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The pathologic lesions of RA are driven through the production of inflammatory mediators in the synovium mediated, in part, by the transcription factor NF-\u03baB. We have identified a non-steroidal estrogen receptor ligand, WAY-169916, that selectively inhibits NF-\u03baB transcriptional activity but is devoid of conventional estrogenic activity. The activity of WAY-169916 was monitored in two models of arthritis, the HLA-B27 transgenic rat and the Lewis rat adjuvant-induced model, after daily oral administration. In both models, a near complete reversal in hindpaw scores was observed as well as marked improvements in the histological scores. In the Lewis rat adjuvant model, WAY-169916 markedly suppresses the adjuvant induction of three serum acute phase proteins: haptoglobin, \u03b11-acid glycoprotein (\u03b11-AGP), and C-reactive protein (CRP). Gene expression experiments also demonstrate a global suppression of adjuvant-induced gene expression in the spleen, liver, and popliteal lymph nodes. Finally, WAY-169916 was effective in suppressing tumor necrosis factor-\u03b1-mediated inflammatory gene expression in fibroblast-like synoviocytes isolated from patients with RA. Together, these data suggest the utility of WAY-169916, and other compounds in its class, in treating RA through global suppression of inflammation via selective blockade of NF-\u03baB transcriptional activity.<\/jats:p>","DOI":"10.1186\/ar1692","type":"journal-article","created":{"date-parts":[[2005,2,19]],"date-time":"2005-02-19T07:25:37Z","timestamp":1108797937000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["The utility of pathway selective estrogen receptor ligands that inhibit nuclear factor-\u03baB transcriptional activity in models of rheumatoid arthritis"],"prefix":"10.1186","volume":"7","author":[{"suffix":"Jr","given":"James C","family":"Keith","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leo M","family":"Albert","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yelena","family":"Leathurby","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Max","family":"Follettie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lili","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa","family":"Borges-Marcucci","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher C","family":"Chadwick","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert J","family":"Steffan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Douglas C","family":"Harnish","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2005,2,21]]},"reference":[{"key":"1572_CR1","doi-asserted-by":"publisher","first-page":"1762","DOI":"10.1002\/art.1780381209","volume":"38","author":"ML Handel","year":"1995","unstructured":"Handel ML, McMorrow LB, Gravallese EM: Nuclear factor-kappa B in rheumatoid synovium. 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