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Abstract Number: 773

Adioponectin-Induced p38 MAPK and AMPK Pathways In Rheumatoid Arthritis Synovial Fibroblasts Are Adiponectin Isoform Dependent

Kiran Khawaja1, Klaus W. Frommer1, Stefan Rehart2, Ulf Müller-Ladner1 and Elena Neumann3, 1Internal Medicine and Rheumatology, Justus-Liebig-University of Gießen, Kerckhoff-Klinik, Bad Nauheim, Germany, 2Orthopedics and Trauma Surgery, Markus-Hospital, Frankfurt, Germany, 3Department of Internal Medicine and Rheumatology, Justus-Liebig-University of Gießen, Kerckhoff-Klinik, Bad Nauheim, Germany

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: Adipokines, rheumatoid arthritis (RA) and signal transduction

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Session Information

Title: Cytokines, Mediators, Cell-cell Adhesion, Cell Trafficking and Angiogenesis I: Identifying Novel Factors that Facilitate Neovascularization and Cell Trafficking

Session Type: Abstract Submissions (ACR)

Background/Purpose: Adiponectin, a C1q/tumour necrosis factor (TNF) homologue, was previously known to be secreted by adipocytes. Additionaly, it was found to be synthesized by other cells types like osteoblasts and synovial fibroblasts. Adiponectin levels were found to be high in synovial fluid of rheumatoid arthritis (RA) patients as compared to osteoarthritis patients, hence suggesting a role of adiponectin in the pathophysiology of the disease. Based on this, RA synovial fibroblasts (SF) are the key cells to secrete adiponectin in the synovium in vivo. At present, four different adiponectin isoforms are known, namely the globular, low molecular weight (LMW), middle molecular weight (MMW) and high molecular weight (HMW) form. Adiponectin acts by binding to its receptors AdipoR1, AdipoR2, and potentially PAQR3 and PAQR10, which leads to the activation of signaling cascades involving key molecules like AMPK, p38 MAPK, FAK, and ERK. The aim of the present study was to determine the adiponectin receptor expression in RASF and to elucidate the specificity of adiponectin isoforms mediating different signaling pathways in RASF.

Methods: AdipoR1, AdipoR2, PAQR3 and PAQR10 mRNA and protein expression were analyzed in RASF by real-time PCR, Western blotting, and immunocytochemistry. RASF were preincubated with serum-free medium for 30 min with or without signaling inhibitors. Stimulation of RASF was performed using the respective adiponectin isoforms, WT (wild type, contains all isoforms), LMW, globular and MMW/HMW enriched adiponectin isoform (each 10 µg/ml) for 10 min. Then a phosphorylation analysis of p38 MAPK, AMPK, and FAK by Western blotting was performed.

Results: Real-time PCR and Western blotting results showed that cultured RASF express AdipoR1, AdipoR2, and PAQR3 but not PAQR10. This was further confirmed by immunocytochemical analysis. With respect to signaling, phosphorylation of p38 MAPK increased by adiponectin isoform stimulation, with the strongest induction by the MMW/HMW enriched isoform. Similarly, the phosphorylation of AMPK increased in response to adiponectin isoforms and the effect was stronger with the MMW/HMW enriched isoform. On the contrary, although FAK was detectable, no induction or repression in FAK phosphorylation was observed in response to adiponectin isoform stimulation indicating that FAK does not play a role in adiponectin-mediated signaling. The increase in phosphorylation of AMPK was further enhanced by AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) and was reduced by AMPK inhibitor compound C. Compound C caused a further increase in the adiponectin isoform-induced enhanced phosphorylation of p38. Pre-treatment with p38 inhibitor SB203580 did not have any effect on the phosphorylation of AMPK.

Conclusion: Cultured RASF express the adiponectin receptors AdipoR1, AdipoR2 and PAQR3. Adiponectin signaling in RASF is mediated via the p38 MAPK and AMPK pathway but not FAK, and the effect is adiponectin isoform-dependent. The data suggest that the p38 MAPK pathway is a compensatory pathway for the AMPK pathway but not vice versa.


Disclosure:

K. Khawaja,
None;

K. W. Frommer,
None;

S. Rehart,
None;

U. Müller-Ladner,
None;

E. Neumann,
None.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/adioponectin-induced-p38-mapk-and-ampk-pathways-in-rheumatoid-arthritis-synovial-fibroblasts-are-adiponectin-isoform-dependent/

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