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Abstract Number: 2790

Regulation of ASK1 Expression and Its Role in Rheumatoid Arthritis (RA)

Gyrid Nygaard1, Deepa Hammaker2, David L. Boyle3, Li Li4, Julie Di Paolo5 and Gary S. Firestein6, 1Medicine, UC San Diego, La Jolla, CA, 2Division of Rheumatology, Allergy and Immunology, UCSD School of Medicine, La Jolla, CA, 3University of California San Diego, La Jolla, CA, 4Gilead Sciences, South San Francisco, CA, 5Immunology and Inflammation Biology, Gilead Sciences, Foster City, CA, 6Medicine, University of California San Diego, La Jolla, CA

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

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

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Session Information

Date: Tuesday, November 7, 2017

Title: Rheumatoid Arthritis – Human Etiology and Pathogenesis I

Session Type: ACR Concurrent Abstract Session

Session Time: 2:30PM-4:00PM

Background/Purpose: Rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) reside in the synovial intimal lining. They display a unique aggressive phenotype, invading the articular cartilage and promoting inflammation. Elevated mitogen activated protein kinase (MAPK) signaling occurs in RA, but targeting downstream MAPKs like p38 has had minimal success. As an alternative approach, we focused on the upstream MAPK kinase kinase, apoptosis signal regulating kinase-1 (ASK1). ASK1 can regulate p38 and JNK, and aberrant ASK1 signaling has been implicated in cancer, neurodegenerative diseases and inflammatory and cardiovascular disorders. We examine the regulation of ASK1 expression in RA FLS and its role in the collagen-induced arthritis (CIA) model using a novel ASK1 inhibitor.

Methods: Synovial tissue was obtained from RA and osteoarthritis (OA) patients during joint replacement surgery or synovectomy. Gene expression was assessed by qPCR. ASK1 promoter activity was measured using minimal promoter luciferase reporter constructs that included a 1.3 kb (Full Length) region, a 994 kb lacking the RelA binding site (Truncated), or a full length region with a mutated upstream RelA-binding site. A novel selective ASK1 inhibitor (ASK1i) was used in the rat collagen induced arthritis (CIA) model, and animals received treatment by oral gavage from day 10 through day 16. Ankle diameters were measured and histology was evaluated for inflammation, pannus formation, cartilage damage, and bone resorption.

Results: A strong correlation was found between ASK1 and IL-1β mRNA expression in synovium (n = 20, r2 = 0.62, p = 0.00003), and to a lesser degree between ASK1 and TNF mRNA (r2 = 0.45, p = 0.001). No correlation was found between ASK1 and IL-6 mRNA (r2 = 0.01, p = 0.61). Because previous studies showed that IL-1 increases ASK1 expression in FLS, the mechanism behind the increased gene expression was explored using ASK1 reporter constructs. ASK1 promoter activity for the Full Length construct was significantly increased by IL-1β (40-fold ±10 increase, n = 6, p = 0.012) and TNF (15-fold ± 3, 6 hr, n = 3, p = 0.011) compared with control construct. Increased transcription was eliminated in the Truncated construct and in the construct with the mutated RelA binding motif. These results confirm that ASK1 is induced at the transcriptional level after IL-1β and TNF stimulation and identifies the RelA motif as the primary regulatory region. To determine if ASK1 plays a role in inflammatory arthritis, CIA rats were treated with ASK1i. The inhibitor significantly decreased ankle swelling in the CIA rat model in a dose-dependent fashion, resulting in a 46 ± 8.8% and 48 ± 9.9 % decrease at day 16 for animals treated with 3 mg and 10 mg/kg, respectively, compared with vehicle (n = 8 per group, p < 0.05). ASK1i decreased histologic severity, with 36 ± 12% reduction in total histology score for 10 mg/kg compared with vehicle (n = 8, p < 0.05).

Conclusion: IL-1β and TNF regulate ASK1 through the RelA binding motif in the ASK1 promoter and synovial cytokine expression correlates with synovial ASK1 mRNA. A novel small molecule ASK1 inhibitor significantly decreased disease severity in CIA. The data support advancing an ASK1 inhibitor as a potential therapeutic target for RA.


Disclosure: G. Nygaard, None; D. Hammaker, None; D. L. Boyle, None; L. Li, Gilead, 3; J. Di Paolo, Gilead, 3; G. S. Firestein, Gilead, 2.

To cite this abstract in AMA style:

Nygaard G, Hammaker D, Boyle DL, Li L, Di Paolo J, Firestein GS. Regulation of ASK1 Expression and Its Role in Rheumatoid Arthritis (RA) [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/regulation-of-ask1-expression-and-its-role-in-rheumatoid-arthritis-ra/. Accessed .
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