The mechanism how RasGRP4 promotes proliferation of synovial fibroblasts in rheumatoid arthritis

• Project/Area Number: 15K09514
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• Research Institution: Hokkaido University
• Principal Investigator: Yasuda Shinsuke 北海道大学, 医学研究院, 准教授 (00374231)
• Project Period (FY): 2015-10-21 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 関節リウマチ / 線維芽細胞様滑膜細胞 / Ras / RasGRP4 / farnesyltransferase / MAPキナーゼ / TNFα

Outline of Final Research Achievements

RasGRP4 is a guanine exchange factor for Ras, expressed mainly in mast cells, monocytes and neutrophils. We previously found aberrant RasGRP4 expression in fibriblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA) that controls proliferation of FLS (Kono, Yasuda et al Arthritis Rheumatol 2015). Downstream of RasGRP4, Ras, MAPK activation was confirmed. We investigated the possibility of treatment targeting RasGRP4-Ras-MAPK pathway. Tipifarnib is a farnesyltransferase inhibitor that inhibits Ras activation, mostly tested in clinical trials for neoplasms. Treatment with tipifarnib inhibited FLS proliferation in a dose-dependent manner (Shimamura, Yasuda et al, EAGOR meeting 2017). We suggest inhibition of Ras activation as a feasible treatment for RA).

Research Products

• [Journal Article] Tocilizumab reduced production of scleroderma-related autoantibodies and anti-cyclic citrullinated protein antibodies in two patients overlapping scleroderma and rheumatoid arthritis (2018)
  • Author(s): Kono M, Yasuda S, Kono M, Atsumi T
  • Journal Title: Scand J Rheumatol Volume: 印刷中 Issue: 3 Pages: 248-250
  • DOI: 10.1080/03009742.2017.1297482
  • Peer Reviewed
• [Journal Article] Effectiveness of whole-body magnetic resonance imaging for the efficacy of biologic anti-rheumatic drugs in patients with rheumatoid arthritis: a retrospective pilot study (2017)
  • Author(s): Kono M, Kamishima T, Yasuda S, Sakamoto K, Abe S, Noguchi A, Watanabe T, Shimizu Y, Oku K, Bohgaki T, Amengual O, Horita T, Atsumi T
  • Journal Title: Mod Rheumatol Volume: 27 Pages: 953-960
  • Peer Reviewed
• [Journal Article] Clinical Benefit of 1-Year Certolizumab Pegol (CZP) Add-on Therapy to Methotrexate Treatment in Early Rheumatoid Arthritis Patients was Observed Following CZP Discontinuation: 2-Year Results of the C-OPERA Study (2017)
  • Author(s): Atsumi T, Tanaka Y, Yamamoto K, Takeuchi T, Yamanaka H, Ishiguro N, Eguchi K, Watanabe A, Origasa H, Yasuda S, Yamanishi Y, Kita Y, Matsubara T, Iwamoto M, Shoji T, Togo O, Okada T, van der Heijde D, Miyasaka N, Koike T
  • Journal Title: Ann Rheum Dis Volume: 76 Issue: 8 Pages: 1348-1356
  • DOI: 10.1136/annrheumdis-2016-210246
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Maintenance Treatment using Abatacept with Dose Reduction after Achievement of Low Disease Activity in Patients with Rheumatoid Arthritis (MATADOR) - A prospective, multicenter, single arm pilot clinical trial (2017)
  • Author(s): Yasuda S, Ohmura K, Kanazawa H, Kurita K, Kon Y, Ishii T, Fujieda Y, Jodo S, Tanimura K, Minami M, Izumiyama T, Matsumoto T, Amasaki Y, Suzuki Y, Kasahara H, Yamauchi N, Kato M, Kamishima T, Tsutsumi A, Takemori H, Koike T, Atsumi T
  • Journal Title: Mod Rheumatol Volume: 27 Issue: 6 Pages: 930-937
  • DOI: 10.1080/14397595.2017.1286714
  • Peer Reviewed
• [Journal Article] Ribophorin II is involved in the tissue factor expression mediated by phosphatidylserine-dependent antiprothrombin antibody on monocytes (2016)
  • Author(s): Fujieda Y., Amengual O., Matsumoto M., Kuroki K., Takahashi H., Kono M., Kurita Y., Otomo K., Kato M., Oku K., Bohgaki T., Horita T., Yasuda S., Maenaka K., Hatakeyama S., Nakayama K.I. and Atsumi T. et al.
  • Journal Title: Rheumatology Volume: 印刷中 Issue: 6 Pages: 1117-1126
  • DOI: 10.1093/rheumatology/kew005
  • Peer Reviewed / Open Access
• [Journal Article] Post-steroid neuropsychiatric manifestations are significantly more frequent in SLE compared with other systemic autoimmune diseases and predict better prognosis compared with de novo neuropsychiatric SLE (2016)
  • Author(s): Shimizu Y, Yasuda S, Kato Y, Nakagawa S, Kanda M, Hisada R, Ohmura K, Shimamura S, Shida H, Fujieda Y, Kato M, Oku K, Bohgaki T, Horita T, Kusumi I, Atsumi T
  • Journal Title: Autoimmunity Reviews Volume: Epub ahead Issue: 8 Pages: 786-794
  • DOI: 10.1016/j.autrev.2016.03.017
  • Peer Reviewed / Open Access
• [Journal Article] Autoantibodies against a complement component 1 q subcomponent contribute to complement activation and recurrent thrombosis/pregnancy morbidity in anti-phospholipid syndrome (2016)
  • Author(s): Oku K, Amengual O, Hisada R, Ohmura K, Nakagawa I, Watanabe T, Bohgaki T, Horita T, Yasuda S, Atsumi T
  • Journal Title: Rheumatology(Oxford) Volume: Epub ahead Issue: 8 Pages: 1403-1411
  • DOI: 10.1093/rheumatology/kew196
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Role of apolipoprotein B100 and oxidized low-density lipoprotein in the monocyte tissue factor induction mediated by anti-b2 glycoprotein I antibodies. (2016)
  • Author(s): Otomo K, Amengual O, Fujieda Y, Nakagawa H, Kato M, Oku K, Horita T, Yasuda S, Matsumoto M, Nakayama KI, Hatakeyama S, Koike T, Atsumi T
  • Journal Title: Lupus Volume: Epub ahead Issue: 12 Pages: 1288-1298
  • DOI: 10.1177/0961203316638165
  • Peer Reviewed / Open Access
• [Journal Article] AAA-ATPase p97 suppress apoptotic and autophagy-associated cell death in rheumatoid arthritis synovial fibroblasts (2016)
  • Author(s): Kato M, Ospelt C, Kolling C, Shimizu T, Kono M, Yasuda S, Michel BA, Gay RE, Gay S, Klein K, Atsumi T
  • Journal Title: Oncotarget Volume: 7 Pages: 64221-64232
  • NAID: 120005905626
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The first double-blind, randomised, parallel-group certolizumab pegol study in methotrexate-naive early rheumatoid arthritis patients with poor prognostic factors, C-OPERA, shows inhibition of radiographic progression (2016)
  • Author(s): Atsumi T, Yamamoto K, Takeuchi T, Yamanaka H, Ishiguro N, Tanaka Y, Eguchi K, Watanabe A, Origasa H, Yasuda S, Yamanishi Y, Kita Y, Matsubara T, Iwamoto M, Shoji T, Okada T, van der Heijde D, Miyasaka N, Koike T
  • Journal Title: Annals of the Rheumatic Diseases Volume: 75 Issue: 1 Pages: 75-83
  • DOI: 10.1136/annrheumdis-2015-207511
  • NAID: 120005697202
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Assessment of risks for pulmonary infection during 12 months after commencing or intensifying immunosuppressive treatment for active connective tissue diseases: A report from a large-scale prospective cohort study (2015)
  • Author(s): Yamazaki H, Sakai R, Koike R, Miyazaki Y, Tanaka M, Nanki T, Watanabe K, Yasuda S, Kurita T, Kaneko Y, Tanaka Y, Nishioka Y, Takasaki Y, Nagasaka K, Nagasawa H, Tohma S, Dohi M, Sugihara T, Sugiyama H, Kawaguchi Y, Inase N, Ochi S, Hagiyama H, Kohsaka H, Miyasaka N, Harigai M
  • Journal Title: Journal of Rheumatology Volume: 42 Issue: 4 Pages: 614-622
  • DOI: 10.3899/jrheum.140778
  • Peer Reviewed
• [Journal Article] An independent validation of the global anti-phospholipid syndrome score in Japanese cohort of patients with antoimmune diseases (2015)
  • Author(s): Oku K, Amengual O, Bohgaki T, Horita T, Yasuda S, Atsumi T
  • Journal Title: Lupus Volume: 24 Issue: 7 Pages: 774-775
  • DOI: 10.1177/0961203314561284
  • Peer Reviewed / Open Access
• [Journal Article] Pulmonary infections following immunosuppressive treatment during hospitalization worsen the short-term vital prognosis for patients with connective tissue disease-associated interstitial pneumonia (2015)
  • Author(s): Tanaka M, Koike R, Sakai R, Saito K, Hirata S, Nagasawa H, Kameda H, Hara M, Kawaguchi Y, Tohma S, Takasaki Y, Dohi M, Nishioka Y, Yasuda S, Miyazaki Y, Kaneko Y, Nanki T, Watanabe K, Yamazaki H, Miyasaka N, Harigai M
  • Journal Title: Modern Rheumatology Volume: 25 Issue: 4 Pages: 609-614
  • DOI: 10.3109/14397595.2014.980384
  • Peer Reviewed
• [Journal Article] β2-glycoprotein I/ HLA class II complexes are novel autoantigens in antiphospholipid syndrome. (2015)
  • Author(s): Tanimura K, Jin H, Suenaga T, Morikami S, Arase N, Kishida K, Hirayasu K, Kohyama M, Ebina Y, Yasuda S, Horita T, Takasugi K, Ohmura K, Yamamoto K, Katayama I, Sasazuki T, Lanier LL, Atsumi T, Yamada H, Arase H.
  • Journal Title: Blood Volume: 125 Issue: 18 Pages: 2835-2844
  • DOI: 10.1182/blood-2014-08-593624
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Head-to-head comparison of the safety of tocilizumab and tumor necrosis factor inhibitors in rheumatoid arthritis patients (RA) in clinical practice: results from the registry of Japanese RA patients on biologics for long-term safety (REAL) registry (2015)
  • Author(s): Ryoko Sakai, Soo-Kyung Cho, Toshihiro Nanki, Kaori Watanabe, Hayato Yamazaki, Michi Tanaka, et al , for the REAL Study Group
  • Journal Title: Arthritis Research & Therapy Volume: 17 Issue: 1 Pages: 74-74
  • DOI: 10.1186/s13075-015-0583-8
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Surveillance for the use of mycophenolate mofetil for adult patients with lupus nephritis in Japan (2015)
  • Author(s): Yasuda S, Atsumi T, Shimamura S, Ono K, Hiromura K, Sada K, Mori M, Takei S, Kawaguchi Y, Tamura N, Takasaki Y
  • Journal Title: Modern Rheumatology Volume: 25 Issue: 6 Pages: 854-857
  • DOI: 10.3109/14397595.2015.1031444
  • Peer Reviewed
• [Journal Article] A national surveillance on current use of mycophenolate mofetil for childhood-onset systemic lupus erythematosus in Japan (2015)
  • Author(s): Hara R, Miyazawa H, Nishimura K, Momoi T, Nozawa T, Kikuchi M, Sakurai N, Kizawa T, Shimamura S, Yasuda S, Hiromura K, Sada K, Kawaguchi Y, Tamura N, Takei S, Takasaki Y, Atsumi T, Mori M
  • Journal Title: Modern Rheumatology Volume: 25 Pages: 858-864
  • Peer Reviewed
• [Journal Article] Projectile haemorrhage of a brachial artery in a patient with clinically amyopathic dermatomyositis (2015)
  • Author(s): Kono M, Yasuda S, Watanabe T, Atsumi T
  • Journal Title: Rheumatology (Oxford) Volume: 54 Issue: 8 Pages: 1530-1531
  • DOI: 10.1093/rheumatology/kev206
  • Peer Reviewed
• [Presentation] Inhibition of Ras translocation suppresses RasGRP4-induced proliferation of fibroblast-like synoviocytes from patients with rheumatoid arthritis (2017)
  • Author(s): Shimamura S, Yasuda S, Kono M, Shimizu Y, Fujieda Y, Kato M, Oku K, Bohgaki T, Atsumi T
  • Organizer: EAGOR meeting, Tokyo, Japan