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

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 tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, 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 high-performance liquid chromatography. 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 after induction, whereas bone mineral density changes were greatest at 23 days after induction. After peak response, the time course in IL-1beta, IL-6 mRNA, and paw edema slowly declined toward a disease steady state. Model parameters indicate TNF-alpha and IL-1beta mRNA most significantly induce paw edema, whereas 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.