JPET

Home Help [Feedback] [For Subscribers] [Archive] [Search] --
QUICK SEARCH:   [advanced]


     

Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on April 30, 2008; DOI: 10.1124/jpet.108.137372

This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
jpet.108.137372v1
326/2/532    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Earp, J. C.
Right arrow Articles by Jusko, W. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Earp, J. C.
Right arrow Articles by Jusko, W. J.


Received for publication February 1, 2008.
Revised April 10, 2008.
Accepted for publication April 10, 2008.

Modeling Corticosteroid Effects in a Rat Model of Rheumatoid Arthritis I: Mechanistic Disease Progression Model for the Time Course of Collagen-Induced Arthritis in Lewis Rats

Justin C. Earp 1, Debra C. DuBois 1, Diana S. Molano 2, Nancy A. Pyszczynski 1, Craig E. Keller 1, Richard R. Almon 1, William J. Jusko 1*

1 State University of New York - Buffalo 2 State University of New York - Buffalo

* Address correspondence to: E-mail: wjjusko{at}acsu.buffalo.edu

Abstract

A mechanism-based model was developed to describe the time course of arthritis progression in the rat. Arthritis was induced in male Lewis rats with type II porcine collagen into the base of the tail. Disease progression was monitored by paw swelling, bone mineral density (BMD), body weights, plasma corticosterone (CST) concentrations, and TNF-{alpha}, IL-1{beta}, IL-6, and glucocorticoid receptor (GR) mRNA expression in paw tissue. Bone mineral density was determined by PIXImus II dual energy x-ray densitometry. Plasma CST was assayed by HPLC. Cytokine and GR mRNA were determined by quantitative real-time polymerase chain reaction. Disease progression models were constructed from transduction and indirect response models and applied using S-ADAPT software. A delay in the onset of increased paw TNF-{alpha} and IL-6 mRNA concentrations was successfully characterized by simple transduction. This rise was closely followed by an up-regulation of GR mRNA and CST concentrations. Paw swelling and body weight responses peaked approximately 21 days post induction while bone mineral density changes were greatest at 23 days post induction. After peak response the time course in IL-1{beta}, IL-6 mRNA, and paw edema slowly declined towards a disease steady-state. Model parameters indicate TNF-{alpha} and IL-1{beta} mRNA most significantly induce paw edema while IL-6 mRNA exerted the most influence on BMD. The model for bone mineral density captures rates of turnover of cancellous and cortical bone and the fraction of each in the different regions analyzed. This small systems model integrates and quantitates multiple factors contributing to arthritis in rats.


Key words: Arthritis, Bone, Collagen, Corticosteroids, Disease Progression, Inflammation


This article has been cited by other articles:


Home page
 J. Pharmacol. Exp. Ther.Home page
J. C. Earp, D. C. DuBois, D. S. Molano, N. A. Pyszczynski, R. R. Almon, and W. J. Jusko
Modeling Corticosteroid Effects in a Rat Model of Rheumatoid Arthritis II: Mechanistic Pharmacodynamic Model for Dexamethasone Effects in Lewis Rats with Collagen-Induced Arthritis
J. Pharmacol. Exp. Ther., August 1, 2008; 326(2): 546 - 554.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] --
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2008 by the American Society for Pharmacology and Experimental Therapeutics.