The Evolving Systemic and Local Biomarker Milieu at Different Stages of Disease Progression in Rat Adjuvant-Induced Arthritis

Rats with adjuvant-induced arthritis (AIA) were necropsied on 14 occasions during preclinical, acute clinical and chronic clinical stages of AIA progression to characterize local (joint protein extracts) and systemic (serum) levels of mediators regulating inflammation and bone erosion in conjunction with lymphoid tissue-specific leukocyte kinetics. Systemic increases in alpha1 acid glycoprotein, tumor necrosis factor-alpha (TNF alpha), interleukin (IL)-17, transforming growth factor beta (TGF beta), and chemokine (C-C motif) ligand 2 (CCL2) together with local IL-1 alpha/beta and TGF beta enrichment and local lymphoid hyperplasia preceded the onset of clinical disease and joint damage. Systemic upregulation of TNF alpha, IL-6, IL-17, TGF beta, IL-18, CCL2, receptor activator of nuclear factor-kappa I(2) ligand (RANKL), and prostaglandin E(2) during acute and/or chronic AIA coincided with systemic leukocytosis and CD4+ T cell increase in blood and spleen. In contrast, progression of joint erosions during clinical AIA was associated with intra-articular increases in IL-1 alpha/beta, IL-6, RANKL, IL-17, TGF beta, CCL2, and KC/GRO and also a dramatic decline in osteoprotegerin. These data indicate that systemic and local events in inflammatory arthritis are discrete processes, driven by multiple cellular and humoral mediators with distinct kinetic profiles.