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Abstract Number: 456

AAA-Atpase p97 Regulates Autophagy-Associated Cell Death in Arthritis

Masaru Kato1, Kerstin Klein2, Caroline Ospelt2, Christoph Kolling3, Michihito Kono1, Shinsuke Yasuda1, Renate E. Gay4, Steffen Gay2 and Tatsuya Atsumi1, 1Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo, Japan, 2Center of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland, 3Schulthess Clinic, Zurich, Switzerland, 4Center of Experimental Rheumatology, Zurich University Hospital, Zurich, Switzerland

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: Autophagy and rheumatoid arthritis, synovium

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Session Information

Session Title: Rheumatoid Arthritis - Human Etiology and Pathogenesis

Session Type: Abstract Submissions (ACR)

Background/Purpose: Recently we described a hypersensitivity of rheumatoid arthritis synovial fibroblasts (RASF) compared to osteoarthritis synovial fibroblasts to autophagy under conditions of severe endoplasmic reticulum (ER) stress, leading to a massive cytoplasmic vacuolization, the formation of poly-ubiquitinated protein aggeregates and non-apoptotic cell death. Valosin containing protein (p97/VCP) is an ATPase implicated in the degradation of ubiquitin-labelled proteins through the proteasome. We hypothesized that the inhibition of p97 further sensitizes RASF to autophagy-associated cell death due to impaired proteasomal degradation and subsequent overloaded autophagy.

Methods: RASF were transfected with siRNA targeting p97 or treated with the selective p97 inhibitor DBeQ (5 μM). To induce ER stress, RASF were treated with thapsigargin (TG, 5 nM-5 μM). 3-methyladenine (5 mM) was used as an autophagy inhibitor. The distribution of poly-ubiquitinated proteins was evaluated by immunofluorescence microscopy. Cell death was evaluated by flow cytometry using annexin V/propidium iodide staining. Collagen-induced arthritis (CIA) was induced in Lewis rats. Scrambled or p97 siRNA-atelocollagen complexes were injected into ankle joints of rats. Three, seven and eleven days after the injection, CIA was scored from 0 to 4 according to paw thickness and ankle diameter.

Results: Both siRNA-mediated knockdown and inhibition of p97 in RASF boosted a cytoplasmic vacuolization, the formation of poly-ubiquitinated protein aggeregates and cell death under 5 μM TG treatment, and this cell death was inhibited by 3-methyladenine. Smaller amounts of TG (50 or 500 nM) induced a cytoplasmic vacuolization and the formation of poly-ubiquitinated protein aggeregates in p97–inhibited RASF but not in control RASF. Intra-articular injection of p97 siRNA significantly suppressed CIA (Day 3, p = 0.002; Day 7, p = 0.002; Day 11, p = 0.04; n = 6) in rats.

Conclusion: Our data indicate that the inhibition of p97 promotes autophagy-associated cell death in RASF and suppresses CIA in vivo. p97 may be a new potential target in the treatment of arthritis.


Disclosure:

M. Kato,
None;

K. Klein,
None;

C. Ospelt,
None;

C. Kolling,
None;

M. Kono,
None;

S. Yasuda,
None;

R. E. Gay,
None;

S. Gay,
None;

T. Atsumi,
None.

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