Organ messenger ribonucleic acid and plasma proteome changes in the adjuvant-induced arthritis model: responses to disease induction and therapy with the estrogen receptor-beta selective agonist ERB-041.
Two receptors [estrogen receptor (ER)alpha and ERbeta] mediate the manifold effects of estrogens throughout the body. Although a clear role has been established for ERalpha in the classical effects of estrogen activity, the physiological role of ERbeta is less well understood. A small-molecule ERbeta selective agonist, ERB-041, has potent antiinflammatory activity in the Lewis rat model of adjuvant-induced arthritis. To characterize the response of target organs and pathways responsible for this antiinflammatory effect, mRNA expression profiling of the spleen, lymph node, and liver was performed, in conjunction with a global analysis of the plasma proteome. We find that the expression of a large number of genes and proteins are altered in the disease model and the majority of these are partially or fully reversed by ERB-041 treatment. Regulated pathways include the acute-phase response, eicosanoid synthesis, fatty acid metabolism, and iron metabolism. In addition, many of the regulated genes and proteins are known to be dysregulated in human rheumatoid arthritis, providing further evidence that the manifestations of the Lewis rat adjuvant-induced arthritis model bear similarity to the human disease.
Follettie
Maximillian T
MT
Biological Technologies, Wyeth Research, Cambridge, Massachusetts 02140, USA.
Pinard
Marc
M
Keith
James C
JC
Wang
Lili
L
Chelsky
Daniel
D
Hayward
Clive
C
Kearney
Paul
P
Thibault
Pierre
P
Paramithiotis
Eustache
E
Dorner
Andrew J
AJ
Harris
Heather A
HA
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D001798:Blood Proteins / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000819:agonists*; D020869:Gene Expression Profiling; D008099:Liver / Q000378:metabolism; D008198:Lymph Nodes / Q000378:metabolism; D008297:Male; D009928:Organ Specificity; D010080:Oxazoles / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D011917:Rats, Inbred Lew; D013154:Spleen / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D001798:Blood Proteins; C478102:ERB 041; D047629:Estrogen Receptor beta; D010080:Oxazoles; D012333:RNA, Messenger