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The utility of pathway selective estrogen receptor ligands that inhibit nuclear factor-κB transcriptional activity in models of rheumatoid arthritis

James C Keith1, Leo M Albert1, Yelena Leathurby1, Max Follettie2, Lili Wang2, Lisa Borges-Marcucci3, Christopher C Chadwick4, Robert J Steffan5 and Douglas C Harnish3*

Author Affiliations

1 Cardiovascular and Metabolic Disease Research, Wyeth Research, Cambridge, MA, USA

2 Department Biological Technologies, Cambridge, MA, USA

3 Cardiovascular and Metabolic Disease Research, Collegeville, PA, USA

4 Women's Health Research Institute, Collegeville, PA, USA

5 Chemical and Screening Sciences, Collegeville, PA, USA

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Arthritis Research & Therapy 2005, 7:R427-R438  doi:10.1186/ar1692

Published: 21 February 2005


Rheumatoid arthritis (RA) is a chronic inflammatory disease that produces synovial proliferation and joint erosions. The pathologic lesions of RA are driven through the production of inflammatory mediators in the synovium mediated, in part, by the transcription factor NF-κB. We have identified a non-steroidal estrogen receptor ligand, WAY-169916, that selectively inhibits NF-κB 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, α1-acid glycoprotein (α1-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-α-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-κB transcriptional activity.