Molecular mechanisms of knee pain associated with osteoarthritis

• Project/Area Number: 25460716
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pain science
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: JU YOUNG-JIN 東京医科歯科大学, 医学部附属病院, 非常勤講師 (10436636)
• Co-Investigator(Kenkyū-buntansha): TSUJI KUNIKAZU 東京医科歯科大学, 医歯学総合研究科, 准教授 (20323694) ; MUNETA TAKESHI 東京医科歯科大学, 医歯学総合研究科, 教授 (50190864) ; TSUJI KUNIKAZU 東京医科歯科大学, 再生医療研究センター, 教授 (10345291) ; AKAZAWA CHIHIRO 東京医科歯科大学, 保健衛生学研究科, 教授 (80291160)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 変形性膝関節症 / 疼痛 / Osteoarthritis / Synovitis / Pain / Mesenchymal Stem Cells / Osteopontin / Cytokine / 関節疼痛 / 前十字靭帯再建術 / 炎症性サイトカイン / オステオポンチン / マクロファージ / CD105 / 関節液 / 炎症

Outline of Final Research Achievements

This study was aimed to analyze the molecular mechanisms of joint pain associated with knee osteoarthritis. In this study we reported that intra-articular injection of mesenchymal stem cells isolated from syonovial membrane in the knee joint had chondroprotective and anti-inflammatory effects in monoiodoacetic acid (MIA)-induced osteoarthritis model in rats. In addition, we reported that joint pain induced by the intra-articular injection of MIA was significantly alleviated by the intra-articular injection of mesenchymal stem cells. This effect was observed only when we injected mesenchymal stem cells in the acute phase (within 1 to 5 days) of joint inflammation induced by MIA injection. These data suggest that mesenchymal stem cells might have some inhibitory effects on the pro-inflammatory mediators functioning in the immediate early stage after joint injury.

Research Products

• [Journal Article] Weekly injections of Hylan G-F 20 delay cartilage degeneration inpartial meniscectomized rat knees. (2016)
  • Author(s): Yanagisawa K, Muneta T, Ozeki N, Nakagawa Y, Udo M, Saito R, Koga H, Tsuji K, Sekiya I
  • Journal Title: BMC Musculoskelet Disord. Volume: 17 Issue: 1 Pages: 188-188
  • DOI: 10.1186/s12891-016-1051-6
  • Peer Reviewed / Open Access
• [Journal Article] Transplantation of autologous synovial mesenchymal stem cells promotes meniscus regeneration in aged primates. (2016)
  • Author(s): Kondo S, Muneta T, Nakagawa Y, Koga H, Watanabe T, Tsuji K, Sotome S, Okawa A, Kiuchi S, Ono H, Mizuno M, Sekiya I
  • Journal Title: J Orthop Res Volume: in press Issue: 6 Pages: 1274-1282
  • DOI: 10.1002/jor.23211
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Monoiodoacetic acid induces arthritis and synovitis in rats in a dose- and time-dependent manner: proposed model-specific scoring systems. (2016)
  • Author(s): Udo M, Muneta T, Tsuji K, Ozeki N, Nakagawa Y, Ohara T, Saito R, Yanagisawa K, Koga H, Sekiya I.
  • Journal Title: Osteoarthritis Cartilage Volume: in press Issue: 7 Pages: 1284-91
  • DOI: 10.1016/j.joca.2016.02.005
  • Peer Reviewed / Open Access
• [Journal Article] Platelet-derived growth factor (PDGF)-AA/AB in human serum are potential indicators of the proliferative capacity of human synovial mesenchymal stem cells. (2015)
  • Author(s): Mizuno M, Katano H, Otabe K, Komori K, Matsumoto Y, Fujii S, Ozeki N, Tsuji K, Koga H, Muneta T, Matsuyama A, Sekiya
  • Journal Title: Stem Cell Res Ther. Volume: 10 Issue: 1 Pages: 243-243
  • DOI: 10.1186/s13287-015-0239-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Elimination of BMP7 from the developing limb mesenchyme leads to articular cartilage degeneration and synovial inflammation with increased age. (2015)
  • Author(s): Abula K, Muneta T, Miyatake K, Yamada J, Matsukura Y, Inoue M, Sekiya I, Graf D, Economides AN, Rosen V, Tsuji K.
  • Journal Title: FEBS Lett. Volume: in press Issue: 11 Pages: 197-200
  • DOI: 10.1016/j.febslet.2015.04.004
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Effect of posterolateral bundle graft fixation angles on clinical outcomes in double-bundle anterior cruciate ligament reconstruction: a randomized controlled trial. (2015)
  • Author(s): Koga H, Muneta T, Yagishita K, Watanabe T, Mochizuki T, Horie M, Nakamura T, Otabe K, Sekiya I.
  • Journal Title: Am J Sports Med. Volume: 43 Issue: 5 Pages: 1157-64
  • DOI: 10.1177/0363546514567069
  • Peer Reviewed
• [Journal Article] Arthroscopic Transplantation of Synovial Stem Cells Improves Clinical Outcomes in Knees With Cartilage Defects. (2015)
  • Author(s): Sekiya I, Muneta T, Horie M, Koga H.
  • Journal Title: Clin Orthop Relat Res. Volume: in press
  • NAID: 40020986754
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Effect of Initial Graft Tension on Knee Stability and Graft Tension Pattern in Double-Bundle Anterior Cruciate Ligament Reconstruction. (2015)
  • Author(s): Koga H, Muneta T, Yagishita K, Watanabe T, Mochizuki T, Horie M, Nakamura T, Otabe K, Sekiya I.
  • Journal Title: Arthroscopy. Volume: in press Issue: 9 Pages: 1756-1763
  • DOI: 10.1016/j.arthro.2015.03.012
  • Peer Reviewed
• [Journal Article] A modified quadrant method for describing the femoral tunnel aperture positions in ACL reconstruction using two-view plain radiographs. (2015)
  • Author(s): Horie M, Muneta T, Yamazaki J, Nakamura T, Koga H, Watanabe T, Sekiya I.
  • Journal Title: Knee Surg Sports Traumatol Arthrosc. Volume: 23 Pages: 981-5
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Evaluation of a behind-remnant approach for femoral tunnel creation in remnant-preserving double-bundle anterior cruciate ligament reconstruction - Comparison with a standard approach. (2015)
  • Author(s): Koga H, Muneta T, Yagishita K, Watanabe T, Mochizuki T, Horie M, Nakamura T, Otabe K, Sekiya I.
  • Journal Title: Knee Volume: in press Issue: 3 Pages: 249-255
  • DOI: 10.1016/j.knee.2015.02.017
  • Peer Reviewed
• [Journal Article] Behind-remnant arthroscopic observation and scoring of femoral attachment of injured anterior cruciate ligament. (2015)
  • Author(s): Muneta T, Koga H, Nakamura T, Horie M, Watanabe T, Sekiya I.
  • Journal Title: Knee Surg Sports Traumatol Arthrosc. Volume: in press
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Synovial mesenchymal stem cells promote healing after meniscal repair in microminipigs. (2015)
  • Author(s): Nakagawa Y, Muneta T, Kondo S, Mizuno M, Takakuda K, Ichinose S, Tabuchi T, Koga H, Tsuji K, Sekiya I.
  • Journal Title: Osteoarthritis Cartilage. Volume: in press Issue: 6 Pages: 1007-1017
  • DOI: 10.1016/j.joca.2015.02.008
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Mouse synovial mesenchymal stem cells increase in yield with knee inflammation. (2015)
  • Author(s): Matsukura Y, Muneta T, Tsuji K, Miyatake K, Yamada J, Abula K, Koga H, Tomita M, Sekiya I.
  • Journal Title: J Orthop Res. Volume: 33 Issue: 2 Pages: 246-53
  • DOI: 10.1002/jor.22753
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Mid- to long-term results of single-bundle versus double-bundle anterior cruciate ligament reconstruction: randomized controlled trial. (2015)
  • Author(s): Koga H, Muneta T, Yagishita K, Watanabe T, Mochizuki T, Horie M, Nakamura T, Otabe K, Sekiya I.
  • Journal Title: Arthroscopy Volume: 31 Issue: 1 Pages: 69-76
  • DOI: 10.1016/j.arthro.2014.07.020
  • Peer Reviewed
• [Journal Article] Repetitive allogeneic intraarticular injections of synovial mesenchymal stem cells promote meniscus regeneration in a porcine massive meniscus defect model (2014)
  • Author(s): Hatsushika D, Muneta T, Nakamura T, Horie M, Koga H, Nakagawa Y, Tsuji K, Hishikawa S, Kobayashi E, Sekiya I
  • Journal Title: Osteoarthritis Cartilage Volume: in press Issue: 7 Pages: 941-50
  • DOI: 10.1016/j.joca.2014.04.028
  • Peer Reviewed / Open Access
• [Journal Article] Teneurin-4, a transmembrane protein, is a novel regulator that suppresses chondrogenic differentiation. (2014)
  • Author(s): Suzuki N, Mizuniwa C, Ishii K, Nakagawa Y, Tsuji K, Muneta T, Sekiya I, Akazawa C
  • Journal Title: J Orthop Res. Volume: in press Issue: 7 Pages: 915-922
  • DOI: 10.1002/jor.22616
  • Peer Reviewed
• [Journal Article] Meniscus regeneration by syngeneic, minor mismatched, and major mismatched transplantation of synovial mesenchymal stem cells in a rat model. (2014)
  • Author(s): Okuno M, Muneta T, Koga H, Ozeki N, Nakagawa Y, Tsuji K, Yoshiya S, Sekiya I.
  • Journal Title: J Orthop Res. Volume: in press Issue: 7 Pages: 928-36
  • DOI: 10.1002/jor.22614
  • Peer Reviewed / Open Access
• [Journal Article] Mesenchymal stem cells in synovial fluid increase after meniscus injury. (2014)
  • Author(s): Matsukura Y, Muneta T, Tsuji K, Koga H, Sekiya I
  • Journal Title: Clin Orthop Relat Res. Volume: 472 Issue: 5 Pages: 1357-1364
  • DOI: 10.1007/s11999-013-3418-4
  • Peer Reviewed / Open Access
• [Journal Article] Transplantation of Achilles tendon treated with bone morphogenetic protein 7 promotes meniscus regeneration in a rat model of massive meniscal defect. (2013)
  • Author(s): Ozeki N, Muneta T, Koga H, Katagiri H, Otabe K, Okuno M, Tsuji K, Kobayashi E, Matsumoto K, Saito H, Saito T, Sekiya I.
  • Journal Title: Arthritis Rheum. Volume: 65 Issue: 11 Pages: 2876-2886
  • DOI: 10.1002/art.38099
  • Peer Reviewed
• [Journal Article] Transplantation of aggregates of synovial mesenchymal stem cells regenerates meniscus more effectively in a rat massive meniscal defect (2013)
  • Author(s): Katagiri H, Muneta T, Tsuji K, Horie M, Koga H, Ozeki N, Kobayashi E, Sekiya I.
  • Journal Title: Biochem Biophys Res Commun. Volume: 435 Issue: 4 Pages: 603-609
  • DOI: 10.1016/j.bbrc.2013.05.026
  • Peer Reviewed
• [Journal Article] Intraarticular Injection of Synovial Stem Cells Promotes Meniscal Regeneration in a Rabbit Massive Meniscal Defect Model. (2013)
  • Author(s): Hatsushika D.
  • Journal Title: JOURNAL OF ORTHOPAEDIC RESEARCH Volume: In Press Issue: 9 Pages: 1354-1359
  • DOI: 10.1002/jor.22370
  • Peer Reviewed
• [Journal Article] Human YKL39 (chitinase 3-like protein 2), an osteoarthritis-associated gene, enhances proliferation and type II collagen expression in ATDC5 cells. (2013)
  • Author(s): Miyatake K.
  • Journal Title: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS Volume: 431(1) Issue: 1 Pages: 52-57
  • DOI: 10.1016/j.bbrc.2012.12.094
  • Peer Reviewed
• [Presentation] Different methods of detaching adherent cells significantly affect the detection of stem cell antigens in synovial mesenchymal stem cells. (2016)
  • Author(s): Miyoko Ojima, Kunikazu Tsuji, Koji Otabe, Masafumi Horie, Hideyuki Koga, Ichiro Sekiya, and Takeshi Muneta
  • Organizer: Osteoarthritis Research Society International
  • Place of Presentation: Amsterdam Netherlands
  • Year and Date: 2016-03-31
  • Int'l Joint Research
• [Presentation] Dynamic analysis of inflammatory cells in synovial fluid after index anterior cruciate ligament reconstruction surgery. (2016)
  • Author(s): Kaori Nakamura, Kunikazu Tsuji, Hiroki Katagiri, Makiko Inoue, Miyoko Ojima, Ichiro Sekiya, Takeshi Muneta
  • Organizer: Osteoarthritis Research Society International
  • Place of Presentation: Amsterdam Netherlands
  • Year and Date: 2016-03-31
  • Int'l Joint Research
• [Presentation] 滑膜由来間葉系幹細胞を特徴付ける表面抗原の網羅的解析 (2016)
  • Author(s): 辻 邦和、尾島美代子、小田邉浩二、堀江雅史、古賀英之、関矢一郎、宗田 大
  • Organizer: 軟骨代謝学会
  • Place of Presentation: 広島県広島市、広島大学応仁会館
  • Year and Date: 2016-02-19
• [Presentation] ラット変形性膝関節疼痛モデルの膝関節・膝周囲組織の脊髄後根神経節での組織学的検討 (2015)
  • Author(s): 宇土美於、 辻邦和、 大関信武、 星野傑、 山﨑勇大、 関矢一郎、 宗田大
  • Organizer: 日本運動器疼痛学会
  • Place of Presentation: 愛知県名古屋市、名古屋国際会議場
  • Year and Date: 2015-12-12
• [Presentation] 滑膜由来間葉系幹細胞を特徴付ける表面抗原の網羅的解析 (2015)
  • Author(s): 辻 邦和、尾島美代子、小田邉浩二、堀江雅史、古賀英之、関矢一郎、宗田 大
  • Organizer: 日本運動器移植、再生医学研究会
  • Place of Presentation: 山口県宇部市、ANAクラウンプラザホテル
  • Year and Date: 2015-09-25
• [Presentation] 細胞剥離法の差異が滑膜由来間葉系幹細胞の表面抗原解析の結果に及ぼす影響 (2015)
  • Author(s): 尾島美代子、辻邦和、小田邉浩二、 堀江雅史、古賀英之、 関矢一郎、宗田 大
  • Organizer: 日本運動器移植、再生医学研究会
  • Place of Presentation: 山口県宇部市、ANAクラウンプラザホテル
  • Year and Date: 2015-09-25
• [Presentation] Diagnostic Workup of Recurrent Lateral Patellar Instability. (2014)
  • Author(s): Takeshi Muneta
  • Organizer: Vail International Complex Knee Symposium (VICKS)
  • Place of Presentation: U.S.A.
  • Year and Date: 2014-07-18
• [Presentation] 変形性膝関節症の診断と治療：常識と疑問 (2014)
  • Author(s): 宗田 大
  • Organizer: 第87 回日本整形外科学会学術総会
  • Place of Presentation: 神戸
  • Year and Date: 2014-05-22
• [Presentation] A History and Outcome of our Double-bundle ACL Reconstruction -20- year experience-. (2014)
  • Author(s): Takeshi Muneta
  • Organizer: 2014 Annual Spring Congress of the Korean Orthopaedic Association
  • Place of Presentation: Korea
  • Year and Date: 2014-04-17
• [Presentation] A backside approach for a remnant preserving double-bundle ACL reconstruction by three different techniques. (2014)
  • Author(s): Takeshi Muneta
  • Organizer: 1st Congress of APKASS in Nara
  • Place of Presentation: 奈良
  • Year and Date: 2014-04-15
• [Presentation] Granulocyte population in synovial fluid varies in patients after anterior cruciate ligament reconstruction and positively correlates with the protein levels of a pro-inflammatory cytokine, IL-1 beta (2014)
  • Author(s): M. Inoue, K. Tsuji, K. Nakamura, H. Katagiri, I. Sekiya, M. Okazaki, T. Muneta.
  • Organizer: Osteoarthritis Research International
  • Place of Presentation: Paris, France
• [Presentation] Elimination of bmp7 expression from the limb enhances articular cartilage degeneration and synovial hyperplasia in adult mice (2014)
  • Author(s): K. Abula, T. Muneta, K. Miyatake, J. Yamada, Y. Matsukura, M. Inoue, I. Sekiya, D. Graf, A. Economides, V. Rosen, K. Tsuji.
  • Organizer: Osteoarthritis Research International
  • Place of Presentation: Paris, France
• [Presentation] Strain diversity of articular cartilage degeneration induced by ovariectomy and forced running in mice (2014)
  • Author(s): J. Yamada, K. Tsuji, K. Miyatake, Y. Matsukura, A. Kahaer, I. Sekiya, T. Muneta.
  • Organizer: Osteoarthritis Research International
  • Place of Presentation: Paris, France
• [Presentation] Coordinate and synergistic effects of extensive treadmill exercise and ovariectomy on articular cartilage degeneration (2014)
  • Author(s): K. Miyatake, K. Tsuji, J. Yamada, Y. Matsukura, A. Kahaer, I. Sekiya, T. Muneta.
  • Organizer: Osteoarthritis Research International
  • Place of Presentation: Paris, France
• [Presentation] Negative correlation between the population of cd105 positive subset of monocytes/macrophages in synovial fluid and the severity of joint pain after anterior cruciate ligament reconstruction surgery (2014)
  • Author(s): K. Nakamura, K. Tsuji, H. Katagiri, M. Inoue, K. Abula, I. Sekiya, T. Muneta.
  • Organizer: Osteoarthritis Research International
  • Place of Presentation: Paris, France
• [Presentation] Endogenous BMP7 activity maintains articular cartilage integrity by modulating inflammatory and catabolic factors. (2013)
  • Author(s): K. Abula, T. Muneta, K. Miyatake, J. Yamada, Y. Matsukura, M. Inoue, I. Sekiya, D. Graf, A. Economides, V. Rosen, K. Tsuji.
  • Organizer: American Society for Bone and Mineral Research,
  • Place of Presentation: Baltimore, MD, USA