Analysis on function of Smpd3 in chondrocyte maturation and hyaluronan synthesis

• Project/Area Number: 25462376
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Kagoshima University
• Principal Investigator: Kakoi Hironori 鹿児島大学, 医歯学域医学系, 助教 (50423728)
• Co-Investigator(Kenkyū-buntansha): Maeda Shingo 鹿児島大学, 医歯(薬)学総合研究科, 特任准教授 (60353463) ; Komiya Setsuro 鹿児島大学, 医歯学域医学系, 教授 (30178371) ; Ishidou Yasuhiro 鹿児島大学, 医歯(薬)学総合研究科, 特任准教授 (10300740)
• 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: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: Smpd3 / BMP / 変形性関節症 / 軟骨細胞成熟 / BMPシグナル / 軟骨細胞

Outline of Final Research Achievements

Normal chondrocytes remain in immature state, however, chondrocytes in osteoarthritis (OA) cartilage undergo this endochondral ossification-like process, which is driven by BMP signaling.Treatment of BMP induced Smpd3 expression in a Runx2-dependent manner in chondrocytes. Loss-of-funtion of Smpd3 promoted chondrocyte maturation and Akt signaling. Smpd3 gain-of-function experiments resulted in inhibition of chondrocyte differentiation and Akt-S6 pathway.Hyaluronan (HA) synthesis was inhibited by Smpd3 via Akt pathway in chondrocytes. Hence, BMP signaling promoted OA initiation of cartilage, at the same time, it activated Smpd3 pathway to suppress Akt signaling and chondrocyte maturation as well as HA synthesis, as a negative feedback mechanism. Our results suggested that promotion of Smpd3 pathway (by application of mimicking compound like ceramide) may be valuable in treatment and/or prevention of OA progression.

Research Products

• [Journal Article] BMP signaling upregulates neutral sphingomyelinase 2 to suppress chondrocyte maturation via the Akt signaling pathway as a negative feedback mechanism. (2014)
  • Author(s): Kakoi H, Maeda S, Shinohara N, Matsuyama K, Imamura K, Kawamura I, Nagano S, Setoguchi T, Yokouchi M, Ishidou Y, Komiya S.
  • Journal Title: Journal of Biological Chemistry Volume: 289 Issue: 12 Pages: 8135-8150
  • DOI: 10.1074/jbc.m113.509331
  • Peer Reviewed
• [Journal Article] Human Immunodeficiency Virus Type I Enhancer Binding Protein 3 is Essential for the Expression of Asparagine-linked Glycosylation 2 in the Regulation of Osteoblast and Chondrocyte Differentiation. (2014)
  • Author(s): Imamura K, Maeda S, Kawamura I, Matsuyama K, Shinohara N, Yahiro Y, Nagano S, Setoguchi T, Yokouchi M, Ishidou Y, Komiya S.
  • Journal Title: Journal of Biological Chemistry Volume: 289 Issue: 14 Pages: 9865-9879
  • DOI: 10.1074/jbc.m113.520585
  • Peer Reviewed / Open Access
• [Presentation] 変形性関節症予防を目的とした関節軟骨変性とリンクする肥大軟骨細胞分化を制御する標的分子の同定と機能解析 (2015)
  • Author(s): 前田 真吾
  • Organizer: 第26回 股 関 節 研 究 セ ミ ナ ー
  • Place of Presentation: ＡＰ大阪駅前梅田1丁目(大阪府大阪市)
  • Year and Date: 2015-10-29
• [Presentation] BMP-誘導因子による軟骨・骨代謝制御 (2015)
  • Author(s): 前田 真吾
  • Organizer: JCRベーシックリサーチカンファレンス
  • Place of Presentation: 東京大学(東京都文京区)
  • Year and Date: 2015-10-02
• [Presentation] BMPシグナルにより誘導されるSmpd3はセラミド-Akt経路を介して軟骨細胞分化成熟を抑制する (2014)
  • Author(s): 前田 真吾、栫 博則、篠原 直弘、松山 兼寛、今村 勝行、河村 一郎、横内 雅博、石堂康弘、小宮節郎
  • Organizer: 第27回日本軟骨代謝学会
  • Place of Presentation: 京都府医師会館, 京都市
• [Presentation] Neutral Sphingomyelinase 2 Is Increased During BMP-induced Differentiation of ATDC5 Chondrocytes to Suppress the Maturation as a Negative Feedback Mechanism (2013)
  • Author(s): Shingo Maeda, Hironori Kakoi, Kanehiro Matsuyama, Katsuyuki Imamura, Ichiro Kawamura, Naohiro Shinohara, Masahiro Yokouchi, Yasuhiro Ishidou, Setsuro Komiya
  • Organizer: The American Society for Bone and Mineral Rresearch 2013
  • Place of Presentation: Baltimore Covention Center, Baltimore, USA
• [Presentation] Smpd3 prevents maturation and expression of hyaluronan synthase 2 in ATDC5 chondrocytes (2013)
  • Author(s): Kakoi H, Maeda S, Imamura K, Kawamura I, Ishidou Y, Yokouchi M, Komiya S
  • Organizer: ESCEO13-IOF Rome 2013
  • Place of Presentation: Rome Cavalieri, Rome, Italy
• [Presentation] BMP signaling induces sphingomyelin phosphodiesterase 3 to suppress chondrocyte maturation and expression of hyaluronan synthase 2 in ATDC5 chondrocytes (2013)
  • Author(s): Shingo Maeda, Hironori Kakoi, Kanehiro Matsuyama, Ichiro Kawamura, Katsuyuki Imamura, Naohiro Shinohara, Masahiro Yokouchi, Yasuhiro Ishidou, Setsuro Komiya
  • Organizer: TGF-β meeting in Uppsala
  • Place of Presentation: Uppsala University, Uppsala, Sweden
• [Presentation] Smpd3/nSMase2 suppresses Akt signaling pathway to inhibit chondrogenic differentiation and expression of Has2 in ATDC5 cells (2013)
  • Author(s): Hironori Kakoi, Shingo Maeda, Ichiro Kawamura, Katsuyuki Imamura, Naohiro Shinohara, Masahiro Yokouchi, Yasuhiro Ishidou, Setsuro Komiya
  • Organizer: 国際骨代謝学会・日本骨代謝学会 第２回合同国際会議
  • Place of Presentation: 神戸国際会議場, 神戸市
• [Presentation] BMP シグナルがRunx2依存的に誘導するSmpd3/nSMase2は、セラミド・ シグナルによるAkt 経路の抑制によって軟骨細胞分化とHas2発現を抑制する (2013)
  • Author(s): 前田真吾
  • Organizer: 第１４回運動器科学研究会
  • Place of Presentation: ホテル・ヴィラフォンテーヌ, 東京都
• [Presentation] Smpd3/nSMase2はセラミドを介したAktシグナル経路阻害によりATDC5軟骨細胞分化とヒアルロン酸合成酵素Has2の発現を抑制する (2013)
  • Author(s): 栫博則、前田真吾、松山兼寛、今村勝行、河村一郎、篠原直弘、横内雅博、石堂康弘、小宮節郎
  • Organizer: 第28回日本整形外科学会基礎学術集会
  • Place of Presentation: 幕張メッセ, 千葉市
• [Presentation] BMP-2シグナルはneutral sphingomyelinase 2の誘導によるAktシグナル経路の抑制を介して軟骨細胞分化成熟を制御する (2013)
  • Author(s): 前田真吾、栫博則、松山金寛、河村一郎、今村勝行、篠原直弘、永野聡、瀬戸口啓夫、横内雅博、石堂康弘、小宮節郎
  • Organizer: 第３６回日本分子生物学会年会
  • Place of Presentation: 神戸国際会議場, 神戸市