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As tendon degeneration has been noted in vivo in areas of decreased tendon vascularity, we hypothesized that hypoxia is responsible for the development of the tendinosis phenotype, and that these effects are more pronounced in aged tenocytes. Hypoxic (1% O<jats:sub>2<\/jats:sub>) culture of aged, tendinotic, and young human tenocytes resulted in a mineralized fibrochondrocyte phenotype in aged tenocytes, and a fibrochondrocyte phenotype in young and tendinotic tenocytes. Investigation of the molecular mechanism responsible for this phenotype change revealed that the fibrochondrocyte phenotype in aged tenocytes occurs with decreased Rac1 activity in response to hypoxia. In young hypoxic tenocytes, however, the fibrochondrocyte phenotype occurs with concomitant decreased Rac1 activity coupled with increased RhoA activity. Using pharmacologic and adenoviral manipulation, we confirmed that these hypoxic effects on the tenocyte phenotype are linked directly to the activity of RhoA\/Rac1 GTPase in in vitro human cell culture and tendon explants. These results demonstrate that hypoxia drives tenocyte phenotypic changes, and provide a molecular insight into the development of human tendinosis that occurs with aging.<\/jats:p>","DOI":"10.1111\/acel.12934","type":"journal-article","created":{"date-parts":[[2019,4,2]],"date-time":"2019-04-02T09:05:21Z","timestamp":1554195921000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Tendinosis develops from age\u2010 and oxygen tension\u2010dependent modulation of Rac1 activity"],"prefix":"10.1111","volume":"18","author":[{"given":"Rowena","family":"McBeath","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery Thomas Jefferson University Philadelphia Pennsylvania"},{"name":"Division of Orthopaedic Research, Department of Orthopaedic Surgery Thomas Jefferson University Philadelphia Pennsylvania"},{"name":"Philadelphia Hand to Shoulder Center Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard W.","family":"Edwards","sequence":"additional","affiliation":[{"name":"Division of Orthopaedic Research, Department of Orthopaedic Surgery Thomas Jefferson University Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian J.","family":"O\u2019Hara","sequence":"additional","affiliation":[{"name":"Department of Pathology, Anatomy and Cell Biology Thomas Jefferson University Hospital Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitchell G.","family":"Maltenfort","sequence":"additional","affiliation":[{"name":"The Applied Clinical Research Center, Department of Biomedical and Health Informatics Children's Hospital of Philadelphia Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan M.","family":"Parks","sequence":"additional","affiliation":[{"name":"Division of Geriatric Medicine &amp; Palliative Care, Department of Family &amp; Community Medicine Thomas Jefferson University Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrzej","family":"Steplewski","sequence":"additional","affiliation":[{"name":"Division of Orthopaedic Research, Department of Orthopaedic Surgery Thomas Jefferson University Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. Lee","family":"Osterman","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Thomas Jefferson University Philadelphia Pennsylvania"},{"name":"Philadelphia Hand to Shoulder Center Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irving M.","family":"Shapiro","sequence":"additional","affiliation":[{"name":"Division of Orthopaedic Research, Department of Orthopaedic Surgery Thomas Jefferson University Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,4,2]]},"reference":[{"key":"e_1_2_8_2_1","first-page":"625","article-title":"Fibrocartilage associated with human tendons and their pulleys","volume":"187","author":"Benjamin M.","year":"1995","journal-title":"Journal of Anatomy"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00586-011-1975-3"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm1630"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1177\/036354657900700206"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0009188"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1474-9726.2007.00307.x"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2015.06.020"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1474-9726.2007.00336.x"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-018-0064-2"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/stem.308"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0307512101"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.aca.2013.03.053"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.23797"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M100677200"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.2106\/00004623-199173100-00009"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1034\/j.1600-0838.2000.010006312.x"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200201105"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1186\/scrt165"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1177\/0363546514526691"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13287-015-0097-y"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0278-5919(03)00004-8"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/boneres.2015.15"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1097\/BSD.0000000000000330"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1534-5807(04)00075-9"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2016.213"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2011.154229"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.183699"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1097\/00003086-196500410-00020"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.139303"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.112714"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.00427"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2474-13-140"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2007.03.520"},{"key":"e_1_2_8_35_1","first-page":"50","article-title":"The effects of hypoxia on human skin, lung and tendon cells in vitro","volume":"63","author":"Webster D. 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