The Effects of Wheel-Running Using the Upper Limbs Following Immobilization After Inducing Arthritis in the Knees of Rats

This study investigated the effects of wheel-running using the upper limbs following immobilization after inducing arthritis in the knees of rats. Forty male Wistar rats (aged 8 weeks) divided into four groups randomly: arthritis (AR), immobilization after arthritis (Im), wheel-running exercise with the upper limbs following immobilization after arthritis induction (Im+Ex) and sham arthritis induction (Con). The knee joints of the Im and Im+Ex groups were immobilized with a cast for 4 weeks. In the Im+Ex group, wheel-running exercise was administered for 60 min/day (5 times/week). The swelling and the pressure pain threshold (PPT) of the knee joint were evaluated for observing the condition of inflammatory symptoms in affected area, and the paw withdraw response (PWR) was evaluated for observing the condition of secondary hyperalgesia in distant area. Especially, in order to evaluate histological inflammation in the knee joint, the number of macrophage (CD68-positive cells) in the synovium was examined. The expression of calcitonin gene-related peptide (CGRP) in the spinal dorsal horn (L2-3 and L4-5) was examined to evaluate central sensitization. The Im+Ex group showed a significantly better recovery than the Im group in the swelling, PPTs, and PWRs. Additionally, CGRP expression of the spinal dorsal horn (L2-3 and L4-5) in the Im+Ex group was significantly decreased compared with the Im group. According to the results, upper limb exercise can decrease pain in the affected area, reduce hyperalgesia in distant areas, and suppress the central sensitization in the spinal dorsal horn by triggering exercise-induced hypoalgesia (EIH).

Benzylideneacetophenone Derivative Alleviates Arthritic Symptoms via Modulation of the MAPK Signaling Pathway

The benzylideneacetophenone derivative 3-(4-hydroxy-3-methoxy-phenyl)-1-{3-[1]-phenyl}-propenone (JC3 dimer) was synthesized through the dimerization of JC3. To investigate the inhibitory effects of JC3 dimer, the carrageenan/kaolin (C/K)-induced knee arthritis rat model was used in vivo and rheumatoid arthritis (RA) patient-derived fibroblast-like synoviocytes (FLS) were used in vitro. In the C/K rat model, JC3 dimer was given after arthritis induction for 6 days at the concentrations of 1, 5, or 10 mg/kg/day. Manifestation of arthritis was evaluated using knee thickness, weight distribution ratio (WDR), and squeaking test. The levels of prostaglandin E2 (PGE2), interleukin (IL)-6, and tumor necrosis factor (TNF)-α in the serum of JC3 dimer-treated arthritic rats were also analyzed. Histological examination of the knee joints was also done. For the FLS, the cells were stimulated using IL-1β and concentrations of 1, 5, and 10 μg/mL JC3 dimer were used. The levels of IL-8, IL-6, and PGE2 were measured in stimulated FLS treated with JC3 dimer. At days 5 to 6 after arthritis induction, JC3 dimer treatment significantly decreased arthritic symptoms and reduced the inflammation in the knee joints in the histology of knee tissues in C/K-arthritic rats. In stimulated FLS, JC3 dimer suppressed the increase of IL-8, IL-6, and PGE2. These findings suggest that JC3 dimer has suppressive effects on arthritis, and that JC3 dimer can be a potential agent for arthritis therapy.

THU0068 COMPARISON OF INFLAMMATION DURING METABOLIC CHANGES IN RHEUMATOID AND OSTEOARTHRITIS MOUSE MODELS

Background:Arthritis is influenced by metabolic changes. Adipokines are bioactive factors produced by adipose tissue with important effects on energy homeostasis and immune responses but are also involved in the pathogenesis of rheumatoid arthritis (RA) and osteoarthritis (OA).Objectives:To evaluate inflammation during metabolic and adipokine induced changes in experimental models of RA and OA at different time points, an obesity model (high-fat-died, HFD) was therefore combined with an OA (DMM, destabilization of the medial meniscus) and RA (collagen induced arthritis, CIA) mouse model.Methods:Mice were fed with HFD or ND (normal diet) for 12 (OA) or 6 (RA) weeks prior to arthritis induction. DMM was performed in C57Bl/6 mice and CIA was induced in DBA/1Rj mice. After 4, 6 and 8 (DMM) or after 4, 5 and 7 weeks (CIA) of arthritis induction animals were sacrificed to collect histological and serological data. Clinical scoring for CIA and histological scorings for both models were performed to evaluate disease development and progression. Diet-induced effects were monitored by weight, fatty liver score and crown-like structures (CLS) counts in adipose tissue. To evaluate HFD-induced adipokine levels adiponectin, leptin and visfatin serum concentrations were measured in parallel to the CRP. Local tissue adipokine expression was evaluated by immunohistochemistry.Results:Induction of OA and RA was successful in an HFD setting, shown by histological joint destruction and the increased fatty liver score and bodyweight. Compared to healthy animals, CRP levels were significantly increased after CIA induction, confirming systemic inflammation. In DMM, the number of CLS were significantly higher in HFD (0.2 ± 0.16, n=7) compared to ND (5.2 ± 0.98, n=8). No difference was found in CIA-severity between HFD and ND. However, CIA induction increased the number of CLS in HFD (2.77 ± 1.07, n=6) and interestingly in ND animals (8.14 ± 0.23, n=5) compared to healthy ND (0.45 ± 0.03, n=4) and healthy HFD mice (2.57 ± 0.53, n=4) without CIA. As expected, HFD led to a significant increase in systemic leptin in healthy animals in both models. Interestingly, CIA and DMM induction decreased systemic leptin levels significantly in ND and HFD, which was more prominent in CIA. The systemic effect was not reflected by local leptin distribution in the joints (CIA) which were not altered by diet. 5. and 7 weeks after CIA induction HFD led to a reduction in local adiponectin and visfatin expression, which were not reflected in systemic levels.Conclusion:The data show that HFD deteriorates OA, which is similar to observations in humans. In contrast, HFD induction showed no significant difference in CIA severity compared to ND. Furthermore, CIA reduced local adipokine expression under HFD at later time points but not under ND. According to high numbers of CLS in ND/CIA animals and the strong reduction of leptin in CIA with HFD, CIA onset and severity seems to be obesity independent and more dependent on inflammation while OA appears to be directly influenced by obesity. However, HFD-induced obesity seems to alter local and systemic adipokine expression also in CIA. Interestingly, local adipokine distribution in affected joints was independent from systemic adipokine levels.Disclosure of Interests:Hani Manfred Sauermilch: None declared, Marie-Lisa Hülser: None declared, Carina Schreiyäck: None declared, Yubin Luo: None declared, Aline Bozec: None declared, Georg Schett Speakers bureau: AbbVie, BMS, Celgene, Janssen, Eli Lilly, Novartis, Roche and UCB, Ulf Müller-Ladner Speakers bureau: Biogen, Elena Neumann: None declared

Evaluation of Anti-Inflammatory Potential of the New Ganghwaljetongyeum on Adjuvant-Induced Inflammatory Arthritis in Rats

Ganghwaljetongyeum (GHJTY) has been used as a standard treatment for arthritis for approximately 15 years at the Korean Medicine Hospital of Dongshin University. GHJTY is composed of 18 medicinal herbs, of which five primary herbs were selected and named new Ganghwaljetongyeum (N-GHJTY). The purpose of the present study was to observe the effect of N-GHJTY on arthritis and to determine its mechanism of action. After confirming arthritis induction using complete Freund’s adjuvant (CFA) in rats, N-GHJTY (62.5, 125, and 250 mg/kg/day) was administered once a day for 10 days. In order to determine pathological changes, edema of the paws and weight were measured before and for 10 days after N-GHJTY administration. Cytokine (TNF-α, IL-1β, and IL-6) levels and histopathological lesions in the knee joint were also examined. Edema in the paw and knee joint of N-GHJTY-treated rats was significantly decreased at 6, 8, and 10 days after administration, compared to that in the CFA-control group, while weight consistently increased. Rats in N-GHJTY-treated groups also recovered from the CFA-induced pathological changes and showed a significant decline in cytokine levels. Taken together, our results showed that N-GHJTY administration was effective in inhibiting CFA-induced arthritis via anti-inflammatory effects while promoting cartilage recovery by controlling cytokine levels.