Challenge for liquid biopsy of osteoarthritis

• Project/Area Number: 17K19727
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Research Field: Surgery related to the biological and sensory functions and related fields
• Research Institution: Okayama University
• Principal Investigator: HIROHATA SATOSHI 岡山大学, 保健学研究科, 教授 (90332791)
• Co-Investigator(Kenkyū-buntansha): 大月 孝志 岡山大学, 保健学研究科, 非常勤研究員 (10534802) ; 臼井 真一 岡山大学, 保健学研究科, 准教授 (50346417) ; 稲垣 純子 岡山大学, 医歯薬学総合研究科, 助教 (90271056)
• Project Period (FY): 2017-06-30 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2018: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2017: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
• Keywords: 遺伝子

Outline of Final Research Achievements

There is no definite early diagnosis of osteoarthritis. Can liquid biopsy be a new early diagnosis for osteoarthritis?
To answer this important question, rat anterior cruciate ligament and the medial collateral ligament of the rat knee joint were dissected and the medial meniscus was taken, and the osteoarthritis surgical model was prepared. The joint fluid and peripheral blood were collected over time. The vesicle component containing exosomes was purified from the sample and the particle size was measured. Next, RNA components contained in exosomes were quantified. From the series of results, it was considered appropriate to aim at liquid biopsy with blood rather than joint fluid at the early stage of osteoarthritis. Furthermore, the analysis of RNA in exosomes in blood revealed that a highly sensitive measurement system is required.

Academic Significance and Societal Importance of the Research Achievements

ラット変形性関節症モデルを作製、関節液および末梢血液を採取して、リキッドバイオプシーが可能であるかに挑戦した。ヒト変形性関節症においても膝に水（関節液）がたまるといった状況は、早期ではなくむしろ進行期で見られることから、X線などで診断可能な進行期ではなく早期の診断目的としては、そのソースは関節液よりも血液に注目すべきであることが明らかとなった。さらに血液中のエクソソームに着目してRNA解析を行ったところ、非常に微量であり実用化を目指すには超高感度解析系の構築が求められる。

Research Products

• [Journal Article] Serum malondialdehyde-modified low-density lipoprotein levels on admission predict prognosis in patients with acute coronary syndrome undergoing percutaneous coronary intervention. (2019)
  • Author(s): Amioka N , Miyoshi T , Otsuka H , Yamada D , Takaishi A , Ueeda M , Hirohata S , Ito H.
  • Journal Title: J Cardiol. Volume: S0914-5087(19) Issue: 3 Pages: 30051-6
  • DOI: 10.1016/j.jjcc.2019.02.012
  • Peer Reviewed / Open Access
• [Journal Article] A High-Fat and High-Cholesterol Diet Induces Cardiac Fibrosis, Vascular Endothelial, and Left Ventricular Diastolic Dysfunction in SHRSP5/Dmcr Rats (2018)
  • Author(s): Watanabe S, Kumazaki S, Kusunoki K, Inoue T, Maeda Y, Usui S, Shinohata R, Ohtsuki T, Hirohata S, Kusachi S, Kitamori K, Mori M, Yamori Y, Oka H.
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 25 Issue: 5 Pages: 439-453
  • DOI: 10.5551/jat.40956
  • NAID: 130006729837
  • ISSN: 1340-3478, 1880-3873
  • Year and Date: 2018-05-01
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Non-alcoholic steatohepatitis aggravates nitric oxide synthase inhibition-induced arteriosclerosis in SHRSP5/Dmcr rat model (2018)
  • Author(s): Watanabe Shogo、Kumazaki Shota、Yamamoto Shusei、Sato Ikumi、Kitamori Kazuya、Mori Mari、Yamori Yukio、Hirohata Satoshi
  • Journal Title: International Journal of Experimental Pathology Volume: 99 Issue: 6 Pages: 282-294
  • DOI: 10.1111/iep.12301
  • Peer Reviewed / Open Access
• [Journal Article] High molecular weight hyaluronan protects cartilage from degradation by inhibiting aggrecanase expression. (2018)
  • Author(s): Ohtsuki T, Asano K, Inagaki J, Shinaoka A, Kumagishi-Shinaoka K, Cilek MZ, Hatipoglu OF, Oohashi T, Nishida K, Komatsubara I, Hirohata S.
  • Journal Title: J Orthop Res Volume: 36 Issue: 12 Pages: 3247-3255
  • DOI: 10.1002/jor.24126
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Adjunctive left anterior line ablation induced left atrial dysfunction and dyssynchrony in atrial fibrillation ablation (2018)
  • Author(s): Yamaji Hirosuke、Murakami Takashi、Hina Kazuyoshi、Higashiya Shunichi、Kawamura Hiroshi、Murakami Masaaki、Kamikawa Shigeshi、Hirohata Satoshi、Kusachi Shozo
  • Journal Title: Heart and Vessels Volume: 34 Issue: 2 Pages: 331-342
  • DOI: 10.1007/s00380-018-1238-x
  • Peer Reviewed / Open Access
• [Journal Article] Host-produced ADAMTS4 Inhibits Early-Stage Tumor Growth (2018)
  • Author(s): Asano K, Edamatsu M, Hatipoglu OF, Inagaki J, Ono M, Ohtsuki T, Oohashi T, Hirohata S.
  • Journal Title: Acta Medica Okayama Volume: 72 Issue: 3 Pages: 257-266
  • DOI: 10.18926/AMO/56071
  • NAID: 120006482820
  • URL: https://ousar.lib.okayama-u.ac.jp/56071
  • Peer Reviewed / Open Access
• [Journal Article] Differences in activated clotting time and initial heparin dosage during atrial fibrillation ablation for patients with edoxaban compared with warfarin. (2018)
  • Author(s): Yamaji H, Murakami T, Hina K, Higashiya S, Kawamura H, Murakami M, Kamikawa S, Hirohata S, Kusachi S.
  • Journal Title: J Cardiovasc Electrophysiol. Volume: 印刷中 Issue: 6 Pages: 835-843
  • DOI: 10.1111/jce.13483
  • Peer Reviewed / Open Access
• [Journal Article] Host-produced ADAMTS4 Inhibits Early- Stage Tumor Growth. (2018)
  • Author(s): Asano K, Edamatsu M, Hatipoglu OF, Inagaki J, Ono M, Ohtsuki T, Oohashi T, Hirohata S.
  • Journal Title: Acta Med. Okayama. Volume: 72（3）
  • NAID: 120006482820
  • Peer Reviewed / Open Access
• [Journal Article] Stromal Versican Regulates Tumor Growth by Promoting Angiogenesis (2017)
  • Author(s): Asano Keiichi、Nelson Courtney M.、Nandadasa Sumeda、Aramaki-Hattori Noriko、Lindner Daniel J.、Alban Tyler、Inagaki Junko、Ohtsuki Takashi、Oohashi Toshitaka、Apte Suneel S.、Hirohata Satoshi
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 1-11
  • DOI: 10.1038/s41598-017-17613-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Circulating adipocyte fatty acid-binding protein is a predictor of cardiovascular events in patients with stable angina undergoing percutaneous coronary intervention. (2017)
  • Author(s): Takagi W, Miyoshi T, Doi M, Okawa K, Nosaka K, Nishibe T, Matsuo N, Hirohata S, Ito H.
  • Journal Title: BMC Cardiovasc Disord. Volume: 17(1) Issue: 1 Pages: 258-258
  • DOI: 10.1186/s12872-017-0691-2
  • Peer Reviewed / Open Access
• [Presentation] メカニカルストレスによるHYBID遺伝子の発現抑制 (2019)
  • Author(s): 大月 孝志、劉 国楽、西村 拓人、立木 美穂、岡田 真澄、品岡 玲、チレッキ メフメット、オメル ハティポール、稲垣 純子、古松 毅之、西田 圭一郎、下田 将之、岡田 保典、廣畑 聡
  • Organizer: 第32回日本軟骨代謝学会
• [Presentation] The Westerizaton of Life Style and Atherosclerosis in Japan ?The Balance of EPA and AA- (2018)
  • Author(s): N. Matsuo, K. Hayashi, Y. Katou, M. Hasegawa, M. Tanimoto, T. Fujiwara, K. Kagawa, Y. Nakano, N. Oonishi, A. Takaishi, S. Hirohata, M. Ueeda.
  • Organizer: 第86回欧州動脈硬化会議（EAS congress）
  • Int'l Joint Research
• [Presentation] Supplementation of Omega-3 PUFAs could improve long term prognosis after PCI in patients without hyperlipidemia and diabetes. (2018)
  • Author(s): N. Matsuo, K. Hayashi, Y. Katou, M. Hasegawa, M. Tanimoto, T.Fujiwara, K. Kagawa, Y. Nakano, N. Oonishi, A. Takaishi, S. Hirohata, M. Ueeda.
  • Organizer: 第86回欧州動脈硬化会議（EAS congress）
  • Int'l Joint Research
• [Presentation] Analysis of serum HDL subclass from rats with non-alcoholic fatty liver disease induced by high-fat and high-cholesterol diet. (2018)
  • Author(s): Shinohata R, Watanabe S, Hirohata S, Nakajima K, Okazaki M, Usui S.
  • Organizer: 第70回米国臨床化学会学術集会(AACC 70th Annual Scientific Meeting)
  • Int'l Joint Research
• [Presentation] Bile acid metabolic disorder aggravates cardiac dysfunction in SHRSP5/Dmcr rat that induced non-alcoholic steatohepatitis. (2018)
  • Author(s): Shota Kumazaki, Shun Sasaki, Rina Tagashira, Mayu Nakamura, Nozomi Maruyama, Satoshi Hirohata, Shogo Watanabe
  • Organizer: The 7th International Congress on Lipid & Atherosclerosis 2018
  • Int'l Joint Research
• [Presentation] Non-alcoholic steatohepatitis aggravates myocardial infarction induced by NO synthase inhibitor. (2018)
  • Author(s): Shota Kumazaki, Shun Sasaki, Rina Tagashira, Mayu Nakamura, Nozomi Maruyama, Satoshi Hirohata, Hisao Oka, Shogo Watanabe
  • Organizer: The 18th International SHR Symposium (official satellite symposium of ISH2018)
  • Int'l Joint Research
• [Presentation] AN69ST膜のlifetime関連因子の膜面積による比較検討 (2018)
  • Author(s): 岡田 真澄、平山 隆浩、末永 健二、藤原 宏成、落葉 佑昌、岩藤 晋、内藤 宏道、中尾 篤典、廣畑 聡
  • Organizer: 第8回中四国臨床工学会
• [Presentation] 高度救命救急センターにおける CRRT 膜の lifetime に関する検討 (2018)
  • Author(s): 岡田 真澄、平山 隆浩、末永 健二、藤原 宏成、落葉 佑昌、岩藤 晋、内藤 宏道、中尾 篤典、廣畑 聡
  • Organizer: 第29回 日本急性血液浄化学会学術集会
• [Presentation] 好酸球由来カチオン性タンパクの精製および酸化ストレス下での心筋芽細胞保護効果の検討 (2018)
  • Author(s): 西村 拓人、 立木 美穂、 稲垣 純子、 Omer Faruk Hatipoglu、 大月 孝志、 池村 健太郎、 劉 国楽、 廣畑 聡
  • Organizer: 第13回 日本臨床検査学教育学会学術大会
• [Presentation] Isolation and characterization of extracellular microvesicles in osteoarthritis (2018)
  • Author(s): Liu G, Ohtsuki T, Shinaoka A, Komatsu K, Notsu Y, Hatipoglu OF, Nishimura T, Inagaki J, Yamada H, Nishida K, Sun L, Hirohata S.
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] 癌微小環境におけるVersicanおよびADAMTSによる分解産物の分布様式 (2018)
  • Author(s): 廣畑 聡
  • Organizer: 第27回プロテオグリカンフォーラム グルコサミノグリカン/プロテオグリカン（GAG/PG）研究の最前線
• [Presentation] The Peculiar Factor Contributed to the Occurrence of Adverse Events Related to Use of Tolvaptan in Congestive Heart Failure Cases. (2018)
  • Author(s): Yuichi Kato, Kazuna Hayashi, Misao Hasegawa, Naoaki Matsuo, Takashi Fujiwara, Masafumi Tanimoto, Kenzo Kagawa, Yukari Nakano, Nobuhiko Ohnishi, Atsushi Takaishi, Satoshi Hirohata, Masayuki Ueeda
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] A Trend of Increase in TG and Omega-3 PUFAs was Observed in All Age Groups of Patients with AMI. (2018)
  • Author(s): Takashi Fujiwara, Yukari Nakano, Kazuna Hayashi, Yuichi Kato, Misao Hasegawa, Naoaki Matsuo, Masafumi Tanimoto, Kenzo Kagawa, Nobuhiko Ohnishi, Atsushi Takaishi, Satoshi Hirohata, Masayuki Ueeda.
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] The Clinical Pathway with Early Administration of Tolvaptan was Useful and Safe Even in Super-Elder Patients with Congestive Heart Failure. (2018)
  • Author(s): Naoaki Matsuo, Kazuna Hayashi, Yuichi Kato, Misao Hasegawa, Takashi Fujiwara, Masafumi Tanimoto, Kenzo Kagawa, Nobuhiko Ohnishi, Satoshi Hirohata, Masayuki Ueeda, Atsushi Takaishi.
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] Supplementation of Omega-3 PUFAs to Patients with IHD Still Improved Their Long-term Prognosis in Strong Statin Era. (2018)
  • Author(s): Naoaki Matsuo, Kazuna Hayashi, Yuichi Kato, Misao Hasegawa, Masafumi Tanimoto, Kenzo Kagawa, Yukari Nakano, Nobuhiko Ohnishi, Satoshi Hirohata, Masayuki Ueeda, Atsushi Takaishi.
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] Hospitalization Period could be Significantly Shortened by the Clinical Pathway with Early Administration of Tolvaptan in Congestive Heart Failure Cases. (2018)
  • Author(s): Yuichi Kato, Kazuna Hayashi, Misao Hasegawa, Naoaki Matsuo, Masafumi Tanimoto, Takashi Fujiwara, Kenzo Kagawa, Yukari Nakano, Nobuhiko Ohnishi, Atsushi Takaishi, Satoshi Hirohata, Masayuki Ueeda
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] ApoE-rich HDL in pre-heparin plasma may be HDL remnants which remain in the circulation. (2017)
  • Author(s): Usui S, Shinohata R, Miyashita K, Hirohata S, Shibakura M, Fukamachi I, Nakajima K.
  • Organizer: 67th AACC annual scientifi meeting & clinical lab expo.
  • Int'l Joint Research
• [Presentation] SHRSP5/Dmcr rats fed on high-fat and high-cholesterol diet develop non-alcoholic steatohepatitis that aggravates cardiac or vascular dysfunction (2017)
  • Author(s): Shota Kumazaki, Katsuhiro Kusunoki, Terumi Inoue, Yui Maeda, Satoshi Hirohata, Hisao Oka, Shogo Watanabe.
  • Organizer: The 6th International Congress on Lipid & Atherosclerosis 2017
  • Int'l Joint Research
• [Presentation] Uric acid aggravates cardiac inflammation via adipocyte URAT-1 in non-alcoholic steatohepatitis. (2017)
  • Author(s): Shota Kumazaki, Katsuhiro Kusunoki, Terumi Inoue, Yui Maeda, Satoshi Hirohata, Hisao Oka, Shogo Watanabe
  • Organizer: The 6th International Congress on Lipid & Atherosclerosis 2017
  • Int'l Joint Research
• [Presentation] 炎症性サイトカイン誘導性マトリックス分解酵素発現のイオンチャネルを介した抑制とその機構解析 Inflammatory cytokine-induced matrix degrading enzymes expression were attenuated by mechanical stress through transient receptor potential cation channel (2017)
  • Author(s): 大月孝志、品岡 玲、品岡 加苗、Cilek Mehmet、Hatipoglu Omer、西村 拓人、稲垣 純子、西田 圭一郎、廣畑 聡
  • Organizer: 2017 年度生命科学系学会合同年次大会（ConBio2017）
• [Presentation] SHRSP5/Dmcrラットを用いた非アルコール性脂肪性肝炎と心血管傷害の仲介因子とし ての胆汁酸代謝 (2017)
  • Author(s): 熊崎章太、佐々木駿、田頭里菜、中村茉由、丸山望美、廣畑 聡、渡邉彰吾
  • Organizer: 第50回日本動脈硬化学会総会・学術集会