Background/Purpose: Arthritis is among the most common chronic diseases in both children and adults. Joint inflammation is a feature in both age groups but there are age-related disparities in clinical manifestations, disease courses, and treatment efficacy and safety.  Collagen-Induced Arthritis (CIA) in rodents is a model of arthritis that has utility in assessing pathogenic processes and efficacy of treatments. However, the CIA model has been applied to adult animals but not to juveniles.  This study compared clinical, imaging and biologic characteristics of CIA in adult and juvenile animals. Determining age-related differences of CIA should improve understanding of age-specific inflammatory processes and help design treatment interventions tailored to age.

Methods: Juvenile (5 wks old) and young adult (13 wks old) male Wistar rats were immunized with an emulsion of bovine type II collagen/incomplete Freund’s adjuvant. Naïve juvenile and adult rats served as controls.  Baseline measures included paw thickness, thermal and mechanical thresholds and footprint analysis.  Following arthritis onset, measures were repeated every 3 days. For each animal, the Maximum Daily Arthritis Index (MAI) score and daily weight were measured. Fourteen days after arthritis onset, animals were euthanized and blood and tissues collected.  Paws were imaged by Micro-CT and quantified with a 6 point scale to rate bone destruction and density. Plasma was assayed by enzyme immunoassay with a rat 27-plex cytokine/chemokine array. Dorsal root ganglia and spinal cord immunohistochemistry assessed pro-inflammatory high mobility group box-1 (HMGB1), receptor for advanced glycation end products (RAGE) and the resolvin  D1 receptors G-protein coupled receptor 32 (GPR32) and formyl peptide receptor 2 (FPR2). 

Results: Juvenile CIA rats had significantly lower MAI compared to adults (p<0.0001).  Adult CIA rats had significant increases in the thickness of the ankle (p=<0.0001), the paw distal to the tarsus (p=<0.0001) and the phalanges (p=<0.0001) while juvenile rats had significant increase only in paw thickness distal to the tarsus (p=<0.0001). Analysis of chemokine/cytokine profiles revealed that Juvenile CIA rats had lower levels of interleukin-10 (p=0.04); and higher levels of the chemokine fracktalkine (p=0.02). Levels of HMGB1 and RAGE were highest in adult CIA rats while juvenile rats had higher levels of GPR32 and FPR2. Adult CIA rats had a decrease in toe spread compared to juvenile CIA rats (p<0.0001). Micro-CT scores were not significantly different between the two groups (p=0.40).

Conclusion: Adult rats have more severe CIA than juveniles. Our results indicate age-related differences in arthritis severity are related to the balance between HMGB1 and resolvins and their respective receptors with the balance favouring promotion of inflammation in adults associated with higher levels of HMGB1 and lower levels of resolvins. Juveniles produce more resolvins that may impede transition from acute to chronic arthritis. We postulate that anti-inflammatory effects of endongenous resolvins are mediated by impeding production of HMGB1 and/or HMGB1 binding to its receptors.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/age-related-differences-in-collagen-induced-arthritis-clinical-imaging-and-biological-characteristics-in-juvenile-compared-to-adult-animals/