Exploration of the mechanisms underlying synovial changes in osteoarthritic through comprehensive analysis of signal transduction pathways.

• Project/Area Number: 17K11040
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Clinical Research Center for Allergy and Rheumatology, National Hospital Organization, Sagamihara National Hospital
• Principal Investigator: Fukui Naoshi 独立行政法人国立病院機構(相模原病院臨床研究センター), 政策医療企画部, 特別研究員 (10251258)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 変形性関節症 / 滑膜 / 関節 / 膝 / 滑膜病変 / 関節液 / 痛み

Outline of Final Research Achievements

In this study, signal transduction mechanisms underlying expression of various proteinases in osteoarthritic (OA) synovium were explored by semi-comprehensive analysis using antibody arrays. Through the analysis of human OA synovium, we obtained results indicating that intracellular signal pathways involving Akt, c-Jun and ERK could be involved in the expression of MMPs-1 and 3 in OA synovium. This result supported our hypothesis that these proteinases are expressed together by activated synovial fibroblasts in OA synovium; fibroblasts are known to express MMPs-1 and 3 abundantly when activated in response to the change in the surrounding matrix via integrins. The result also suggested that other mechanisms are likely involved in the induction of those MMP expression. We also explored signal pathways involved in the expression of urokinase in OA synovium, but could not obtain significant results in the given research term.

Academic Significance and Societal Importance of the Research Achievements

最近の疫学研究によってOAにおいても滑膜病変が症状、とくに痛みの出現と軟骨基質の変性・消失の両方に深く関係していることが明らかになってきた。しかし今のところOAにおいてなぜ滑膜に変化が生じるのかは明らかになっていない。本研究の最終的な目的はOAの滑膜病変を解明し、滑膜病変を改善するための治療法を見出すことであった。今回の研究の結果からOAの滑膜で大量に産生され、関節液を介して軟骨変性に関与すると考えられるMMP-1、３の発現機序について若干の知見を得ることができた。今後さらに知見を積むことでOAにおける滑膜病変を軽減する手法が確立されることが期待される。

Research Products

• [Journal Article] Expression of minor cartilage collagens and small leucine rich proteoglycans may be relatively reduced in osteoarthritic cartilage. (2019)
  • Author(s): Tanaka N, Tashiro T, Katsuragawa Y, Sawabe M, Furukawa H, Fukui N.
  • Journal Title: BMC Musculoskelet Disord. Volume: 20 Issue: 1 Pages: 232-232
  • DOI: 10.1186/s12891-019-2596-y
  • Peer Reviewed / Open Access
• [Journal Article] Human leukocyte antigen in Japanese patients with idiopathic inflammatory myopathy (2019)
  • Author(s): Furukawa H, Oka S, Kawasaki A, Hidaka M, Shimada K, Kondo Y, Ihata A, Matsushita T, Matsumoto T, Hashimoto A, Matsumoto I, Komiya A, Kobayashi K, Osada A, Katayama M, Okamoto A, Setoguchi K, Kono H, Hamaguchi Y, Matsui T, Fukui N, Tamura H, Takehara K, Nagaoka S, Sugii S, Sumida T, Tsuchiya N, Tohma S.
  • Journal Title: Mod Rheumatol. Volume: 30 Issue: 4 Pages: 696
  • DOI: 10.1080/14397595.2019.1637593
  • Peer Reviewed
• [Journal Article] Serum Metabolomic Profiles of Rheumatoid Arthritis Patients With Acute-Onset Diffuse Interstitial Lung Disease. (2019)
  • Author(s): Furukawa H, Oka S, Shimada K, Hashimoto A, Komiya A, Matsui T, Fukui N, Tohma S.
  • Journal Title: Biomark Insights Volume: 22 Pages: 14-14
  • DOI: 10.1177/1177271919870472
  • Peer Reviewed / Open Access
• [Journal Article] Association of HLA-DRB1 genotype with younger age onset and elder age onset rheumatoid arthritis in Japanese populations. (2019)
  • Author(s): Oka S, Furukawa H, Shimada K, Hashimoto A, Komiya A, Tsunoda S, Saisho K, Tsuchiya N, Katayama M, Shinohara S, Matsui T, Fukui N, Sano H, Migita K, Tohma S.
  • Journal Title: Medicine (Baltimore). Volume: 98(48) Issue: 48 Pages: 18218-18218
  • DOI: 10.1097/md.0000000000018218
  • NAID: 120007132911
  • Peer Reviewed / Open Access
• [Journal Article] Sox4 is involved in osteoarthritic cartilage deterioration through induction of ADAMTS4 and ADAMTS5. (2019)
  • Author(s): Takahata Y, Nakamura E, Hata K, Wakabayashi M, Murakami T, Wakamori K, Yoshikawa H, Matsuda A, Fukui N, Nishimura R.
  • Journal Title: FASEB J Volume: 1 Pages: 619-630
  • Peer Reviewed
• [Journal Article] Development and validation of a culturally relevant Japanese KOOS. (2019)
  • Author(s): Lyman S, Omori G, Nakamura N, Takahashi T, Tohyama H, Fukui N, Ikeda H, Sasho T, Saito T, Hayashi Y, Deie M.
  • Journal Title: J Orthop Sci. Volume: 3 Issue: 3 Pages: 514-520
  • DOI: 10.1016/j.jos.2018.11.014
  • Peer Reviewed
• [Journal Article] Alteration of gait parameters in a mouse model of surgically induced knee osteoarthritis. (2018)
  • Author(s): Makii Y, Asaka M, Setogawa S, Fujiki S, Hosaka Y, Yano F, Oka H, Tanaka S, Fukui N, Yanagihara D, Saito T.
  • Journal Title: J Orthop Surg (Hong Kong). Volume: 26 Issue: 2 Pages: 2-2
  • DOI: 10.1177/2309499018768017
  • Peer Reviewed
• [Journal Article] Independent association of HLA-DPB1*02:01 with rheumatoid arthritis in Japanese populations. (2018)
  • Author(s): Furukawa H, Oka S, Shimada K, Hashimoto A, Komiya A, Tsunoda S, Suda A, Ito S, Saisho K, Katayama M, Shinohara S, Sato T, Nagatani K, Minota S, Matsui T, Fukui N, Sugii S, Sano H, Migita K, Nagaoka S, Tohma S.
  • Journal Title: PLoS One Volume: 13 Pages: 9-9
  • NAID: 120007128212
  • Peer Reviewed / Open Access
• [Journal Article] Chromatin accessibility landscape of articular knee cartilage reveals aberrant enhancer regulation in osteoarthritis. (2018)
  • Author(s): Liu Y, Chang JC, Hon CC, Fukui N, Tanaka N, Zhang Z, Lee MTM, Minoda A.
  • Journal Title: Sci Rep Volume: 1 Issue: 1 Pages: 15499-15499
  • DOI: 10.1038/s41598-018-33779-z
  • NAID: 120007133482
  • Peer Reviewed / Open Access
• [Journal Article] Plasma miRNA Expression Profiles in Rheumatoid Arthritis Associated Interstitial Lung Disease. (2017)
  • Author(s): Oka S, Furukawa H, Shimada K, Hashimoto A, Komiya A, Fukui N, Tsuchiya N, Tohma S.
  • Journal Title: BMC Musculoskelet Disord. Volume: 18 Issue: 1 Pages: 21-21
  • DOI: 10.1186/s12891-017-1389-4
  • NAID: 120007134825
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] 関節リウマチ（RA）と変形性関節症（OA）における疼痛に関与しうるmiRNAの検討-関節液中のexosomeに含まれるmiRNAの解析結果から- (2019)
  • Author(s): 津野 宏隆、田中 信帆、大橋 暁、岩澤 三康,松井 利浩、福井 尚志
  • Organizer: 第63回日本リウマチ学会
• [Presentation] 変形性関節症では変性軟骨から遊離した活性型TGFβ１によって滑膜においてウロキナーゼの発現が誘導されている (2019)
  • Author(s): 田中 信帆、大橋 暁、高群 浩司、田代 俊之、桂川 陽三、福井 尚志
  • Organizer: 第11回JOSKAS
• [Presentation] Significance of Synovitis in Early Osteoarthritis (2019)
  • Author(s): Fukui N,Tanaka N,Ohashi S
  • Organizer: 第11回JOSKAS
• [Presentation] Ehlers-Danlos症候群に伴う高度外反不安定膝に対してPS型人工関節置換術を施行した一例 (2019)
  • Author(s): 大橋 暁、福井 尚志、高群 浩司、田中 信帆
  • Organizer: 第11回JOSKAS
• [Presentation] 変形性関節症における疼痛に関与しうるmiRNAの検討-関節液中のexosomeに含まれるmiRNAの解析結果から- (2019)
  • Author(s): 田中 信帆, 津野宏隆,大橋 暁, 岩澤 三康, 田代 俊之, 桂川 陽三,福井 尚志
  • Organizer: 第32回 日本軟骨代謝学会
• [Presentation] 変形性関節症ではangiopietin-2とVEGF-Aが協調的に作用して滑膜に血管新生が誘導される (2018)
  • Author(s): 福井 尚志, 田中 信帆, 大橋 暁,増田 公男, 田代 俊之, 桂川 陽三
  • Organizer: 第10回JOSKAS
• [Presentation] 変形性関節症では変性軟骨からMIFが遊離して滑膜病変に関与する可能性がある (2018)
  • Author(s): 田中 信帆, 大橋 暁, 高群 浩司, 増田 公男, 田代 俊之, 桂川 陽三, 福井 尚志
  • Organizer: 第10回JOSKAS
• [Presentation] 滑膜病変と早期OA (2018)
  • Author(s): 福井 尚志, 田中 信帆, 大橋 暁, 岩澤 三康, 田代 俊之, 桂川 陽三
  • Organizer: 第46回日本関節病学会
• [Presentation] 変形性関節症ではangiopietin-2とVEGF-Aが協調的に作用して滑膜に血管新生が誘導される (2018)
  • Author(s): 福井 尚志
  • Organizer: 第31回日本軟骨代謝学会
• [Presentation] 早期ＯＡの病態 (2017)
  • Author(s): 福井 尚志
  • Organizer: 第9回JOSKAS
• [Presentation] 変形性関節症-病態と治療に関する最近の知見- (2017)
  • Author(s): 福井 尚志
  • Organizer: 弘前変形性関節症講演会
  • Invited
• [Presentation] 変形性関節症ではangiopietin-2とVEGF-Aが協調的に作用して滑膜に血管新生が誘導される (2017)
  • Author(s): 福井 尚志
  • Organizer: 第32回日本整形外科基礎学術集会
• [Book] 早期膝OAの病態． (2019)
  • Author(s): 福井尚志、田中信帆、大橋 暁、岩澤三康．
  • Total Pages: 5
  • Publisher: 日本関節病学会会誌
• [Book] 変形性膝関節症の予防と改善．スポーツでのばす健康寿命．（深代千之，安部 孝 編）． (2019)
  • Author(s): 福井尚志．
  • Total Pages: 11
  • Publisher: 東京大学出版会
• [Book] ロコモティブシンドロームとその予防 (2019)
  • Author(s): 福井 尚志
  • Total Pages: 9
  • Publisher: 公益財団法人 神奈川県予防医学協会