SAT0036 Brain IGF1 Receptor Signaling Controls Behavior of Arthritic Mice
Authors: K. Andersson, L. Leifsdottir, M. Erlandsson, S. Töyrä, M. Pekna, M. Pekny, K. Olmarker, M. Bokarewa
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background</h3> Insulin-like growth factor (IGF-1) signaling is essential for development and function of the brain. It helps to improve neuronal plasticity in response to stress, and recently it has been reported to mediate depression [1]. In rheumatoid arthritis (RA), depression is a serious comorbidity with a tight connection to functional disability and early mortality [2]. The serum levels of IGF-1 and the local expression of its receptor (IGF-1R) in inflamed joints are affected in RA [3]. However, the brain IGF-1R signaling in arthritis and its consequences for behavior has not been studied previously. <h3>Objectives</h3> In this study we analyze how arthritis affects IGF-1R expression and activity in the brain and its relation to behavioral changes. <h3>Methods</h3> Arthritis was induced in DBA/1 mice by immunization with collagen type II. Development of arthritis was followed clinically. One group was treated with shRNA targeting IGF1R, second group obtained control shRNA, and naïve healthy siblings comprised the control group. Behavioral pattern of each mouse was registered by filming at different stages. Protein and mRNA levels of IGF-1R, CD68 and IL-1b were measured in different parts of the brain with IHC and real-time PCR. Serum IGF-1 and IL6 were analyzed with a sandwich ELISA. We validated the findings from experimental arthritis with a cohort of 235 patients with established RA. <h3>Results</h3> In RA patients, the arbitrary measure of pain (VAS) was mainly associated with depression index (FIQ, r=0.46), fatigue (r=0.44), and disability index (r=0.68) rather than to RA activity (DAS28, r=0.36). In mice, arthritis decreased locomotion and rearing, corresponding to the depressive-like behavioral pattern. Severity of arthritis and decreased mobility correlated with the increased mRNA levels of inflammatory cytokine IL-1, and a marker of activated microglia CD68. We observed a decreased expression of IGF-1R and a remarkable reduction in the number and regularity of the Purkinje cells in the cerebellum accompanied by an accumulation of phosphorylated tau along these cells. Arthritis increased serum levels of IGF-1, which correlated with behavioral pattern in arthritic mice. When the IGF1R signaling was inhibited with shIGF1R-treatment, the arthritic mice showed aggravation of the depressive-like behavior, including increased immobility time, which was no longer correlated to severity of arthritis. <h3>Conclusions</h3> Depression and functional disability aggravate pain experience in RA patients. Arthritis-induced inhibition of IGF-1R expression and signaling provide molecular mechanism of depression in RA. <h3>References</h3> Kopczak A, et al. IGF-I in major depression and antidepressant treatment response. Eur Neuropsychopharmacol. 2015 Jun; 25(6):864–872. Ang DC, et al. Comorbid depression is an independent risk factor for mortality in patients with rheumatoid arthritis. J Rheumatol. 2005 Jun; 32(6):1013–1019. Bostrom EA, et al Resistin and insulin/insulin-like growth factor signaling in rheumatoid arthritis. Arthritis Rheum. 2011 Oct; 63(10):2894–2904. <h3>Disclosure of Interest</h3> None declared