Molecular Mechanism of Comprehensive Signal for Bone Formation

• Project/Area Number: 26253085
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Functional basic dentistry
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: NODA Masaki 東京医科歯科大学, 大学院医歯学総合研究科, 非常勤講師 (50231725)
• Co-Investigator(Kenkyū-buntansha): 江面 陽一 東京医科歯科大学, 難治疾患研究所, 准教授 (50333456) ; 早田 匡芳 筑波大学, 医学医療系, 准教授 (40420252) ; 伊豆 弥生 千葉科学大学, 危機管理学部, 講師 (90431949)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥41,730,000 (Direct Cost: ¥32,100,000、Indirect Cost: ¥9,630,000); Fiscal Year 2017: ¥7,930,000 (Direct Cost: ¥6,100,000、Indirect Cost: ¥1,830,000); Fiscal Year 2016: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000); Fiscal Year 2015: ¥8,060,000 (Direct Cost: ¥6,200,000、Indirect Cost: ¥1,860,000); Fiscal Year 2014: ¥18,590,000 (Direct Cost: ¥14,300,000、Indirect Cost: ¥4,290,000)
• Keywords: 骨芽細胞 / 破骨細胞 / 骨形成 / メカニカルストレス / 骨量 / シグナル / Bardet-Biedl Syndrome 3 / 繊毛 / 骨代謝 / 副甲状腺ホルモン

Outline of Final Research Achievements

Musculoskeletal diseases are rapidly increasing with the aging of society, and therefore, establishment of "coping method based on bone formation" is urgent, but "molecular mechanism of osteogenic control leading to regulation failure in diseased pathology of decreased osteogenesis" including reduction of bone mass due to decrease in mechanical stimulus is still not clear enough. We discovered the role of Nck as a molecular mechanism by which bone mass is regulated by the movement of osteoblasts is elucidated (PNAS 2015), control of TGFbeta signal by Dullard during endochondral bone formation (JBMR 2015), and function of osteoclastic TPC (JBC 2017). In addition, regulation of adrenergic receptors by PTH, isoproterenol regulation of osteoblastic ALP , osteoblast proliferation promoting action through UPS by PTH and molecular mechanism of oxidative stress control of osteoblasts were established. These discoveries contribute to understand the molecular mechanism of bone formation.

Research Products

• [Journal Article] Dullard deficiency causes hemorrhage in the adult ovarian follicles (2018)
  • Author(s): Hayata Tadayoshi、Chiga Masahiko、Ezura Yoichi、Asashima Makoto、Katabuchi Hidetaka、Nishinakamura Ryuichi、Noda Masaki
  • Journal Title: Genes to Cells Volume: 23 Pages: 345-356
  • DOI: 10.1111/gtc.12575
• [Journal Article] Dok-3 and Dok-1/-2 adaptors play distinctive roles in cell fusion and proliferation during osteoclastogenesis and cooperatively protect mice from osteopenia (2018)
  • Author(s): Kajikawa Shuhei、Taguchi Yuu、Hayata Tadayoshi、Ezura Yoichi、Ueta Ryo、Arimura Sumimasa、Inoue Jun-ichiro、Noda Masaki、Yamanashi Yuji
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 498 Pages: 967-974
  • DOI: 10.1016/j.bbrc.2018.03.090
  • Peer Reviewed
• [Journal Article] FGF Suppresses Poldip2 Expression in Osteoblasts (2017)
  • Author(s): Katsumura Sakie、Izu Yayoi、Yamada Takayuki、Griendling Kathy、Harada Kiyoshi、Noda Masaki、Ezura Yoichi
  • Journal Title: Journal of Cellular Biochemistry Volume: 118 Pages: 1670-1677
  • DOI: 10.1002/jcb.25813
• [Journal Article] Role of lysosomal channel protein TPC2 in osteoclast differentiation and bone remodeling under normal and low-magnesium conditions (2017)
  • Author(s): Notomi Takuya, Kuno M, Hiyama A, Nozaki T, Ohura K, Ezura Y, Noda M,
  • Journal Title: Journal of Biological Chemistry Volume: 292 Pages: 20998-21010
  • DOI: 10.1074/jbc.m117.780072
  • Peer Reviewed / Open Access
• [Journal Article] Profilin1 is expressed in osteocytes and regulates cell shape and migration (2017)
  • Author(s): Lin W, Izu Y, Smriti A, Kawasaki M, Pawaputanon C, Bottcher RT, Costell M, Moriyama K, Noda M, Ezura Y.
  • Journal Title: Journal of Cellular Physiology Volume: 印刷中 Pages: 259-268
  • DOI: 10.1002/jcp.25872
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Bardet-Biedl Syndrome 3 regulates development of cranial base midline structures. (2016)
  • Author(s): Muraki S, Akune T, Ishimoto Y, Nagata K, Yoshida M, Tanaka S, Oka H, Kawaguchi H, Nakamura K, and Yoshimura N
  • Journal Title: BONE Volume: 51(4) Pages: 242-248
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Interleukin-1β Suppresses the Transporter Genes Ank and Ent1 Expression in Stromal Progenitor Cells Retaining Mineralization. (2016)
  • Author(s): Ezura Y, Lin X, Hatta A, Izu Y, Noda M.
  • Journal Title: Calcif Tissue Int. Volume: 99 Pages: 199-208
  • DOI: 10.1007/s00223-016-0139-1
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] PTH-Induced Osteoblast Proliferation Requires Upregulation of the Ubiquitin-Specific Peptidase 2 (Usp2) Expression. (2016)
  • Author(s): Shirakawa J, Harada H, Noda M, Ezura Y.
  • Journal Title: Calcif Tissue Int. Volume: 98 Pages: 306-315
  • DOI: 10.1007/s00223-015-0083-5
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Nck influences preosteoblastic/osteoblastic migration (2015)
  • Author(s): Aryal Smriti, Kentaro Miyai, Yayoi Izu, Tadayoshi Hayata, Takuya Notomi, Masaki Noda, Yoichi Ezura
  • Journal Title: Proc Natl Acad Sci U S A Volume: 112 Pages: 15432-15437
  • DOI: 10.1073/pnas.1518253112
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Hindlimb-unloading suppresses B cell population in the bone marrow and peripheral circulation associated with OPN expression in circulating blood cells. (2015)
  • Author(s): Ezura Y1, Nagata J, Nagao M, Hemmi H, Hayata T, Rittling S, Denhardt DT, Noda M.
  • Journal Title: J Bone Miner Metab. Volume: 33 Pages: 48-54
  • DOI: 10.1007/s00774-014-0568-8
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Migration linked to FUCCI-indicated cell cycle is controlled by PTH and mechanical stress. (2014)
  • Author(s): Shirakawa J, Ezura Y, Moriya S, Kawasaki M, Yamada T, Notomi T, Nakamoto T, Hayata T, Miyawaki A, Omura K, Noda M.
  • Journal Title: J Cell Physiol Volume: - Pages: 1353-8
  • DOI: 10.1002/jcp.24605
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Control of lymphocyte egress from lymph nodes through β2-adrenergic receptors. (2014)
  • Author(s): Notomi T, Karasaki I, Okazaki Y, Okimoto N, Kato Y, Ohura K, Noda M, Nakamura T, Suzuki M.
  • Journal Title: J Exp Med Volume: 65 Pages: 42-48
  • DOI: 10.1084/jem.20141132
  • Peer Reviewed / Open Access
• [Presentation] Oxidative stress impairs the expression levels of of Lgr4 in osteoblastic cells. (2016)
  • Author(s): Chantida Pawaputanon Na Mahasarakham, Yoichi Ezura, Yayoi Izu, Katsuhiko Nishimori, Yuichi Izumi, Masaki Nada.
  • Organizer: The 38th Annual Meeting of the American Society for Bone and Mineral Research
  • Place of Presentation: Atlanta, Georgia, U.S.A.
  • Year and Date: 2016-09-16
  • Int'l Joint Research
• [Presentation] Changes in Membrane Potential Regulates RANKL Intracellular Transport via Voltage-gated Calcium Channels in Osteoblasts. (2016)
  • Author(s): Takuya Notomi, Miyuki Kuno, Akiko Hiyama, Yoichi Ezura, Kiyoshi Ohura, Masaki Noda.
  • Organizer: The 38th Annual Meeting of the American Society for Bone and Mineral Research
  • Place of Presentation: Atlanta, Georgia, U.S.A.
  • Year and Date: 2016-09-15
  • Int'l Joint Research
• [Presentation] Dexamethasone-induced Poldip2 expression possibly recapitulating the osteoblast aging was suppressed by a longevity factor basic-FGF. (2016)
  • Author(s): Sakie Katsumura, Yoichi Ezura, Kathy Griendling, Masaki Noda.
  • Organizer: The 38th Annual Meeting of the American Society for Bone and Mineral Research
  • Place of Presentation: Atlanta, Georgia, U.S.A.
  • Year and Date: 2016-09-15
  • Int'l Joint Research