Development of new therapeutic strategy for the craniosynostosis patients

2013 Fiscal Year Final Research Report

• Project/Area Number: 23390471
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Orthodontic/Pediatric dentistry
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: MORIYAMA Keiji 東京医科歯科大学, 医歯(薬)学総合研究科, 教授 (20262206)
• Co-Investigator(Kenkyū-buntansha): OGAWA Takuya 東京医科歯科大学, 大学院・医歯(薬)学総合研究科, 講師 (50401360) ; HIGASHIHORI Norihisa 東京医科歯科大学, 大学院・医歯(薬)学総合研究科, 助教 (50585221) ; KOBAYASHI Yukiho 東京医科歯科大学, 大学院・医歯(薬)学総合研究科, 助教 (20596233) ; AKIYOSHI Kazunari 京都大学, 工学部, 教授 (90201285)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Keywords: 歯学 / 頭蓋冠縫合部早期癒合症 / ナノサイエンス

Research Abstract

Here we aimed to clarify the etiological mechanisms of craniosynostosis in mouse models of Apert syndrome and verify the effects of purified soluble FGFR2 harboring the S252W mutation (sFGFR2IIIcS252W) on calvarial sutures in Apert syndrome mice in vitro. We observed increased expression of Fgf10, Esrp1, and Fgfr2IIIb, which are indispensable for epidermal development, in coronal sutures in Apert syndrome mice. Purified sFGFR2IIIcS252W exhibited binding affinity for Fgf2 but also formed heterodimers with FGFR2IIIc, FGFR2IIIcS252W, and FGFR2IIIbS252W. sFGFR2IIIcS252W complexed with nanogels maintained the patency of coronal sutures, whereas synostosis was observed where the nanogel without sFGFR2S252W was applied. Thus, based on our current data, we suggest that increased Fgf10 and Fgfr2IIIb expression may induce the onset of craniosynostosis in patients with Apert syndrome and that the appropriate delivery of purified sFGFR2IIIcS252W could be effective for treating this disorder.

Research Products

• [Journal Article] Soluble form of FGFR2 with S252W partially prevents craniosynostosis of the apert mouse model (2014)
  • Author(s): Morita J, Nakamura M, Kobayashi Y, Deng CX, Funato N, Moriyama K
  • Journal Title: Dev Dyn Volume: 243(4) Pages: 560-567
  • DOI: 10.1002/dvdy.24099
  • Peer Reviewed
• [Journal Article] The stability of mRNA influences osteoporotic bone mass via Cnot3 (2014)
  • Author(s): Watanabe C, Morita M, Hayata T, Nakamoto T, Kikuguchi C, Li X, Kobayashi Y, Takahashi N, Notomi T, Moriyama K, Yamamoto T, Ezura Y, Noda M
  • Journal Title: Proc Natl Acad Sci USA Volume: 111(7) Pages: 2692-2697
  • DOI: 10.1073/pnas.1316932111
  • Peer Reviewed
• [Journal Article] Relaxin receptors 1 and 2 and nuclear receptor subfamily 3, group C, member 1 (glucocorticoid receptor) mRNAs are expressed in oral components of developing mice (2014)
  • Author(s): Duarte C, Kobayashi Y, Kawamoto T, Moriyama K
  • Journal Title: Arch Oral Biol Volume: 59(2) Pages: 111-118
  • DOI: 10.1016/j.archoralbio.2013.10.010
  • Peer Reviewed
• [Journal Article] Hydroxyapatite/collagen nanocomposite-coated titanium rod for achieving rapid osseointegration onto bone surface (2013)
  • Author(s): Uezono M, Takakuda K, Kikuchi M, Suzuki S, Moriyama K
  • Journal Title: J Biomed Mater Res B Appl Biomater Volume: 101 Pages: 1031-1038
  • DOI: 10.1002/jbm.b.32913
  • Peer Reviewed
• [Journal Article] Periostin inhibits hypoxia-induced apoptosis in human periodontal ligament cells via TGF-β signaling (2013)
  • Author(s): Aukkarasongsup P, Haruyama N, Matumoto T, Shiga M, Moriyama K
  • Journal Title: Biochem Biophys Res Commun Volume: 441 Pages: 126-32
  • DOI: 10.1016/j.bbrc.2013.10.027
  • Peer Reviewed
• [Journal Article] Apert syndrome mutant FGFR2 and its soluble form reciprocally alter osteogenesis of primary calvarial osteoblasts (2012)
  • Author(s): Suzuki H, Suda N, Shiga M, Kobayashi Y, Nakamura M, Iseki S, Moriyama K
  • Journal Title: Journal of Cellular Physiology Volume: 227(9) Pages: 3267-77
  • DOI: 10.1002/jcp.24021
  • Peer Reviewed
• [Journal Article] Stage-specific functions of leukemia/lymphoma-related factor (LRF) in the transcriptional control of osteoclast development (2012)
  • Author(s): Tsuji-Takechi K, Negishi-Koga T, Sumiya E, Kukita A, Kato S, Maeda T, Pandolfi PP, Moriyama K, Takayanagi H
  • Journal Title: Proc Natl Acad Sci USA Volume: 109 Pages: 2561-6
  • DOI: 10.1073/pnas.1116042109
  • Peer Reviewed
• [Journal Article] Systemic and maxillofacial characteristics of patients with Beckwith-Wiedemann syndrome not treated with glossectomy (2011)
  • Author(s): Kawafuji A, Suda N, Ichikawa N, Kakara S, Suzuki T, Baba Y, Ogawa T, Tsuji M, Moriyama K
  • Journal Title: Am J Orthod Dentofacial Orthop Volume: 139(4) Pages: 517-25
  • DOI: 10.1016/j.ajodo.2009.07.021
  • Peer Reviewed
• [Journal Article] Non-syndromic oligodontia with a novel mutation of PAX9 (2011)
  • Author(s): Suda N, Ogawa T, Kojima T, Saito C, Moriyama K
  • Journal Title: J Dent Res Volume: 90(3) Pages: 382-6
  • DOI: 10.1177/0022034510390042
  • Peer Reviewed
• [Presentation] アペール型変異(S252W)を伴う可溶型FGFR2 はアペール症候群モデルマウスの頭蓋冠早期癒合症の発症を抑制する (2013)
  • Author(s): 森田淳平, 船戸紀子, 小林起穂, 中村正孝, 森山啓司
  • Organizer: 第72回日本矯正歯科学会大会
  • Place of Presentation: 松本
  • Year and Date: 20131007-09
• [Presentation] 頭蓋冠縫合部早期癒合症に対するFGF/FGFR シクナルを標的とした新規治療法開発への試み (2013)
  • Author(s): 吉崎正子, 小林起穂, 佐々木善浩, 秋吉一成, 森山啓司
  • Organizer: 第72回日本矯正歯科学会大会
  • Place of Presentation: 松本
  • Year and Date: 20131007-09
• [Presentation] Soluble fibroblast growth factor receptor 2 with Apert mutation inhibits differentiation and mineralization of osteoblast (2013)
  • Author(s): Yoshizaki M, Kobayashi Y, Moriyama K
  • Organizer: 2nd Joint Meeting of the International Bone Mineral Society and The Japanese Society for Bone and Mineral Research
  • Place of Presentation: Kobe
  • Year and Date: 20130528-0601
• [Presentation] Soluble FGFR2 with Apert mutation inhibits osteoblastic proliferation and differentiation (2013)
  • Author(s): Yoshizaki M, Kobayashi Y, Moriyama K
  • Organizer: The 91st General Session & Exhibition of the International Association for Dental Research
  • Place of Presentation: Seattle
  • Year and Date: 20130320-23
• [Presentation] Outcome and stability of surgical treatment for mandibular prognathism with long face (2012)
  • Author(s): Moriyama K
  • Organizer: 8th Asian Pacific Orthodontic Conference
  • Place of Presentation: New Delhi
  • Year and Date: 2012-12-01
• [Presentation] Osteocyte is a key modulator for orthodontic tooth movement induced by mechanical stress (2012)
  • Author(s): Moriyama K
  • Organizer: 112th American Association of Orthodontists
  • Place of Presentation: Hawaii
  • Year and Date: 2012-05-07
• [Presentation] 矯正学的歯の移動における骨細胞の役割 (2011)
  • Author(s): 松本力, 森山啓司, 山口朗
  • Organizer: 第70回日本矯正歯科学会&第4回国際会議
  • Place of Presentation: 名古屋
  • Year and Date: 20111017-20
• [Presentation] The Transcriptional Repressor LRF Regulates Osteoclastogenesis (2011)
  • Author(s): Tsuji K, Koga T, Moriyama K, Takayanagi H
  • Organizer: The 59th Japanese Association for Dental Research
  • Place of Presentation: Hiroshima
  • Year and Date: 20111008-09
• [Presentation] Cnot3, a crucial factor of mRNA stability, controls osteoblastic differentiation (2011)
  • Author(s): Watanabe C, Morita M, Ezura T, Nakamoto T, Hayata T, Hemmi H, Notomi T, Moriyama K, Yamamoto T, Noda M
  • Organizer: The American Society for Bone and Mineral Research 2011 Annual Meeting
  • Place of Presentation: San Diego
  • Year and Date: 20110916-20
• [Presentation] Clinical surveys on associated anomalies in cases with isolated cleft palate (2011)
  • Author(s): Ogawa T, Ohya A, Sato M, Baba Y, Moriyama K
  • Organizer: The 9th European Craniofacial Congress
  • Place of Presentation: Salzburg
  • Year and Date: 20110914-17
• [Book] NTS INC, アンチエイジングシリーズ3 骨研究最前線 (2013)
  • Author(s): 森山啓司, 上園将慶, 鈴木聖一, 高久田和夫, 菊地正紀
  • Total Pages: 145-155
• [Book] Atlas of orthodontic treatment for patients with birth defect (2012)
  • Author(s): Kuroda T, Ohyama K, Motohashi N, Moriyama K
  • Total Pages: 207
  • Publisher: Needham Press
• [Book] Clinical correlate : cleidocranial dysplasia. Mineralized tissues in oral and craniofacial science (2012)
  • Author(s): Takeda S, Haga N, Moriyama K
  • Total Pages: 59-63
  • Publisher: WILEY-BLACKWELL
• [Remarks] 日本経済新聞 2013年4月9日付掲載. 日刊工業新聞 2013年4月9日付掲載. 科学新聞 2013年5月3日付掲載. マイナビニュース掲載
  • URL: http://news.mynavi.jp/news/2013/04/09/061/
• [Remarks] 東京医科歯科大学ホームページ掲載
  • URL: http://www.tmd.ac.jp/press-release/index.html
• [Remarks] NIMS ホームページ掲載
  • URL: http://www.nims.go.jp/news/press/2013/04/p201304080.html
• [Patent(Industrial Property Rights)] HAp/Col 複合体によって被覆された生体材料 (2013)
  • Inventor(s): 菊池正紀, 高久田和夫, 森山啓司, 鈴木聖一, 上園将慶
  • Industrial Property Rights Holder: 東京医科歯科大学, 物質・材料研究機構
  • Industrial Property Rights Type: 発明
  • Industrial Property Number: PTC/JP2013/061666
  • Filing Date: 2013-04-19
  • Overseas