{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T20:16:31Z","timestamp":1793132191778,"version":"4.5.0"},"reference-count":80,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2021,2,7]],"date-time":"2021-02-07T00:00:00Z","timestamp":1612656000000},"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":["RO1HL132353"],"award-info":[{"award-number":["RO1HL132353"]}],"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":["RO1HL142935"],"award-info":[{"award-number":["RO1HL142935"]}],"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":["T32 HL007822"],"award-info":[{"award-number":["T32 HL007822"]}],"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":["F31HL142223"],"award-info":[{"award-number":["F31HL142223"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["#18IPA34170040"],"award-info":[{"award-number":["#18IPA34170040"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2021,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Pro\u2010inflammatory cytokines play critical roles in regulating valvular interstitial cell (VIC) phenotypic changes that can cause heart valve fibrosis and calcification. Tumor necrosis factor alpha (TNF\u2010\u03b1) is a cytokine known to influence VIC behavior and has been reported at high levels in calcified valves ex vivo. We sought to understand the specific effects of TNF\u2010\u03b1 on VIC phenotypes (eg, fibroblast, profibrotic activated myofibroblasts) and its link with heart valve disorders. We characterize human aortic valve tissue from patients with valve disorders and identify a high variability of fibrotic and calcific markers between tissues. These results motivated in vitro studies to explore the effects of TNF\u2010\u03b1 on defined VIC fibroblasts and profibrotic activated myofibroblasts, induced via FGF\u20102 and TGF\u2010\u03b21 treatment. Using 3D hydrogels to culture VICs, we measure the effect of TNF\u2010\u03b1 (0.1\u201010\u00a0ng\/mL) on key markers of fibrosis (eg, \u03b1SMA, COL1A1) and calcification (eg, RUNX2, BMP2, and calcium deposits). We observe calcification in TNF\u2010\u03b1\u2010treated VIC activated myofibroblasts and identify the MAPK\/ERK signaling cascade as a potential pathway for TNF\u2010\u03b1 mediated calcification. Conversely, VIC fibroblasts respond to TNF\u2010\u03b1 with decreased calcification. Treatment of VIC profibrotic activated myofibroblast populations with TNF\u2010\u03b1 leads to increased calcification. Our in vitro findings correlate with findings in diseased human valves and highlight the importance of understanding the effect of cytokines and signaling pathways on specific VIC phenotypes. Finally, we reveal MAPK\/ERK as a potential pathway involved in VIC\u2010mediated matrix calcification with TNF\u2010\u03b1 treatment, suggesting this pathway as a potential pharmaceutical target for aortic valve disease.<\/jats:p>","DOI":"10.1096\/fj.202002013rr","type":"journal-article","created":{"date-parts":[[2021,2,8]],"date-time":"2021-02-08T18:27:49Z","timestamp":1612808869000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Tumor necrosis factor\u2010\u03b1 promotes and exacerbates calcification in heart valve myofibroblast populations"],"prefix":"10.1096","volume":"35","author":[{"given":"Andrea","family":"Gonzalez Rodriguez","sequence":"first","affiliation":[{"name":"Department of Chemical and Biological Engineering University of Colorado Boulder Boulder CO USA"},{"name":"BioFrontiers Institute University of Colorado Boulder Boulder CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan E.","family":"Schroeder","sequence":"additional","affiliation":[{"name":"BioFrontiers Institute University of Colorado Boulder Boulder CO USA"},{"name":"Materials Science and Engineering Program University of Colorado Boulder Boulder CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph C.","family":"Grim","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biological Engineering University of Colorado Boulder Boulder CO USA"},{"name":"BioFrontiers Institute University of Colorado Boulder Boulder CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cierra J.","family":"Walker","sequence":"additional","affiliation":[{"name":"BioFrontiers Institute University of Colorado Boulder Boulder CO USA"},{"name":"Materials Science and Engineering Program University of Colorado Boulder Boulder CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly F.","family":"Speckl","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biological Engineering University of Colorado Boulder Boulder CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert M.","family":"Weiss","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine University of Iowa Iowa City IA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristi S.","family":"Anseth","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biological Engineering University of Colorado Boulder Boulder CO USA"},{"name":"BioFrontiers Institute University of Colorado Boulder Boulder CO USA"},{"name":"Materials Science and Engineering Program University of Colorado Boulder Boulder CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,2,7]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.110.006767"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2016.6"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.109.195271"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(06)69208\u20108"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.21037\/jtd.2016.12.23"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.114.302523"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1313875"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000227513.13697.ac"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2009.09.025"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbm.a.34162"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.108.182394"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-17437-2_3"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000136520.07995.aa"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.07\u2010087627"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.CYTOGFR.2017.09.003"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.2353\/AJPATH.2008.080365"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.MATBIO.2005.06.007"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtcvs.2017.01.052"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10753\u2010012\u20109565\u2010z"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00441\u2010009\u20100765\u20102"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.carpath.2005.01.002"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.16.12.1573"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365\u20103083.1993.tb01672.x"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0923\u20101811(96)00562\u20102"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.119.313067"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2002\u20100046OC"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.171.7.3855"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.23645"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014\u20105793(88)80283\u20107"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.110.234138"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.113.300153"},{"issue":"35","key":"e_1_2_9_33_1","first-page":"S141","article-title":"Unusual toxicities with TNF inhibition: heart failure and drug\u2010induced lupus","volume":"22","author":"Cush JJ","year":"2004","journal-title":"Clin Exp Rheumatol"},{"issue":"6","key":"e_1_2_9_34_1","first-page":"S152","article-title":"Side effects of anti\u2010TNF therapy: current knowledge","volume":"20","author":"Antoni C","year":"2002","journal-title":"Clin Exp Rheumatol"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2004.09.004"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00526.2001"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.EJIM.2012.12.015"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1136\/hrt.70.2.141"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00380\u2010016\u20100909\u20108"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000036607.05037.DA"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.CARPATH.2014.08.003"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2016.03.004"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.IJCARD.2013.09.012"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtcvs.2011.03.002"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.3892\/etm.2014.1529"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10741\u2010012\u20109365\u20104"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.101.7.765"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehn080"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10554\u2010012\u20100123\u20104"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2015.09.035"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1002\/adma.200901808"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2019"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1063\/1.5042430"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1574\u20106968.1991.tb04969.x"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/173.1.38"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1080\/15216549700203841"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1136\/hrt.70.2.141"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/1043\u20104666(90)90002\u2010B"},{"key":"e_1_2_9_59_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.84.15.5277"},{"key":"e_1_2_9_60_1","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/875363"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2014.02.009"},{"key":"e_1_2_9_62_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2019.12.003"},{"key":"e_1_2_9_63_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.110.177915"},{"key":"e_1_2_9_64_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.102.21.2636"},{"key":"e_1_2_9_65_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aav3233"},{"key":"e_1_2_9_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.actbio.2016.03.007"},{"key":"e_1_2_9_67_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2007.070251"},{"key":"e_1_2_9_68_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.carpath.2010.12.001"},{"key":"e_1_2_9_69_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.AJPATH.2016.05.003"},{"key":"e_1_2_9_70_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1209288"},{"key":"e_1_2_9_71_1","doi-asserted-by":"publisher","DOI":"10.1080\/13543784.2017.1351543"},{"key":"e_1_2_9_72_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10637\u2010015\u20100212\u2010z"},{"key":"e_1_2_9_73_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1605943"},{"key":"e_1_2_9_74_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvr301"},{"key":"e_1_2_9_75_1","doi-asserted-by":"publisher","DOI":"10.1042\/CS20160571"},{"key":"e_1_2_9_76_1","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.10905"},{"key":"e_1_2_9_77_1","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.117.006339"},{"key":"e_1_2_9_78_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00726\u2010017\u20102432\u20103"},{"key":"e_1_2_9_79_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.112.300912"},{"key":"e_1_2_9_80_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2011.06.007"},{"key":"e_1_2_9_81_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523\u20101755.2001.059002579.x"}],"container-title":["The FASEB Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.202002013RR","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1096\/fj.202002013RR","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.202002013RR","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T21:28:43Z","timestamp":1761686923000},"score":1,"resource":{"primary":{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/10.1096\/fj.202002013RR"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,7]]},"references-count":80,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2021,3]]}},"alternative-id":["10.1096\/fj.202002013RR"],"URL":"https:\/\/doi.org\/10.1096\/fj.202002013rr","archive":["Portico"],"relation":{},"ISSN":["0892-6638","1530-6860"],"issn-type":[{"value":"0892-6638","type":"print"},{"value":"1530-6860","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,7]]},"assertion":[{"value":"2020-09-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-01-06","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-02-07","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e21382"}}