The evolving systemic and local biomarker milieu at different stages of disease progression in rat adjuvant-induced arthritis.
BACKGROUND
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.


RESULTS
Systemic increases in alpha1 acid glycoprotein, tumor necrosis factor-alpha (TNFalpha), interleukin (IL)-17, transforming growth factor beta (TGFbeta), and chemokine (C-C motif) ligand 2 (CCL2) together with local IL-1alpha/beta and TGFbeta enrichment and local lymphoid hyperplasia preceded the onset of clinical disease and joint damage. Systemic upregulation of TNFalpha, IL-6, IL-17, TGFbeta, IL-18, CCL2, receptor activator of nuclear factor-kappabeta 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-1alpha/beta, IL-6, RANKL, IL-17, TGFbeta, CCL2, and KC/GRO and also a dramatic decline in osteoprotegerin.


CONCLUSIONS
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.
Stolina
Marina
M
Department of Metabolic Disorders, Amgen, Thousand Oaks, CA 91320-1799, USA. mstolina@amgen.com
Bolon
Brad
B
Middleton
Scot
S
Dwyer
Denise
D
Brown
Heather
H
Duryea
Diane
D
Zhu
Li
L
Rohner
Alison
A
Pretorius
James
J
Kostenuik
Paul
P
Feige
Ulrich
U
Zack
Debra
D
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology*; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology*; D018450:Disease Progression; D007136:Immunoglobulins / Q000097:blood*; D007962:Leukocytes / Q000276:immunology* / Q000378:metabolism; D008297:Male; D053244:Osteoprotegerin / Q000097:blood; D053245:RANK Ligand / Q000097:blood; D051381:Rats; D011917:Rats, Inbred Lew
D000276:Adjuvants, Immunologic; D015415:Biomarkers; D016207:Cytokines; D007136:Immunoglobulins; D053244:Osteoprotegerin; D053245:RANK Ligand