Role and mechanism of action of IL-11 on the regulation of bone and adipose tissue interaction

2018 Fiscal Year Annual Research Report

• Project/Area Number: 16H05327
• Research Institution: The University of Tokushima
• Principal Investigator: 松本 俊夫 徳島大学, 先端酵素学研究所(オープンイノベ), 名誉教授 (20157374)
• Co-Investigator(Kenkyū-buntansha): 福本 誠二 徳島大学, 先端酵素学研究所(オープンイノベ), 特任教授 (30202287) ; 沢津橋 俊 徳島大学, 先端酵素学研究所(オープンイノベ), 特任講師 (70535103)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 遺伝子 / シグナル伝達 / 脂質 / 老化 / 骨粗鬆症 / 骨代謝

Outline of Annual Research Achievements

我々は骨においてIL-11がWntシグナル抑制因子の発現抑制を介してWntシグナルを促進し骨芽細胞分化・骨形成を促進することを見出した。さらにIL-11の全身欠損マウスでは脂肪組織の増大と肥満が認められインスリン抵抗性が発現することが明らかとなった。そこでosteocalcin-Creとadiponectin-CreトランスジェニックマウスをIL-11-floxマウスと交配し骨芽細胞・骨細胞および脂肪細胞特異的IL-11欠損マウスを作成し何れの組織由来のIL-11が関与するかについて解明を進めた。
骨芽細胞・骨細胞特異的IL-11欠損マウスでは全身性IL-11欠損マウスと同様に血清IL-11濃度が低下し、骨でのWntシグナル抑制因子の発現が亢進し骨形成低下に基づく骨量減少が認められた。これらのマウスでは全身の白色脂肪の数・大きさが何れも増大し脂肪組織量が増加していた。
一方、脂肪細胞特異的IL-11欠損マウスでは、骨形成・骨量の低下を認めず、白色脂肪組織量にも変化は認められなかった。以上より、骨由来のIL-11がWntシグナル抑制因子の発現制御を介し骨形成・骨量の維持と共に、全身脂肪組織量の制御にも重要な役割を果たすことが明らかとなった。そこでIL-11作用を媒介する受容体および細胞内情報伝達系を解明するため、IL-11受容体α、LIF受容体、OSM (oncostatin M)受容体を各々或いは2つずつ欠損する骨芽細胞株をCRISPR-Casを用いて作成し、IL-11と他のリガンドがどの受容体を介してSTAT1~6のどのシグナルを活性化するか、その結果RANKL, OPGおよびsclerostin, DKK-1,2等のWntシグナル阻害因子の発現に影響を及ぼすか否かの検討を進めている。

Research Progress Status

平成30年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

平成30年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Persistent activation of calcium-sensing receptor suppresses bone turnover, increases microcracks and decreases bone strength (2019)
  • Author(s): Bingzi Dong, Itsuro Endo, Yukiyo Ohnishi, Yukari Mitsui, Kiyoe Kurahashi, Mai Kanai, Masahiro Hiasa, Jumpei Teramachi, Hirofumi Tenshin, Seiji Fukumoto, Masahiro Abe, Toshio Matsumoto.
  • Journal Title: JBMR Plus Volume: inpress Pages: inpress
  • DOI: 10.1002/jbm4.10182
  • Peer Reviewed
• [Journal Article] FRAME Study: The Foundation Effect of Building Bone With 1 Year of Romosozumab Leads to Continued Lower Fracture Risk After Transition to Denosumab (2018)
  • Author(s): Cosman, F., Crittenden, D. B., Ferrari, S., Khan, A., Lane, N. E., Lippuner, K., Matsumoto, T., Milmont, C. E., Libanati, C., Grauer, A.
  • Journal Title: J Bone Miner Res Volume: 33(7) Pages: 1219-1226
  • DOI: 10.1002/jbmr.3427
  • Peer Reviewed
• [Journal Article] Development of versatile non-homologous end joining-based knock-in module for genome editing (2018)
  • Author(s): Sawatsubashi, S., Joko, Y., Fukumoto, S., Matsumoto, T., Sugano, S. S
  • Journal Title: Sci Rep Volume: 8(1) Pages: 593
  • DOI: 10.1038/s41598-017-18911-9
  • Peer Reviewed
• [Journal Article] Pim-2 is a critical target for treatment of osteoclastogenesis enhanced in myeloma. (2018)
  • Author(s): Teramachi J, Hiasa M, Oda A, Harada T, Nakamura S, Amachi R, Tenshin H, Iwasa M, Fujii S, Kagawa K, Miki H, Kurahashi K, Yoshida S, Endo I, Haneji T, Matsumoto T, Abe M.
  • Journal Title: Br J Haematol Volume: 180(4) Pages: 581-585
  • DOI: 10.1111/bjh.14388.
• [Journal Article] Endothelial Nitric Oxide Synthase-Independent Pleiotropic Effects of Pitavastatin Against Atherogenesis and Limb Ischemia in Mice. (2018)
  • Author(s): Mitsuhashi T, Uemoto R, Ishikawa K, Yoshida S, Ikeda Y, Yagi S, Matsumoto T, Akaike M, Aihara KI.
  • Journal Title: J Atheroscler Thromb. Volume: 25(1) Pages: 65-80
  • DOI: 10.5551/jat.37747
• [Presentation] FGF Receptor 1c Works as a Phosphate-Sensor to Regulate FGF23 Production (2018)
  • Author(s): Yuichi Takashi, Yuka Kinoshita, Nobuaki Ito, Shun Sawatsubashi, Hidetaka Kosako, Masahiro Abe, Munehide Matsuhisa, Toshio Matsumoto, and Seiji Fukumoto
  • Organizer: American Society for Bone and Mineral Research, 2018 Annual Meeting, Montreal, Quebec, Canada
  • Int'l Joint Research
• [Presentation] Disruption of a progressive vicious cycle between myeloma tumor growth and bone destruction by TAK1 inhibition (2018)
  • Author(s): Jumpei Teramachi, Hirofumi Tenshin, Masahiro Hiasa, Asuka Oda, Ariunzaya Bat-Erdene, Takeshi Harada, Shingen Nakamura, Hirokazu Miki, Itsuro Endo, Toshio Matsumoto and Masahiro Abe.
  • Organizer: American Society for Bone and Mineral Research, 2018 Annual Meeting, Montreal, Quebec, Canada
  • Int'l Joint Research
• [Presentation] Opposite effects of TRAIL on the Sp1-c-FLIP survival pathway in myeloma cells and osteoclasts. (2018)
  • Author(s): Hirofumi Tenshin, Jumpei Teramachi, Masahiro Hiasa, Asuka Oda, Mohannad Ashtar, Kotaro Tanimoto, Iwasa Masami, Ariunzaya Bat-Erdene, Takeshi Harada, Shingen Nakamura, Hirokazu Miki, Itsuro Endo, Eiji Tanaka, Toshio Matsumoto, Masahiro Abe.
  • Organizer: American Society for Bone and Mineral Research, 2018 Annual Meeting, Montreal, Quebec, Canada
  • Int'l Joint Research
• [Presentation] Eldecalcitol Increases BMD More Than Alfacalcidol in Chinese Osteoporotic Patients without Vitamin D or Calcium Supplementation (2018)
  • Author(s): Yan Jiang, Hai Tang, Xinlong Ma, Qun Cheng, Hua Lin, Xiaolan Jin, Zhenlin Zhang, Wei Yu, Shuli He, Tsuyoshi Kobayashi, Satomi Uehara, Toshio Matsumoto, Weibo Xia.
  • Organizer: American Society for Bone and Mineral Research, 2018 Annual Meeting, Montreal, Quebec, Canada
  • Int'l Joint Research
• [Presentation] Calcilytic, the calcium-sensing receptor antagonist, enhances bone remodeling and increases bone mineral density without increasing urinary calcium excretion (2018)
  • Author(s): Bingzi Dong, Itsuro Endo, Yukiyo Ohnishi, Zhengju Fu, Toshio Matsumoto, Yangang Wang.
  • Organizer: American Society for Bone and Mineral Research, 2018 Annual Meeting, Montreal, Quebec, Canada
  • Int'l Joint Research
• [Remarks] 徳島大学藤井節郎記念医科学センター
  • URL: http://www.fujii.tokushima-u.ac.jp/nuclearreceptor/