{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T20:40:41Z","timestamp":1784234441581,"version":"3.55.0"},"reference-count":43,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2020,8,9]],"date-time":"2020-08-09T00:00:00Z","timestamp":1596931200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AG049617"],"award-info":[{"award-number":["AG049617"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AG059418"],"award-info":[{"award-number":["AG059418"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2020,9]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Osteoarthritis (<jats:styled-content style=\"fixed-case\">OA<\/jats:styled-content>) is the most common age\u2010related joint disease. With aging and in <jats:styled-content style=\"fixed-case\">OA<\/jats:styled-content>, the expression of FoxO transcription factors is reduced, diminishing their chondroprotective actions. In order to elucidate the molecular mechanisms by which FoxO1 protects chondrocytes, we sought to identify the genome\u2010wide occupancy profile of FoxO1.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We performed FoxO1 chromatin immunoprecipitation followed by high\u2010throughput sequencing (Ch<jats:styled-content style=\"fixed-case\">IP<\/jats:styled-content>\u2010Seq) on human primary chondrocytes. Ch<jats:styled-content style=\"fixed-case\">IP<\/jats:styled-content>\u2010Seq data were integrated with <jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content> sequencing (<jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content>\u2010Seq) data sets. Bioinformatics results were confirmed in primary chondrocytes that were treated with a FoxO1 inhibitor.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Analysis of FoxO1 Ch<jats:styled-content style=\"fixed-case\">IP<\/jats:styled-content>\u2010Seq on human primary chondrocytes showed that pathways implicated in <jats:styled-content style=\"fixed-case\">OA<\/jats:styled-content> pathogenesis are mainly regulated by FoxO1 binding to tissue\u2010specific enhancers with suboptimal binding sites (20% of the peaks), while more ubiquitous FoxO1 pathways are regulated at the promoter level through interaction with its canonical binding motif (7% of the peaks). Integrating FoxO1 occupancy data with <jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content>\u2010Seq data comparing <jats:styled-content style=\"fixed-case\">OA<\/jats:styled-content> and healthy human cartilage revealed 428 putative FoxO1 target genes that are dysregulated in <jats:styled-content style=\"fixed-case\">OA<\/jats:styled-content>. Pathway analysis showed enrichment for genes belonging to the senescence pathway (log<jats:italic>P<\/jats:italic> = \u22126.73), extracellular matrix (<jats:styled-content style=\"fixed-case\">ECM<\/jats:styled-content>) pathway (log<jats:italic>P<\/jats:italic> = \u221212.97), and circadian clock pathway (log<jats:italic>P<\/jats:italic> = \u22126.30), which suggests that FoxO1 dysregulation plays an important role in their abnormal expression in <jats:styled-content style=\"fixed-case\">OA<\/jats:styled-content>. Using an inhibitor of FoxO1, we confirmed that FoxO1 regulates these pathways in cultured human chondrocytes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>FoxO1 regulates ubiquitous and cartilage\u2010specific genes in chondrocytes by using different mechanisms. The FoxO1 transcriptional network is a key player in regulating homeostasis, <jats:styled-content style=\"fixed-case\">ECM<\/jats:styled-content>, and circadian clock genes and plays an important role in the abnormal expression of these pathways observed in <jats:styled-content style=\"fixed-case\">OA<\/jats:styled-content> pathogenesis.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.41284","type":"journal-article","created":{"date-parts":[[2020,4,13]],"date-time":"2020-04-13T02:54:12Z","timestamp":1586746452000},"page":"1514-1523","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Genome\u2010Wide Occupancy Profiling Reveals Critical Roles of FoxO1 in Regulating Extracellular Matrix and Circadian Rhythm Genes in Human Chondrocytes"],"prefix":"10.1002","volume":"72","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4330-9748","authenticated-orcid":false,"given":"Tomas","family":"Duffy","sequence":"first","affiliation":[{"name":"Scripps Research  La Jolla California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1590-8340","authenticated-orcid":false,"given":"Hirofumi","family":"Bekki","sequence":"additional","affiliation":[{"name":"Scripps Research  La Jolla California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6299-8799","authenticated-orcid":false,"given":"Martin K.","family":"Lotz","sequence":"additional","affiliation":[{"name":"Scripps Research  La Jolla California"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,8,9]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2013.11.004"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.38868"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.27305"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/glu044"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2008.02.005"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/msb.2012.74"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.27056"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2014.02.003"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1069004"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature01036"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2009.12.009"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2010.01.001"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2007.11.004"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(04)00400-3"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aan0746"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1080\/15384101.2016.1192732"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu372"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2010.05.004"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts277"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1310430110"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2010.11.025"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2015.10.015"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12479"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2018.07.012"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12891-016-0944-8"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.matbio.2014.08.008"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI82755"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2010.03.008"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/jor.23583"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3507"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1177\/1941738109350438"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.09.018"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aac6948"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.11.041"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature07829"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt1010-1045"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.09.045"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2016.11.007"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-019-1832-z"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.1177\/0748730417704534"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2014.04.018"},{"key":"e_1_2_6_43_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2012.4889"},{"key":"e_1_2_6_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-018-0096-9"}],"container-title":["Arthritis 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