{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T21:51:28Z","timestamp":1792705888947,"version":"4.5.0"},"reference-count":50,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2014,11,25]],"date-time":"2014-11-25T00:00:00Z","timestamp":1416873600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Health Research Board of Ireland"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2014,12]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Inflammatory arthritis is associated with joint inflammation, synovial tissue proliferation, and degradation of articular cartilage and bone. Angiogenesis is an early and fundamental component of synovial inflammation. Oxygen metabolism is recognized as an important mediator of joint vascular remodeling. The aim of this study was to determine whether in vivo synovial hypoxia (tissue P<jats:sc>O<\/jats:sc><jats:sub>2<\/jats:sub> [tP<jats:sc>O<\/jats:sc><jats:sub>2<\/jats:sub>]) and tumor necrosis factor (TNF) blocking therapy alter synovial vascular expression of NADPH oxidase (NOX) and how this action regulates angiogenic mechanisms.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>NOX\u20102 protein and messenger RNA expression was examined in patients with inflammatory arthritis before and after receiving TNF inhibitor (TNFi) therapy and in mice with collagen\u2010induced arthritis (CIA). Proangiogenic processes were assessed in human microvascular endothelial cells (HMVECs) following culture with NOX\u20102 activators (TNF\u03b1 and 4\u2010hydroxynonenal), small interfering RNA (siRNA) for NOX, and the inhibitor diphenyleneiodonium (DPI) under conditions of normoxia or 3% hypoxia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We demonstrated significantly increased NOX\u20102 expression in the joints of patients with inflammatory arthritis and the joints of mice with CIA as compared to controls. NOX\u20102 expression was higher in patients with synovial tP<jats:sc>O<\/jats:sc><jats:sub>2<\/jats:sub> levels &lt;3% than in those with tP<jats:sc>O<\/jats:sc><jats:sub>2<\/jats:sub> levels &gt;3% (<jats:italic>P<\/jats:italic> &lt; 0.05), and correlated with in vivo macroscopic\/microscopic measures of angiogenesis, such as vascularity and levels of vascular endothelial growth factor, angiopoietin 2, factor VIII, neural cell adhesion molecule, and \u03b1\u2010smooth muscle actin (<jats:italic>P<\/jats:italic> &lt; 0.05 for all). A decrease in NOX\u20102 expression was paralleled by an increase in in vivo tP<jats:sc>O<\/jats:sc><jats:sub>2<\/jats:sub>levels only in those patients who were defined as TNFi responders. In vitro NOX\u20102 activators and 3% hypoxia significantly promoted HMVEC migration, angiogenic tube formation, and secretion of proangiogenic mediators, effects that were blocked by siRNA for NOX\u20102 or the NOX\u20102 inhibitor DPI.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>We demonstrated that hypoxia activates NOX\u20102 protein expression, and NOX\u20102\u2013induced oxidative stress may be an initiating factor in driving angiogenesis.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.38822","type":"journal-article","created":{"date-parts":[[2014,8,22]],"date-time":"2014-08-22T11:47:47Z","timestamp":1408708067000},"page":"3300-3310","source":"Crossref","is-referenced-by-count":45,"title":["Redox\u2010Mediated Angiogenesis in the Hypoxic Joint of Inflammatory Arthritis"],"prefix":"10.1002","volume":"66","author":[{"given":"Monika","family":"Biniecka","sequence":"first","affiliation":[{"name":"Dublin Academic Medical Centre and St. Vincent's University Hospital Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Connolly","sequence":"additional","affiliation":[{"name":"Dublin Academic Medical Centre and St. Vincent's University Hospital Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Gao","sequence":"additional","affiliation":[{"name":"Dublin Academic Medical Centre and St. Vincent's University Hospital Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chin T.","family":"Ng","sequence":"additional","affiliation":[{"name":"University of Malaya Kuala Lumpur Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emese","family":"Balogh","sequence":"additional","affiliation":[{"name":"Dublin Academic Medical Centre and St. Vincent's University Hospital Dublin 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