilization of the medial meniscus (DMM). Chondrocyte autophagy, apoptosis, mitochondrial content, and expression of mitochondrial biogenesis markers were determined in cartilage and cultured chondrocytes from wild‐type and REDD1−/− mice.
Results
REDD1 deficiency increased the severity of changes in cartilage, menisci, subchondral bone, and synovium in the DMM model of OA. Chondrocyte death was increased in the cartilage of REDD1−/− mice and in cultured REDD1−/− mouse chondrocytes under oxidative stress conditions. Expression of key autophagy markers (microtubule‐associated protein 1A/1B light chain 3 and autophagy protein 5) was markedly reduced in cartilage from REDD1−/− mice and in cultured human and mouse chondrocytes with REDD1 depletion. Mitochondrial content, ATP levels, and expression of the mitochondrial biogenesis markers peroxisome proliferator–activated receptor γ coactivator 1α (PGC‐1α) and transcription factor A, mitochondrial (TFAM) were also decreased in REDD1‐deficient chondrocytes. REDD1 was required for AMP‐activated protein kinase–induced PGC‐1α in chondrocytes.
Conclusion
Our findings suggest that REDD1 is a key mediator of cartilage homeostasis through regulation of autophagy and mitochondrial biogenesis and that REDD1 deficiency exacerbates the severity of injury‐induced OA. |
| doi_str_mv | 10.1002/art.40104 |
| format | Article |
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Regulated in development and DNA damage response 1 (REDD1) is an endogenous inhibitor of mechanistic target of rapamycin (mTOR) that regulates cellular stress responses. REDD1 expression is decreased in aged and osteoarthritic (OA) cartilage, and it regulates mTOR signaling and autophagy in articular chondrocytes in vitro. This study was undertaken to investigate the effects of REDD1 deletion in vivo using a mouse model of experimental OA.
Methods
OA severity was histologically assessed in 4‐month‐old wild‐type and REDD1−/− mice subjected to surgical destabilization of the medial meniscus (DMM). Chondrocyte autophagy, apoptosis, mitochondrial content, and expression of mitochondrial biogenesis markers were determined in cartilage and cultured chondrocytes from wild‐type and REDD1−/− mice.
Results
REDD1 deficiency increased the severity of changes in cartilage, menisci, subchondral bone, and synovium in the DMM model of OA. Chondrocyte death was increased in the cartilage of REDD1−/− mice and in cultured REDD1−/− mouse chondrocytes under oxidative stress conditions. Expression of key autophagy markers (microtubule‐associated protein 1A/1B light chain 3 and autophagy protein 5) was markedly reduced in cartilage from REDD1−/− mice and in cultured human and mouse chondrocytes with REDD1 depletion. Mitochondrial content, ATP levels, and expression of the mitochondrial biogenesis markers peroxisome proliferator–activated receptor γ coactivator 1α (PGC‐1α) and transcription factor A, mitochondrial (TFAM) were also decreased in REDD1‐deficient chondrocytes. REDD1 was required for AMP‐activated protein kinase–induced PGC‐1α in chondrocytes.
Conclusion
Our findings suggest that REDD1 is a key mediator of cartilage homeostasis through regulation of autophagy and mitochondrial biogenesis and that REDD1 deficiency exacerbates the severity of injury‐induced OA.</description><identifier>ISSN: 2326-5191</identifier><identifier>EISSN: 2326-5205</identifier><identifier>DOI: 10.1002/art.40104</identifier><identifier>PMID: 28334504</identifier><language>eng</language><publisher>United States: Wiley Subscription Services, Inc</publisher><subject>AMP ; AMP-activated protein kinase ; AMP-Activated Protein Kinases - metabolism ; Animals ; Apoptosis ; Apoptosis - genetics ; Arthritis, Experimental - genetics ; Arthritis, Experimental - metabolism ; ATP ; Autophagy ; Autophagy - genetics ; Autophagy-Related Protein 5 - metabolism ; Biocompatibility ; Biomedical materials ; Biosynthesis ; Cartilage ; Cartilage (articular) ; Cartilage diseases ; Cartilage, Articular - metabolism ; Cellular stress response ; Chondrocytes ; Chondrocytes - metabolism ; Clonal deletion ; Damage ; Death ; Deoxyribonucleic acid ; Destabilization ; Disease Models, Animal ; DNA ; DNA damage ; DNA-Binding Proteins - metabolism ; High Mobility Group Proteins - metabolism ; Homeostasis ; Humans ; Immunohistochemistry ; In vitro methods and tests ; In vivo methods and tests ; Inhibitors ; Kinases ; Markers ; Menisci, Tibial - surgery ; Meniscus ; Mice ; Mice, Knockout ; Microtubule-associated protein 1 ; Microtubule-Associated Proteins - metabolism ; Mitochondria ; Mitochondria - metabolism ; Organelle Biogenesis ; Osteoarthritis ; Osteoarthritis, Knee - genetics ; Osteoarthritis, Knee - metabolism ; Oxidative Stress ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism ; Phagocytosis ; Protein kinase ; Proteins ; Rapamycin ; Subchondral bone ; Surgery ; Synovial Membrane - metabolism ; Synovium ; TOR protein ; Transcription Factors - genetics</subject><ispartof>Arthritis & rheumatology (Hoboken, N.J.), 2017-07, Vol.69 (7), p.1418-1428</ispartof><rights>2017, American College of Rheumatology</rights><rights>2017, American College of Rheumatology.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4544-5d59b3545b07b95f5ff137cc33fd6d85354b5afdb61b8a0044074d83b56ca7183</citedby><cites>FETCH-LOGICAL-c4544-5d59b3545b07b95f5ff137cc33fd6d85354b5afdb61b8a0044074d83b56ca7183</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%2Fart.40104$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fart.40104$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>315,781,785,1418,27929,27930,45579,45580</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28334504$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Alvarez‐Garcia, Oscar</creatorcontrib><creatorcontrib>Matsuzaki, Tokio</creatorcontrib><creatorcontrib>Olmer, Merissa</creatorcontrib><creatorcontrib>Plate, Lars</creatorcontrib><creatorcontrib>Kelly, Jeffery W.</creatorcontrib><creatorcontrib>Lotz, Martin K.</creatorcontrib><title>Regulated in Development and DNA Damage Response 1 Deficiency Impairs Autophagy and Mitochondrial Biogenesis in Articular Cartilage and Increases the Severity of Experimental Osteoarthritis</title><title>Arthritis & rheumatology (Hoboken, N.J.)</title><addtitle>Arthritis Rheumatol</addtitle><description>Objective
Regulated in development and DNA damage response 1 (REDD1) is an endogenous inhibitor of mechanistic target of rapamycin (mTOR) that regulates cellular stress responses. REDD1 expression is decreased in aged and osteoarthritic (OA) cartilage, and it regulates mTOR signaling and autophagy in articular chondrocytes in vitro. This study was undertaken to investigate the effects of REDD1 deletion in vivo using a mouse model of experimental OA.
Methods
OA severity was histologically assessed in 4‐month‐old wild‐type and REDD1−/− mice subjected to surgical destabilization of the medial meniscus (DMM). Chondrocyte autophagy, apoptosis, mitochondrial content, and expression of mitochondrial biogenesis markers were determined in cartilage and cultured chondrocytes from wild‐type and REDD1−/− mice.
Results
REDD1 deficiency increased the severity of changes in cartilage, menisci, subchondral bone, and synovium in the DMM model of OA. Chondrocyte death was increased in the cartilage of REDD1−/− mice and in cultured REDD1−/− mouse chondrocytes under oxidative stress conditions. Expression of key autophagy markers (microtubule‐associated protein 1A/1B light chain 3 and autophagy protein 5) was markedly reduced in cartilage from REDD1−/− mice and in cultured human and mouse chondrocytes with REDD1 depletion. Mitochondrial content, ATP levels, and expression of the mitochondrial biogenesis markers peroxisome proliferator–activated receptor γ coactivator 1α (PGC‐1α) and transcription factor A, mitochondrial (TFAM) were also decreased in REDD1‐deficient chondrocytes. REDD1 was required for AMP‐activated protein kinase–induced PGC‐1α in chondrocytes.
Conclusion
Our findings suggest that REDD1 is a key mediator of cartilage homeostasis through regulation of autophagy and mitochondrial biogenesis and that REDD1 deficiency exacerbates the severity of injury‐induced OA.</description><subject>AMP</subject><subject>AMP-activated protein kinase</subject><subject>AMP-Activated Protein Kinases - metabolism</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Apoptosis - genetics</subject><subject>Arthritis, Experimental - genetics</subject><subject>Arthritis, Experimental - metabolism</subject><subject>ATP</subject><subject>Autophagy</subject><subject>Autophagy - genetics</subject><subject>Autophagy-Related Protein 5 - metabolism</subject><subject>Biocompatibility</subject><subject>Biomedical materials</subject><subject>Biosynthesis</subject><subject>Cartilage</subject><subject>Cartilage (articular)</subject><subject>Cartilage diseases</subject><subject>Cartilage, Articular - metabolism</subject><subject>Cellular stress response</subject><subject>Chondrocytes</subject><subject>Chondrocytes - metabolism</subject><subject>Clonal deletion</subject><subject>Damage</subject><subject>Death</subject><subject>Deoxyribonucleic acid</subject><subject>Destabilization</subject><subject>Disease Models, Animal</subject><subject>DNA</subject><subject>DNA damage</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>High Mobility Group Proteins - metabolism</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>In vitro methods and tests</subject><subject>In vivo methods and tests</subject><subject>Inhibitors</subject><subject>Kinases</subject><subject>Markers</subject><subject>Menisci, Tibial - surgery</subject><subject>Meniscus</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Microtubule-associated protein 1</subject><subject>Microtubule-Associated Proteins - metabolism</subject><subject>Mitochondria</subject><subject>Mitochondria - metabolism</subject><subject>Organelle Biogenesis</subject><subject>Osteoarthritis</subject><subject>Osteoarthritis, Knee - genetics</subject><subject>Osteoarthritis, Knee - metabolism</subject><subject>Oxidative Stress</subject><subject>Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism</subject><subject>Phagocytosis</subject><subject>Protein kinase</subject><subject>Proteins</subject><subject>Rapamycin</subject><subject>Subchondral bone</subject><subject>Surgery</subject><subject>Synovial Membrane - metabolism</subject><subject>Synovium</subject><subject>TOR protein</subject><subject>Transcription Factors - genetics</subject><issn>2326-5191</issn><issn>2326-5205</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kcFu1DAQhiNERau2B14AWeJCD9vasZ1kj2G3wEotlZZyjhxnsusqsYPtAHk43o1Jt-WAVF880nzzzz_6k-Qto5eM0vRK-XgpKKPiVXKS8jRbyJTK1881W7Lj5DyEB4pvmdOMyjfJcVpwLiQVJ8mfLezGTkVoiLFkDT-hc0MPNhJlG7L-WpK16tUOyBbC4GwAwpBqjTZg9UQ2_aCMD6Qcoxv2ajc9jt2a6PTe2cYb1ZGPxu3AQjBhXlH6aDRu9GSFzk03a88zG6s9qACBxD2Qb2jEmzgR15Lr3wPWsycUuwsRHA7usWvCWXLUqi7A-dN_mnz_dH2_-rK4ufu8WZU3Cy2kEAvZyGXNpZA1zeulbGXbMp5rzXnbZE0hsVVL1TZ1xupCUSoEzUVT8FpmWuWs4KfJh4Pu4N2PEUKsehM0dJ2y4MZQsaJgacYxD0Tf_4c-uNFbdFdhFoKlNC0EUhcHSnsXgoe2GvBE5aeK0WqOtcIbq8dYkX33pDjWPTT_yOcQEbg6AL9MB9PLSlW5vT9I_gXKMa33</recordid><startdate>201707</startdate><enddate>201707</enddate><creator>Alvarez‐Garcia, Oscar</creator><creator>Matsuzaki, Tokio</creator><creator>Olmer, Merissa</creator><creator>Plate, Lars</creator><creator>Kelly, Jeffery W.</creator><creator>Lotz, Martin K.</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>7QL</scope><scope>7QP</scope><scope>7T5</scope><scope>7TM</scope><scope>7U7</scope><scope>C1K</scope><scope>H94</scope><scope>K9.</scope><scope>7X8</scope></search><sort><creationdate>201707</creationdate><title>Regulated in Development and DNA Damage Response 1 Deficiency Impairs Autophagy and Mitochondrial Biogenesis in Articular Cartilage and Increases the Severity of Experimental Osteoarthritis</title><author>Alvarez‐Garcia, Oscar ; Matsuzaki, Tokio ; Olmer, Merissa ; Plate, Lars ; Kelly, Jeffery W. ; Lotz, Martin K.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4544-5d59b3545b07b95f5ff137cc33fd6d85354b5afdb61b8a0044074d83b56ca7183</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>AMP</topic><topic>AMP-activated protein kinase</topic><topic>AMP-Activated Protein Kinases - metabolism</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Apoptosis - genetics</topic><topic>Arthritis, Experimental - genetics</topic><topic>Arthritis, Experimental - metabolism</topic><topic>ATP</topic><topic>Autophagy</topic><topic>Autophagy - genetics</topic><topic>Autophagy-Related Protein 5 - metabolism</topic><topic>Biocompatibility</topic><topic>Biomedical materials</topic><topic>Biosynthesis</topic><topic>Cartilage</topic><topic>Cartilage (articular)</topic><topic>Cartilage diseases</topic><topic>Cartilage, Articular - metabolism</topic><topic>Cellular stress response</topic><topic>Chondrocytes</topic><topic>Chondrocytes - metabolism</topic><topic>Clonal deletion</topic><topic>Damage</topic><topic>Death</topic><topic>Deoxyribonucleic acid</topic><topic>Destabilization</topic><topic>Disease Models, Animal</topic><topic>DNA</topic><topic>DNA damage</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>High Mobility Group Proteins - metabolism</topic><topic>Homeostasis</topic><topic>Humans</topic><topic>Immunohistochemistry</topic><topic>In vitro methods and tests</topic><topic>In vivo methods and tests</topic><topic>Inhibitors</topic><topic>Kinases</topic><topic>Markers</topic><topic>Menisci, Tibial - surgery</topic><topic>Meniscus</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Microtubule-associated protein 1</topic><topic>Microtubule-Associated Proteins - metabolism</topic><topic>Mitochondria</topic><topic>Mitochondria - metabolism</topic><topic>Organelle Biogenesis</topic><topic>Osteoarthritis</topic><topic>Osteoarthritis, Knee - genetics</topic><topic>Osteoarthritis, Knee - metabolism</topic><topic>Oxidative Stress</topic><topic>Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism</topic><topic>Phagocytosis</topic><topic>Protein kinase</topic><topic>Proteins</topic><topic>Rapamycin</topic><topic>Subchondral bone</topic><topic>Surgery</topic><topic>Synovial Membrane - metabolism</topic><topic>Synovium</topic><topic>TOR protein</topic><topic>Transcription Factors - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Alvarez‐Garcia, Oscar</creatorcontrib><creatorcontrib>Matsuzaki, Tokio</creatorcontrib><creatorcontrib>Olmer, Merissa</creatorcontrib><creatorcontrib>Plate, Lars</creatorcontrib><creatorcontrib>Kelly, Jeffery W.</creatorcontrib><creatorcontrib>Lotz, Martin K.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>Arthritis & rheumatology (Hoboken, N.J.)</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>Plate, Lars</au><au>Kelly, Jeffery W.</au><au>Lotz, Martin K.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Regulated in Development and DNA Damage Response 1 Deficiency Impairs Autophagy and Mitochondrial Biogenesis in Articular Cartilage and Increases the Severity of Experimental Osteoarthritis</atitle><jtitle>Arthritis & rheumatology (Hoboken, N.J.)</jtitle><addtitle>Arthritis Rheumatol</addtitle><date>2017-07</date><risdate>2017</risdate><volume>69</volume><issue>7</issue><spage>1418</spage><epage>1428</epage><pages>1418-1428</pages><issn>2326-5191</issn><eissn>2326-5205</eissn><abstract>Objective
Regulated in development and DNA damage response 1 (REDD1) is an endogenous inhibitor of mechanistic target of rapamycin (mTOR) that regulates cellular stress responses. REDD1 expression is decreased in aged and osteoarthritic (OA) cartilage, and it regulates mTOR signaling and autophagy in articular chondrocytes in vitro. This study was undertaken to investigate the effects of REDD1 deletion in vivo using a mouse model of experimental OA.
Methods
OA severity was histologically assessed in 4‐month‐old wild‐type and REDD1−/− mice subjected to surgical destabilization of the medial meniscus (DMM). Chondrocyte autophagy, apoptosis, mitochondrial content, and expression of mitochondrial biogenesis markers were determined in cartilage and cultured chondrocytes from wild‐type and REDD1−/− mice.
Results
REDD1 deficiency increased the severity of changes in cartilage, menisci, subchondral bone, and synovium in the DMM model of OA. Chondrocyte death was increased in the cartilage of REDD1−/− mice and in cultured REDD1−/− mouse chondrocytes under oxidative stress conditions. Expression of key autophagy markers (microtubule‐associated protein 1A/1B light chain 3 and autophagy protein 5) was markedly reduced in cartilage from REDD1−/− mice and in cultured human and mouse chondrocytes with REDD1 depletion. Mitochondrial content, ATP levels, and expression of the mitochondrial biogenesis markers peroxisome proliferator–activated receptor γ coactivator 1α (PGC‐1α) and transcription factor A, mitochondrial (TFAM) were also decreased in REDD1‐deficient chondrocytes. REDD1 was required for AMP‐activated protein kinase–induced PGC‐1α in chondrocytes.
Conclusion
Our findings suggest that REDD1 is a key mediator of cartilage homeostasis through regulation of autophagy and mitochondrial biogenesis and that REDD1 deficiency exacerbates the severity of injury‐induced OA.</abstract><cop>United States</cop><pub>Wiley Subscription Services, Inc</pub><pmid>28334504</pmid><doi>10.1002/art.40104</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Arthritis & rheumatology (Hoboken, N.J.), 2017-07, Vol.69 (7), p.1418-1428 |
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| subjects | AMP AMP-activated protein kinase AMP-Activated Protein Kinases - metabolism Animals Apoptosis Apoptosis - genetics Arthritis, Experimental - genetics Arthritis, Experimental - metabolism ATP Autophagy Autophagy - genetics Autophagy-Related Protein 5 - metabolism Biocompatibility Biomedical materials Biosynthesis Cartilage Cartilage (articular) Cartilage diseases Cartilage, Articular - metabolism Cellular stress response Chondrocytes Chondrocytes - metabolism Clonal deletion Damage Death Deoxyribonucleic acid Destabilization Disease Models, Animal DNA DNA damage DNA-Binding Proteins - metabolism High Mobility Group Proteins - metabolism Homeostasis Humans Immunohistochemistry In vitro methods and tests In vivo methods and tests Inhibitors Kinases Markers Menisci, Tibial - surgery Meniscus Mice Mice, Knockout Microtubule-associated protein 1 Microtubule-Associated Proteins - metabolism Mitochondria Mitochondria - metabolism Organelle Biogenesis Osteoarthritis Osteoarthritis, Knee - genetics Osteoarthritis, Knee - metabolism Oxidative Stress Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism Phagocytosis Protein kinase Proteins Rapamycin Subchondral bone Surgery Synovial Membrane - metabolism Synovium TOR protein Transcription Factors - genetics |
| title | Regulated in Development and DNA Damage Response 1 Deficiency Impairs Autophagy and Mitochondrial Biogenesis in Articular Cartilage and Increases the Severity of Experimental Osteoarthritis |
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