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

• Project/Area Number: 16H05327
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Metabolomics
• Research Institution: The University of Tokushima
• Principal Investigator: MATSUMOTO Toshio 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) ; MARIA TSOUMPRA 徳島大学, 先端酵素学研究所(オープンイノベ), 特任研究員 (80756198)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2018: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2017: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2016: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: 遺伝子 / シグナル伝達 / 脂質 / 老化 / 骨粗鬆症 / 骨代謝 / 骨・カルシウム代謝異常 / 骨代謝学 / 骨ー脂肪組織関連 / 骨－脂肪組織連関

Outline of Final Research Achievements

Interleukin (IL)-11 enhances osteogenesis and suppresses adipogenesis from bone marrow stromal cells, by enhancing Wnt signaling via suppression of Wnt inhibitors. To clarify the role of IL-11 in bone remodeling, IL-11 knockout (IL-11-/-) mice were created. IL-11-/- mice exhibited reduced bone formation with suppressed Wnt signaling via enhanced expression of Wnt inhibitors. These mice showed not only reduced bone mass but also increased white adipose tissue with glucose intolerance. Osteoblast-specific IL-11 deletion in osteocalcin-Cre;IL-11fl/fl mice showed reduced serum IL-11 level and almost the same phenotype as IL-11-/- mice. Adipocyte-specific IL-11 deletion in adiponectin-Cre; IL-11fl/fl mice exhibited no abnormality. Thus, osteoblast-derived IL-11 controls not only osteogenesis but also systemic adipogenesis and energy metabolism. Receptors and intracellular signaling mediating these effects of IL-11 are currently under investigation.

Academic Significance and Societal Importance of the Research Achievements

骨由来のIL-11が古典的Wntシグナル抑制因子の発現制御を介し、骨髄前駆細胞からの骨芽細胞・脂肪細胞の分化スイッチによる骨形成の促進のみならず、全身脂肪組織にも影響を及ぼし、エネルギー代謝をも制御することが示された。本研究によりオステオカルシンに加え新たに骨と脂肪組織・エネルギー代謝とのIL-11を介する密接な連関が明らかとなり、IL-11シグナルの制御を介する骨粗鬆症およびメタボリック症候群に対する新たな予防・治療法の開発に向けたアプローチに繋がるものと期待される。

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 Issue: 7
  • DOI: 10.1002/jbm4.10182
  • Peer Reviewed / Open Access
• [Journal Article] Grauer A 2018 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 DB, Ferrari S, Khan A, Lane NE, Lippuner K, Matsumoto T, Milmont CE, Libanati C, Grauer A
  • Journal Title: J Bone Miner Res Volume: - Issue: 7 Pages: 1219-1226
  • DOI: 10.1002/jbmr.3427
  • Peer Reviewed / Int'l Joint Research
• [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 SS
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 593-593
  • DOI: 10.1038/s41598-017-18911-9
  • NAID: 120006535030
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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: Journal of Atherosclerosis and Thrombosis Volume: 25 Issue: 1 Pages: 65-80
  • DOI: 10.5551/jat.37747
  • NAID: 130006301202
  • ISSN: 1340-3478, 1880-3873
  • Peer Reviewed
• [Journal Article] Pim-2 is a critical target for treatment of osteoclastogenesis enhanced in myeloma. (2017)
  • 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: E-pub Issue: 4 Pages: 581-585
  • DOI: 10.1111/bjh.14388
  • NAID: 120006549655
  • Peer Reviewed
• [Journal Article] Assessment criteria for vitamin D deficiency/insufficiency in Japan — proposal by an expert panel supported by Research Program of Intractable Diseases, Ministry of Health, Labour and Welfare, Japan, The Japanese Society for Bone and Mineral Research and The Japan Endocrine Society [Opinion] (2017)
  • Author(s): Okazaki R, Ozono K, Fukumoto S, Inoue D, Yamauchi M, Minagawa M, Michigami T, Takeuchi Y, Matsumoto T, Sugimoto T
  • Journal Title: Endocrine Journal Volume: 64 Issue: 1 Pages: 1-6
  • DOI: 10.1507/endocrj.EJ16-0548
  • NAID: 130005306013
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed
• [Journal Article] TAK1 inhibition subverts the osteoclastogenic action of TRAIL while potentiating its antimyeloma effects (2017)
  • Author(s): Tenshin Hirofumi、Teramachi Jumpei、Tanaka Eiji、Matsumoto Toshio、Abe Masahiro (他16人中2番目）
  • Journal Title: Blood Advances Volume: 1 Issue: 24 Pages: 2124-2137
  • DOI: 10.1182/bloodadvances.2017008813
  • Peer Reviewed / Open Access
• [Journal Article] The Role of Heparin Cofactor Ⅱ in the Regulation of Insulin Sensitivity and Maintenance of Glucose Homeostasis in Humans and Mice (2017)
  • Author(s): Kurahashi K, Inoue S, Yoshida S, Ikeda Y, Morimoto K, Uemoto R, Ishikawa K, Kondo T, Yuasa T, Endo I, Miyake M, Oyadomari S, Matsumoto T, Abe M, Sakaue H, Aihara KI.
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 24 Issue: 12 Pages: 1215-1230
  • DOI: 10.5551/jat.37739
  • NAID: 130006235273
  • ISSN: 1340-3478, 1880-3873
  • Peer Reviewed / Open Access
• [Journal Article] Expansion of Th1-like Vγ9Vδ2T cells by new generation IMiDs, lenalidomide and pomalidomide, in combination with zoledronic acid. (2017)
  • Author(s): 2. Harada T, Miki H, Cui Q, Oda A, Amachi R, Teramachi J, Bat-Erdene A, Sogabe K, Iwasa M, Fujii S, Nakamura S, Kagawa K, Yoshida S, Endo I, Aihara K, Ozaki S, Matsumoto T, Abe M.
  • Journal Title: Leukemia Volume: 31 Issue: 1 Pages: 258-262
  • DOI: 10.1038/leu.2016.273
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Recent advances in the management of osteoporosis. (2017)
  • Author(s): Fukumoto S, Matsumoto T
  • Journal Title: F1000Research Volume: 6 Pages: 625-625
  • DOI: 10.12688/f1000research.10682.1
  • NAID: 120006942554
  • Peer Reviewed
• [Journal Article] Total 25-hydroxyvitamin D levels predict fracture risk: Results from the 15-year follow-up of the Japanese Population-based Osteoporosis (JPOS) Cohort Study. (2016)
  • Author(s): Tamaki J, Iki M, Sato Y, Kajita E, Nishino H, Akiba T, Matsumoto T, Kagamimori S
  • Journal Title: Osteoporos Int Volume: E-pub Issue: 6 Pages: 1903-1913
  • DOI: 10.1007/s00198-017-3967-6
  • Peer Reviewed / Open Access
• [Journal Article] Serum carboxy-terminal telopeptide of type I collagen levels are associated with carotid atherosclerosis in patients with cardiovascular risk factors (2016)
  • Author(s): Kondo T, Endo I, Aihara K, Onishi Y, Dong B, Ohguro Y, Kurahashi K, Yoshida S, Fujinaka Y, Kuroda A, Matsuhisa M, Fukumoto S, Matsumoto T, Abe M.
  • Journal Title: Endocrine Journal Volume: 63 Issue: 4 Pages: 397-404
  • DOI: 10.1507/endocrj.EJ15-0589
  • NAID: 130005146452
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed / Open Access
• [Journal Article] A vicious cycle between acid sensing and survival signaling in myeloma cells: acid-induced epigenetic alteration. (2016)
  • Author(s): Amachi R, Hiasa M, Teramachi J, Harada T, Oda A, Nakamura S, Hanson D, Watanabe K, Fujii S, Miki H, Kagawa K, Iwasa M, Endo I, Kondo T, Yoshida S, Aihara KI, Kurahashi K, Kuroda Y, Horikawa H, Tanaka E, Matsumoto T, Abe M
  • Journal Title: Oncotarget Volume: 7 Issue: 43 Pages: 70447-70461
  • DOI: 10.18632/oncotarget.11927
  • NAID: 120006576954
  • Peer Reviewed / Open Access
• [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
• [Presentation] Decreased bone strength induced by persistent activation of calcium-sensing receptor. (2017)
  • Author(s): Itsuro Endo, Bingzi Dong, Yukiyo Ohnishi, Takeshi Kondo, Masahiro Hiasa, Jumpei Teramachi, Shinichi Aizawa, Toshio Matsumoto, Masahiro Abe and Seiji Fukumoto.
  • Organizer: Annual meeting of America Society of Bone and Mineral Research
  • Int'l Joint Research
• [Presentation] FRAME Study: The Foundation Effect of Rebuilding Bone With One Year of Romosozumab Leads to Continued Lower Fracture Risk After Transition to Denosumab. (2017)
  • Author(s): Felicia Cosman, Daria B Crittenden, Serge Ferrari, Aliya Khan, Nancy E Lane, Kurt Lippuner, Toshio Matsumoto, Cassandra E Milmont, Cesar Libanati, and Andreas Grauer.
  • Organizer: Annual meeting of America Society of Bone and Mineral Research
  • Int'l Joint Research
• [Presentation] Alendronate ameliorates the risk of urinary stone formation of astronauts on the International Space Station for 6 months. (2017)
  • Author(s): Okada A, Yasui T, Kohri K, Matsumoto T, LeBlanc A, Sibonga J, Spector E, Jones J, Shapiro J, Lang T, Shackelford L, Smith SM, Evans H, Ploutz-Snyder R, Keyak J, Ohshima H.
  • Organizer: Annual meeting of America Society of Bone and Mineral Research
  • Int'l Joint Research
• [Presentation] TAK1 inhibition impairs myeloma cell-bone marrow interaction to reduce myeloma tumor growth and bone destruction. (2017)
  • Author(s): umpei Teramachi, Masahiro Hiasa, Asuka Oda, Hirofumi Tenshin, Ryota Amachi, Takeshi Harada, Shingen Nakamura, Hirokazu Miki, Itsuro Endo, Akihito Yamamoto, Tatsuji Haneji, Toshio Matsumoto and Masahiro Abe.
  • Organizer: Annual meeting of America Society of Bone and Mineral Research
  • Int'l Joint Research
• [Presentation] Muscle-Specific Vitamin D Receptor (VDR) Ablation Results in Reduced Grip Power and Altered Gene Expression Pattern in Mice. (2017)
  • Author(s): Maria K Tsoumpra, Itsuro Endo, Shun Sawatsubashi, Yuichi Takashi, Seiji Fukumoto and Toshio Matsumoto.
  • Organizer: Annual meeting of America Society of Bone and Mineral Research
  • Int'l Joint Research
• [Presentation] FGF23 enhances CYP24A1 transcription in Klotho-dependent way via ERK pathway (2016)
  • Author(s): Maria K Tsoumpra, Shun Sawatsubashi, Yuichi Takashi, Toshio Matsumoto and Seiji Fukumoto.
  • Organizer: Amer Soc Bone Miner Res 2016 Annual Meeting
  • Place of Presentation: Atlanta, USA
  • Year and Date: 2016-09-16
  • Int'l Joint Research
• [Presentation] The regulatory mechanisms of FGF23 activity via GALNT3 by phosphate (2016)
  • Author(s): Yuichi Takashi, Yuka Kinoshita, Nobuaki Ito, Maria K Tsoumpra, Shun Sawatsubashi, Toshio Matsumoto, Seiji Fukumoto.
  • Organizer: Amer Soc Bone Miner Res 2016 Annual Meeting
  • Place of Presentation: Atlanta, USA
  • Year and Date: 2016-09-16
  • Int'l Joint Research
• [Presentation] Bone Loss Countermeasures for Long Duration Spaceflight (2016)
  • Author(s): E Spector, T Matsumoto, J Jones, J Shapiro, T Lang, L Shackelford, S M Smith, H Evans, R Ploutz-Snyder, J Sibonga, J Keyak, T Nakamura, K Kohri, H Ohshima, G Moralez, A LeBlanc.
  • Organizer: Amer Soc Bone Miner Res 2016 Annual Meeting
  • Place of Presentation: Atlanta, USA
  • Year and Date: 2016-09-16
  • Int'l Joint Research
• [Book] Chapter 93. Eldecalcitol and Osteoporosis. In Feldman D, Editor-in-Chief. Vitamin D, 4th Ed. (2018)
  • Author(s): Matsumoto T, Takahashi F.
  • Total Pages: 90
  • Publisher: Academic Press
• [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/