Regulation and mechanisms elucidation of synovitis in knee osteoarthritis

• Project/Area Number: 18K09083
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56020:Orthopedics-related
• Research Institution: Juntendo University
• Principal Investigator: Kaneko Haruka 順天堂大学, 医学部, 准教授 (50445516)
• Project Period (FY): 2018-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 変形性膝関節症 / 滑膜 / 骨棘 / パールカン / プロテオグリカン / 軟骨下骨 / TGF-β / Smad2 / 滑膜炎 / 炎症性メディエイター / 炎症性メディエーター / マクロファージ

Outline of Final Research Achievements

To develop treatments for knee osteoarthritis (knee OA), it is important to understand the molecular mechanisms of pathophysiology of a wide variety of diseases. In early-stage knee OA, synovitis and osteophytes associated with meniscus extrusion have been shown to be important pathological conditions in the development and progression of the disease. Therefore, we focused our study on synovitis and osteophytes, which are closely related, as osteophytes are formed through a similar process of endochondral ossification via the synovium. We previously reported that perlecan, one of the heparan sulfate proteoglycan (HSPG), is involved in osteophyte formation. In this study, we found that osteophyte maturation was inhibited and synovitis was activated at early stage knee OA by the absence of synovial perlecan in mice.

Academic Significance and Societal Importance of the Research Achievements

健康寿命の延伸や介護にかかる医療経済的問題のため，ロコモティブシンドロームの代表疾患である変形性膝関節症(膝OA)の疾患修飾型治療薬の開発は必須であるが未だ開発されていない．本研究の成果は，早期膝OAにおける臨床上の病態進行に係わる重要な因子である滑膜炎および骨棘に焦点をあて，パールカンという関連因子を同定した．このことは，滑膜や骨棘を治療ターゲットとした早期膝OAに対する疾患修飾型治療薬の開発の一助となることが期待される．

Research Products

• [Journal Article] Implication of HYBID (Hyaluronan-Binding Protein Involved in Hyaluronan Depolymerization) in Hyaluronan Degradation by Synovial Fibroblasts in Patients with Knee Osteoarthritis. (2020)
  • Author(s): Shiozawa J, de Vega S, Cilek MZ, Yoshinaga C, Nakamura T, Kasamatsu S, Yoshida H, Kaneko H, Ishijima M, Kaneko K, Okada Y.
  • Journal Title: American Journal of Pathology Volume: 190 Issue: 5 Pages: 1046-1058
  • DOI: 10.1016/j.ajpath.2020.01.003
  • Peer Reviewed / Open Access
• [Journal Article] Bone marrow lesion is associated with disability for activities of daily living in patients with early stage knee osteoarthritis (2018)
  • Author(s): Sadatsuki Ryo、Ishijima Muneaki、Kaneko Haruka、Liu Lizu、Futami Ippei、Hada Shinnosuke、Kinoshita Mayuko、Kubota Mitsuaki、Aoki Takako、Takazawa Yuji、Ikeda Hiroshi、Okada Yasunori、Kaneko Kazuo
  • Journal Title: Journal of Bone and Mineral Metabolism Volume: 37 Issue: 3 Pages: 529-536
  • DOI: 10.1007/s00774-018-0950-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The medial proximal tibial angle accurately corrects the limb alignment in open-wedge high tibial osteotomy (2018)
  • Author(s): Kubota Mitsuaki、Ohno Ryuichi、Sato Taisuke、Yamaguchi Junichiro、Kaneko Haruka、Kaneko Kazuo、Ishijima Muneaki
  • Journal Title: Knee Surgery, Sports Traumatology, Arthroscopy Volume: ‐ Issue: 8 Pages: 2410-2416
  • DOI: 10.1007/s00167-018-5216-8
  • Peer Reviewed / Open Access
• [Journal Article] Mid and long term outcomes after fixation of osteochondritis dissecans (2018)
  • Author(s): Kubota Mitsuaki、Ishijima Muneaki、Ikeda Hiroshi、Takazawa Yuji、Saita Yoshitomo、Kaneko Haruka、Kurosawa Hisashi、Kaneko Kazuo
  • Journal Title: Journal of Orthopaedics Volume: 15 Issue: 2 Pages: 536-539
  • DOI: 10.1016/j.jor.2018.01.002
  • Peer Reviewed / Open Access
• [Journal Article] The increase in bone mineral density by bisphosphonate with active vitamin D analog is associated with the serum calcium level within the reference interval in postmenopausal osteoporosis (2018)
  • Author(s): Kinoshita Mayuko、Ishijima Muneaki、Kaneko Haruka、Liu Lizu、Nagao Masashi、Sadatsuki Ryo、Hada Shinnosuke、Arita Hitoshi、Aoki Takako、Yamanaka Makoto、Nojiri Hidetoshi、Sakamoto Yuko、Tokita Akifumi、Kaneko Kazuo
  • Journal Title: Modern Rheumatology Volume: - Issue: 1 Pages: 1-8
  • DOI: 10.1080/14397595.2018.1442671
  • Peer Reviewed
• [Presentation] パールカン遺伝子変異による軟骨異常を解析する細胞モデルの構築 (2022)
  • Author(s): 白崎駿, 中田智史, 山下由莉, 金子晴香, 石島旨章, 櫻井英俊, 平澤恵理
  • Organizer: 第37回日本整形外科学会基礎学術集会
• [Presentation] 早期変形性膝関節症の滑膜病変におけるパールカンの機能 (2021)
  • Author(s): 有田均, 金子晴香, 羽田晋之介, 木下真由子, 定月亮, 二見一平, 根岸義文, 百枝雅裕, 平澤恵理, 石島旨章
  • Organizer: 第53回日本結合組織学会学術大会
• [Presentation] Role of synovial perlecan in osteophyte formation in early stage knee osteoarthritis. (2019)
  • Author(s): Arita H, Kaneko H, Kinoshita M, Hada S, Sadatsuki R, Futami I, Negishi Y, Momoeda M, Liu L, Aoki T, Arikawa-Hirasawa E, Kaneko K, Ishijima M.
  • Organizer: OARSI2019
  • Int'l Joint Research
• [Presentation] 早期変形性膝関節症の骨棘形成における滑膜に発現するperlecanの機能解析. (2019)
  • Author(s): 有田均,金子晴香,木下真由子,羽田晋之介,定月亮,根岸義文,百枝雅裕,;劉立足,平澤恵理[有川],金子和夫,石島旨章.
  • Organizer: 第34回日本整形外科学会基礎学術集会
• [Presentation] 変形性膝関節症新規バイオマーカー・コラーゲン由来糖鎖修飾ヒドロキシリジンの有効性評価 診断能の検討. (2019)
  • Author(s): 金子晴香,石島旨章,田中智美,多賀祐喜,平澤恵理[有川],田中啓友,水野一乘,楠畑雅,服部俊治,金子和夫.
  • Organizer: 第34回日本整形外科学会基礎学術集会
• [Presentation] 末期変形性膝関節症のビタミンD充足状態と脛骨近位関節面傾斜角の関連. (2019)
  • Author(s): 金子晴香,石島旨章,有田均劉立足,根岸義文,百枝雅裕,齋田良知,高澤祐治,池田浩,金子和夫.
  • Organizer: 第11回日本関節鏡・膝・スポーツ整形外科学会
• [Presentation] Pain reduction after high tibial osteotomy was associated with reduction of histological synovitis in patients with knee osteoarthritis; a longitudinal study. (2018)
  • Author(s): Kaneko H, Liu L, Arita H, Aoki H, Negishi Y, Momoeda M, Hada S, Okada Y, Kaneko K, Ishijima M.
  • Organizer: OARSI 2018 World Congress
  • Int'l Joint Research
• [Presentation] 初期変形性膝関節症の骨棘幅には性差がある スポートロジーコアスタディ. (2018)
  • Author(s): 金子 晴香,石島 旨章,青木 孝子,劉 立足,羽田 晋之介,有田 均,根岸 義文,百枝 雅裕,田村 好史,岡田 保典,金子 和夫.
  • Organizer: 第91回日本整形外科学会学術集会
• [Presentation] 変形性膝関節症に対する高位脛骨骨切り術による疼痛改善と滑膜炎改善との関連を検討した縦断研究. (2018)
  • Author(s): 金子 晴香,石島 旨章,有田 均,羽田 晋之介,長尾 雅史,齋田 良知,高澤 祐治,池田 浩,金子 和夫.
  • Organizer: 第10回日本関節鏡・膝・スポーツ整形外科学会