Session Title: Rheumatoid Arthritis - Animal Models
Session Type: Abstract Submissions (ACR)
Background/Purpose: AMP-activated protein kinase (AMPK) is a serine/threonine protein kinase involved in the regulation of cellular energy homeostasis. It is a central regulator of both lipid and glucose metabolism. Many studies have suggested that AMPK activation can also exert significant anti-inflammatory and immunosuppressive effects. We evaluated whether modulating this pathway altered pathogenic mechanisms in inflammatory arthritis.
Methods: The AMPK agonist A-769662 (60mg/kg/bid) was tested in two arthritis models: In antigen induced arthritis (AIA), mice were primed with mBSA in complete Freund’s adjuvant and then given an intraarticular challenge with mBSA in the knee on day 21. In passive serum arthritis, K/BxN serum was injected on day 0. Joints were harvested and prepared for histological assessment. IL-6 expression in joints and sera was measured by ELISA. Human fibroblast-like synoviocyte (FLS) and bone marrow derived macrophage (BMDM) function was tested using A-769662 (250uM) as follows: 1) phosphorylation of p65 NF-kappaB by Western Blot, 2) IL-6 secretion by ELISA, 3) NO secretion by Griess method, 4) cell survival in H2O2 treated cells by phase contrast light microscopy.
Results: AMPK pathway activation by A-769662 reduced inflammatory infiltration and joint damage in both animal models. In passive K/BxN model, day 8 scores were 8.2±3 and 2.4±3 (P<0.05) for vehicle and A-769662-treated mice, respectively. In AIA model joint histology scores for vehicle and A-769662-treated mice for synovial hypertrophy were 2.9±0.9 and 1.6±1.1 (p=0.01), bone erosion scores were 2.2±1 and 1.5±1.1 (p<0.05), and cartilage damage scores were 2±0.6 and 1.2±0.6 (p<0.05), respectively. IL-6 expression in serum and arthritic joints was significantly decreased in A-769662 treated mice. The mechanism of AMPK action was evaluated in FLS and BMDM. AMPK activation with A-762664 reduced IL-6 and NO secretion by 52±5.6% and 76±7.5 %respectively (p<0.05), and p65 NF-kappaB phosphorylation after TLR stimulation in BMDM. Additionally, AMPK activation also significantly increased H2O2-induced apoptosis in FLS.
Conclusion: Activating AMPK pathway suppressed inflammatory arthritis in mice as well as IL-6 expression in serum, arthritic joints and cultured BMDM. These data suggest that AMPK signaling activation could be an effective therapeutic strategy for IL-6 dependent inflammatory arthritis.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/ampk-activation-in-inflammatory-arthritis/