Regulation of aging via regulating calcium homeostasis through a transmembrane protein Enpp1

• Project/Area Number: 18H02930
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 56020:Orthopedics-related
• Research Institution: Keio University
• Principal Investigator: MIYAMOTO Takeshi 慶應義塾大学, 医学部(信濃町), 特任教授 (70383768)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2020: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2019: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2018: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: 整形外科 / 骨粗鬆症

Outline of Final Research Achievements

Osteoporosis is developed by various causes such as menopause and aging, and is defined as a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture. Mechanisms underlying bone loss owing to gonadal dysfunction such as menopause was recently clarified, however, those underlying aging dependent bone loss remained unclear. We utilized tip toe walk (ttw) mouse, which is a natural loss of function mutation mouse of ectonucleotide pyrophosphatase/phosphodiesterase 1 (Enpp1), a transmembrane protein, and clarified that ttw mice exhibited significant bone loss under a feeding of high phosphate diet. We also found that ectopic ossification was seen in ttw mice fed a high phosphate diet. Thus, we concluded that Enpp1 was requited to regulate calcium homeostasis through regulating phosphate metabolism.

Academic Significance and Societal Importance of the Research Achievements

近年の超高齢社会の到来により、骨粗鬆症患者数と骨粗鬆症に伴う脆弱性骨折数は増加の一途を辿っており、その対策は喫緊の課題である。本研究成果はカルシウム代謝の恒常性がリン代謝制御を介して制御されていることを明らかにした点、またその制御を膜貫通型分子であるectonucleotide pyrophosphatase/phosphodiesterase 1 (Enpp1)が担っていることを解明した点で学術的に有意義であり、またリン代謝を通じてカルシウムの異所性沈着が制御されているという、骨粗鬆症の発症機構の新たな可能性を示し得た点で社会的にも意義がある研究であると考えている。

Research Products

• [Journal Article] Overexpression of Interleukin-1α Suppresses Liver Metastasis of Lymphoma: Implications for Antitumor Effects of CD8+ T-cells (2021)
  • Author(s): Udagawa K, Niki Y, Kikuchi T, Fukuhara Y, Takeda Y, Miyamoto T, Matsumoto M, Nakamura M
  • Journal Title: J Histochem Cytochem Volume: 69 Issue: 4 Pages: 245-255
  • DOI: 10.1369/0022155421991634
  • Peer Reviewed
• [Journal Article] Compressive mechanical stress enhances susceptibility to interleukin-1 by increasing interleukin-1 receptor expression in 3D-cultured ATDC5 cells (2021)
  • Author(s): Takeda Y, Niki Y, Fukuhara Y, Fukuda Y, Udagawa K, Shimoda M, Kikuchi T, Kobayashi S, Harato K, Miyamoto T, Matsumoto M, Nakamura M
  • Journal Title: BMC Musculoskelet Disord Volume: 22 Issue: 1
  • DOI: 10.1186/s12891-021-04095-x
  • Peer Reviewed
• [Journal Article] Objective characterization of hip pain levels during walking by combining quantitative electroencephalography with machine learning (2021)
  • Author(s): Kimura A, Mitsukura Y, Oya A, Matsumoto M, Nakamura M, Kanaji A, Miyamoto T
  • Journal Title: Sci Rep. Volume: 11 Issue: 1
  • DOI: 10.1038/s41598-021-82696-1
  • Peer Reviewed / Open Access
• [Journal Article] Treatment with an active vitamin D analogue blocks hypothalamic dysfunction-induced bone loss in mice (2021)
  • Author(s): Ito E, Sato Y, Kobayashi T, Nakamura S, Kaneko Y, Soma T, Matsumoto T, Kimura A, Miyamoto K, Matsumoto H, Matsumoto M, Nakamura M, Sato K, Miyamoto T
  • Journal Title: Biochem Biophys Res Commun Volume: 542 Pages: 48-53
  • DOI: 10.1016/j.bbrc.2021.01.026
  • Peer Reviewed
• [Journal Article] Food restriction reduces cortical bone mass and serum insulin-like growth factor-1 levels and promotes uterine atrophy in mice (2021)
  • Author(s): Ito E, Sato Y, Kobayashi T, Nakamura S, Kaneko Y, Soma T, Matsumoto T, Kimura A, Miyamoto K, Matsumoto H, Matsumoto M, Nakamura M, Sato K, Miyamoto T
  • Journal Title: Biochem Biophys Res Commun Volume: 534 Pages: 165-171
  • DOI: 10.1016/j.bbrc.2020.11.122
  • Peer Reviewed
• [Journal Article] ALDH2 mutation promotes skeletal muscle atrophy in mice via accumulation of oxidative stress (2021)
  • Author(s): Kobayashi H, Nakamura S, Sato Y, Kobayashi T, Miyamoto K, Oya A, Matsumoto M, Nakamura M, Kanaji A, Miyamoto T
  • Journal Title: Bone Volume: 142 Pages: 115739-115739
  • DOI: 10.1016/j.bone.2020.115739
  • Peer Reviewed
• [Journal Article] Meningeal Melanocytoma Occurring at Epidural Region of the Cervical Spine (2020)
  • Author(s): Tateyama M, Fujimoto T, Nakamura T, Miyamoto T
  • Journal Title: Spine Surgery and Related Research Volume: 4 Issue: 4 Pages: 377-379
  • DOI: 10.22603/ssrr.2020-0027
  • NAID: 130007930882
  • ISSN: 2432-261X
  • Year and Date: 2020-10-27
  • Peer Reviewed
• [Journal Article] Femur Bone Mineral Density and Pentosidine Level Distinguish Ankylosing Spinal Disorder Patients with and without Sacroiliac Ankylosis (2020)
  • Author(s): Furukawa M, Okuyama K, Kawano Y, Kikuchi K, Miyamoto T, Nakamura M, Matsumoto M
  • Journal Title: Spine Surgery and Related Research Volume: 4 Issue: 4 Pages: 333-340
  • DOI: 10.22603/ssrr.2020-0001
  • NAID: 130007930885
  • ISSN: 2432-261X
  • Year and Date: 2020-10-27
  • Peer Reviewed
• [Journal Article] Apolipoprotein AI amyloid deposits in the ligamentum flavum in patients with lumbar spinal canal stenosis (2020)
  • Author(s): Tasaki Masayoshi、Okada Masamitsu、Yanagisawa Akihiro、Nomura Toshiya、Matsushita Hiroaki、Ueda Akihiko、Inoue Yasuteru、Masuda Teruaki、Misumi Yohei、Yamashita Taro、Nakamura Takayuki、Miyamoto Takeshi、Obayashi Konen、Ando Yukio、Ueda Mitsuharu
  • Journal Title: Amyloid Volume: 28 Issue: 2 Pages: 1-6
  • DOI: 10.1080/13506129.2020.1858404
  • Peer Reviewed / Open Access
• [Journal Article] Meta-analysis of 208370 East Asians identifies 113 susceptibility loci for systemic lupus erythematosus. (2020)
  • Author(s): Xianyong Yin, et al.
  • Journal Title: Ann Rheum Dis. Volume: 80(5) Issue: 5 Pages: 632-640
  • DOI: 10.1136/annrheumdis-2020-219209
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Role of Scx+/Sox9+ cells as potential progenitor cells for postnatal supraspinatus enthesis formation and healing after injury in mice (2020)
  • Author(s): Ideo K, Tokunaga T, Shukunami C, Takimoto A, Yoshimoto Y, Yonemitsu R, Karasugi T, Mizuta H, Hiraki Y, Miyamoto T
  • Journal Title: PLoS One Volume: 15 Issue: 12 Pages: 1-14
  • DOI: 10.1371/journal.pone.0242286
  • Peer Reviewed / Open Access
• [Journal Article] Tooth extraction in mice administered zoledronate increases inflammatory cytokine levels and promotes osteonecrosis of the jaw (2020)
  • Author(s): Soma T, Iwasaki R, Sato Y, Kobayashi T, Nakamura S, Kaneko Y, Ito E, Okada H, Watanabe H, Miyamoto K, Matsumoto M, Nakamura M, Asoda S, Kawana H, Nakagawa T, Miyamoto T
  • Journal Title: J Bone Miner Metab Volume: - Issue: 3 Pages: 372-384
  • DOI: 10.1007/s00774-020-01174-2
  • Peer Reviewed
• [Journal Article] Smoking cessation increases levels of osteocalcin and uncarboxylated osteocalcin in human sera (2020)
  • Author(s): Kiyota Y, Muramatsu H, Sato Y, Kobayashi T, Miyamoto K, Iwamoto T, Matsumoto M, Nakamura M, Tateno H, Sato K, Miyamoto T
  • Journal Title: Sci Rep Volume: 10 Issue: 1
  • DOI: 10.1038/s41598-020-73789-4
  • Peer Reviewed / Open Access
• [Journal Article] Macrophages fine-tune pupil shape during development (2020)
  • Author(s): Takahashi M, Misaki M, Shibata S, Iga T, Shindo T, Tai-Nagara I, Hirata A, Ogawa M, Miyamoto T, Nakagawa T, Ema M, Ichiyama Y, Shima DT, Hozumi K, Nishimura S, Kubota Y
  • Journal Title: Dev Biol Volume: 464 Issue: 2 Pages: 137-144
  • DOI: 10.1016/j.ydbio.2020.06.004
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Vitamin D protects against immobilization-induced muscle atrophy via neural crest-derived cells in mice (2020)
  • Author(s): Nakamura S, Sato Y, Kobayashi T, Kaneko Y, Ito E, Soma T, Okada H, Miyamoto K, Oya A, Matsumoto M, Nakamura M, Kanaji A, Miyamoto T
  • Journal Title: Sci Rep Volume: 10 Issue: 1
  • DOI: 10.1038/s41598-020-69021-y
  • Peer Reviewed / Open Access
• [Journal Article] Astaxanthin improves osteopenia caused by aldehyde-stress resulting from Aldh2 mutation due to impaired osteoblastogenesis (2020)
  • Author(s): Hoshi H, Monoe F, Ohsawa I, Ohta S, Miyamoto T
  • Journal Title: Biochem Biophys Res Commun Volume: 527 Issue: 1 Pages: 270-275
  • DOI: 10.1016/j.bbrc.2020.04.013
  • Peer Reviewed
• [Journal Article] Sustained anti-osteoporotic action of risedronate compared to anti-RANKL antibody following discontinuation in ovariectomized mice (2020)
  • Author(s): Omiya Toshinobu、Hirose Jun、Omata Yasunori、Tominari Tsukasa、Inada Masaki、Watanabe Hisato、Miyamoto Takeshi、Tanaka Sakae
  • Journal Title: Bone Reports Volume: 13 Pages: 100289-100289
  • DOI: 10.1016/j.bonr.2020.100289
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Oral administration of N-acetyl cysteine prevents osteoarthritis development and progression in a rat model. (2019)
  • Author(s): Kaneko Y, Tanigawa N, Sato Y, Kobayashi T, Nakamura S, Ito E, Soma T, Miyamoto K, Kobayashi S, Harato K, Matsumoto M, Nakamura M, Niki Y, Miyamoto T.
  • Journal Title: Sci Rep. Volume: 9 Issue: 1 Pages: 18741-18741
  • DOI: 10.1038/s41598-019-55297-2
  • Peer Reviewed / Open Access
• [Journal Article] Changes in bone metabolic profile associated with pregnancy or lactation. (2019)
  • Author(s): Miyamoto T, Miyakoshi K, Sato Y, Kasuga Y, Ikenoue S, Miyamoto K, Nishiwaki Y, Tanaka M, Nakamura M, Matsumoto M.
  • Journal Title: Sci Rep. Volume: 9 Issue: 1 Pages: 6787-6787
  • DOI: 10.1038/s41598-019-43049-1
  • Peer Reviewed / Open Access
• [Journal Article] CTLA4-Ig directly inhibits osteoclastogenesis by interfering with intracellular calcium oscillations in bone marrow macrophages. (2019)
  • Author(s): Okada H, Kajiya H, Omata Y, Matsumoto T, Sato Y, Kobayashi T, Nakamura S, Kaneko Y, Nakamura S, Koyama T, Sudo S, Shin M, Okamoto F, Watanabe H, Tachibana N, Hirose J, Saito T, Takai T, Matsumoto M, Nakamura M, Okabe K, Miyamoto T, Tanaka S.
  • Journal Title: J Bone Miner Res Volume: 34 Issue: 9 Pages: 1744-1752
  • DOI: 10.1002/jbmr.3754
  • Peer Reviewed
• [Journal Article] Potential involvement of semaphorin 3A in maintaining intervertebral disc tissue homeostasis (2019)
  • Author(s): Mima Y, Suzuki S, Fujii T, Morikawa T, Tamaki S, Takubo K, Shimoda M, Miyamoto T, Watanabe K, Matsumoto M, Nakamura M, Fujita N.
  • Journal Title: J Orthop Res Volume: 37 Issue: 4 Pages: 972-980
  • DOI: 10.1002/jor.24258
  • Peer Reviewed / Open Access
• [Journal Article] Cooperation of PU.1 with IRF8 and NFATc1 defines chromatin landscapes during RANKL‐induced osteoclastogenesis (2019)
  • Author(s): Izawa Naohiro、Kurotaki Daisuke、Nomura Seitaro、Fujita Takanori、Omata Yasunori、Yasui Tetsuro、Hirose Jun、Matsumoto Takumi、Saito Taku、Kadono Yuho、Okada Hiroyuki、Miyamoto Takeshi、Tamura Tomohiko、Aburatani Hiroyuki、Tanaka Sakae
  • Journal Title: Journal of Bone and Mineral Research Volume: なし Issue: 6 Pages: 1143-1154
  • DOI: 10.1002/jbmr.3689
  • Peer Reviewed / Open Access
• [Journal Article] Insulin-like growth factor-I is required to maintain muscle volume in adult mice. (2019)
  • Author(s): Nakamura S, Sato Y, Kobayashi T, Oike T, Kaneko Y, Miyamoto K, Funayama A, Oya A, Nishiwaki T, Matsumoto M, Nakamura M, Kanaji A, Miyamoto T.
  • Journal Title: J Bone Miner Metab. Volume: 印刷中 Issue: 4 Pages: 627-635
  • DOI: 10.1007/s00774-018-0964-6
  • Peer Reviewed
• [Journal Article] Elevated Creatine Kinase and Lactic Acid Dehydrogenase and Decreased Osteocalcin and Uncarboxylated Osteocalcin are Associated with Bone Stress Injuries in Young Female Athletes (2018)
  • Author(s): Miyamoto T, Oguma Y, Sato Y, Kobayashi T, Ito E, Tani M, Miyamoto K, Nishiwaki Y, Ishida H, Otani T, Matsumoto H, Matsumoto M, Nakamura M.
  • Journal Title: Sci Rep Volume: 8 Issue: 1 Pages: 18019-18019
  • DOI: 10.1038/s41598-018-36982-0
  • Peer Reviewed / Open Access
• [Journal Article] IL-6, IL-17 and Stat3 are required for auto-inflammatory syndrome development in mouse. (2018)
  • Author(s): Oike T, Kanagawa H, Sato Y, Kobayashi T, Nakatsukasa H, Miyamoto K, Nakamura S, Kaneko Y, Kobayashi S, Harato K, Yoshimura A, Iwakura Y, Takeuchi T, Matsumoto M, Nakamura M, Niki Y, Miyamoto T.
  • Journal Title: Sci Rep. Volume: - Issue: 1 Pages: 15783-15783
  • DOI: 10.1038/s41598-018-34173-5
  • Peer Reviewed / Open Access
• [Journal Article] Metabolite profiling of plasma in patients with ossification of the posterior longitudinal ligament. (2018)
  • Author(s): Tsuji T, Matsumoto M, Nakamura M, Miyamoto T, Yagi M, Fujita N, Okada E, Nagoshi N, Tsuji O, Watanabe K.
  • Journal Title: J Orthop Sci Volume: 23 Issue: 6 Pages: 878-883
  • DOI: 10.1016/j.jos.2018.07.001
  • Peer Reviewed
• [Journal Article] Combinatorial CRISPR/Cas9 Approach to Elucidate a Far-Upstream Enhancer Complex for Tissue-Specific Sox9 Expression (2018)
  • Author(s): Mochizuki Yusuke、Chiba Tomoki、Kataoka Kensuke、Yamashita Satoshi、Sato Tempei、Kato Tomomi、Takahashi Kenji、Miyamoto Takeshi、Kitazawa Masashi、Hatta Tomohisa、Natsume Tohru、Takai Shinro、Asahara Hiroshi
  • Journal Title: Developmental Cell Volume: 46 Issue: 6 Pages: 794-806
  • DOI: 10.1016/j.devcel.2018.07.024
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Tumor necrosis factor receptor-associated factor 6 is required to inhibit foreign body giant cell formation and activate osteoclasts under inflammatory and infectious conditions (2018)
  • Author(s): Oya A, Katsuyama E, Morita M, Sato Y, Kobayashi T, Miyamoto K, Nishiwaki T, Funayama A, Fujita Y, Kobayashi T, Matsumoto M, Nakamura M, Kanaji A, Miyamoto T.
  • Journal Title: J Bone Miner Metab Volume: - Issue: 6 Pages: 679-690
  • DOI: 10.1007/s00774-017-0890-z
  • Peer Reviewed
• [Journal Article] Metabolomics-based profiles predictive of low bone mass in menopausal women. (2018)
  • Author(s): Miyamoto T, Hirayama A, Sato Y, Koboyashi T, Katsuyama E, Kanagawa H, Fujie A, Morita M, Watanabe R, Tando T, Miyamoto K, Tsuji T, Funayama A, Soga T, Tomita M, Nakamura M, Matsumoto M.
  • Journal Title: Bone Rep Volume: 9 Pages: 11-18
  • DOI: 10.1016/j.bonr.2018.06.004
  • Peer Reviewed / Open Access
• [Journal Article] OC-STAMP promotes osteoclast fusion for pathogenic bone resorption in periodontitis via up-regulation of permissive fusogen CD9. (2018)
  • Author(s): Ishii T, Ruiz-Torruella M, Ikeda A, Shindo S, Movila A, Mawardi H, Albassam A, Kayal RA, Al-Dharrab AA, Egashira K, Wisitrasameewong W, Yamamoto K, Mira AI, Sueishi K, Han X, Taubman MA, Miyamoto T, Kawai T
  • Journal Title: The FASEB Journal Volume: 32 Issue: 7 Pages: 4016-4030
  • DOI: 10.1096/fj.201701424r
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] TET2-dependent IL-6 induction mediated by the tumor microenvironment promotes tumor metastasis in osteosarcoma. (2018)
  • Author(s): Itoh H, Kadomatsu T, Tanoue H, Yugami M, Miyata K, Endo M, Morinaga J, Kobayashi E, Miyamoto T, Kurahashi R, Terada K, Mizuta H, Oike Y.
  • Journal Title: Oncogene Volume: 印刷中 Issue: 22 Pages: 2903-2920
  • DOI: 10.1038/s41388-018-0160-0
  • Peer Reviewed / Open Access
• [Presentation] 加齢による関節軟骨と骨の障害のマネージメント (2021)
  • Author(s): 宮本健史
  • Organizer: 第33回日本軟骨代謝学会
  • Invited
• [Presentation] 病態に基づく骨粗鬆症の治療戦略 (2021)
  • Author(s): 宮本健史
  • Organizer: 第35回日本日本整形外科学会基礎学術集会
  • Invited
• [Presentation] 脊柱靭帯骨化症の細胞生物学的アプローチ (2021)
  • Author(s): 宮本健史、松本守雄
  • Organizer: 第35回日本日本整形外科学会基礎学術集会
  • Invited
• [Presentation] 整形外科外科から見た脆弱性骨折 女性アスリートにおける疲労骨折 (2020)
  • Author(s): 宮本健史
  • Organizer: 第22回日本骨粗鬆症学会/第38回日本骨代謝学会学術集会
  • Invited
• [Presentation] 妊娠後骨粗鬆症の病態と疫学―どのように予防・早期発見・管理するか？― 妊娠・授乳にともなう骨代謝の変化 (2020)
  • Author(s): 宮本健史
  • Organizer: 第22回日本骨粗鬆症学会/第38回日本骨代謝学会学術集会
  • Invited
• [Presentation] 運動・エクササイズとアンチエイジング (2020)
  • Author(s): 宮本健史
  • Organizer: 第20回日本抗加齢医学会総会
  • Invited
• [Presentation] 骨代謝研究による骨粗鬆症治療の改革 骨吸収の分子制御 (2019)
  • Author(s): 宮本健史
  • Organizer: 第34回日本整形外科学会基礎学術集会
  • Invited
• [Presentation] 骨粗鬆症の予防戦略と慢性痛 (2019)
  • Author(s): 宮本健史
  • Organizer: 第53回日本ペインクリニック学会
  • Invited
• [Presentation] 病態に基づく骨脆弱性骨折防止のための治療選択肢～疼痛への対応も含めて～ (2019)
  • Author(s): 宮本健史
  • Organizer: 第45回日本骨折治療学会
  • Invited
• [Presentation] 筋肉のニューサイエンスー筋骨連関を踏まえてー 筋萎縮の発症メカニズム (2019)
  • Author(s): 宮本健史
  • Organizer: 第19回日本抗加齢医学会総会
  • Invited
• [Presentation] 妊娠・出産・授乳による椎体骨折と骨代謝状態変化 (2019)
  • Author(s): 宮本健史
  • Organizer: 第92回日本整形外科学会総会・学術総会
• [Presentation] 骨と多臓器の連環制御による骨恒常性制御 (2019)
  • Author(s): 宮本健史、松本守雄、中村雅也
  • Organizer: 第92回日本整形外科学会総会・学術総会
  • Invited
• [Presentation] 骨粗鬆症と骨代謝 (2018)
  • Author(s): 宮本健史
  • Organizer: 第２２回顎顔面インプラント学会総会・学術集会
  • Invited
• [Presentation] 炎症性疾患による関節破壊機序と治療標的 (2018)
  • Author(s): 宮本健史、尾池崇嗣、松本守雄、中村雅也
  • Organizer: 第３３回日本整形外科学会基礎学術総会
• [Presentation] 靭帯骨化症の発症機序と治療戦略 (2018)
  • Author(s): 宮本健史、渡辺隆一、松本守雄、中村雅也
  • Organizer: 第３３回日本整形外科学会基礎学術総会
• [Presentation] 骨粗鬆症の基礎と臨床 (2018)
  • Author(s): 宮本健史
  • Organizer: 歯科基礎医学会
  • Invited
• [Presentation] Pathophysiological Regulation of Bone Homeostasis (2018)
  • Author(s): Takeshi Miyamoto
  • Organizer: 51th Bone Biology Forum
  • Int'l Joint Research / Invited
• [Presentation] 骨粗鬆症の基礎と臨床 (2018)
  • Author(s): 宮本健史
  • Organizer: 第４回日本骨免疫学会
  • Invited
• [Presentation] 骨粗鬆症の病態の理解に基づく治療法の選択 (2018)
  • Author(s): 宮本健史
  • Organizer: 第３８回日本骨形態計測学会
  • Invited