Bone regeneration using culture-expanded bone marrow cells-Efficacy of Runx2-activating drugs-

• Project/Area Number: 24592230
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Nagoya University
• Principal Investigator: HIROSHI Kitoh 名古屋大学, 医学(系)研究科(研究院), 准教授 (40291174)
• Co-Investigator(Kenkyū-buntansha): 金子 浩史 名古屋大学, 医学(系)研究科(研究院), 助教 (60566975) [Withdrawn]
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: Runx2 / ランソプラゾール / 骨組織再生 / 培養骨髄細胞 / 骨芽細胞 / 骨形成 / 骨形成促進 / drug repositioning

Outline of Final Research Achievements

We screened for drugs that activate the Runx2 promoter and identified that lansoprazole, a proton pump inhibitor, upregulated the Runx2 activity. Lansoprazole elevated expression levels of Runx2 mRNA and protein in osteoblast-lineage cells in a dose-dependent manner. Lansoprazole exerted an increase of ALP and Osterix activities in osteoblast-lineage cells. Lansoprazole accelerated the matrix calcium deposition in human bone marrow derived osteoprogenitors. Systemic administration of lansoprazole to a rat fracture model increased osteoblastic parameters and facilitated fracture healing. We propose that lansoprazole holds promise as a therapeutic agent for bone regeneration at fracture sites.

Research Products

• [Journal Article] A novel in-flame deletion of the RUNX2 gene causes a classic form of cleidocranial dysplasia (2014)
  • Author(s): Mastushita M., Kitoh H., Kaneko H., Mishima K., Itoh Y., Tokita Y., Ishiguro N.
  • Journal Title: J Bone Miner Metab Volume: 32 Pages: 96-9
  • DOI: 10.1007/s00774-013-0456-7
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Benign prenatal hypophosphatasia: a treatable disease not to be missed (2014)
  • Author(s): Matsushita M, Kitoh H, Michigami T, Tachikawa K, Kaneko H, Mishima K, Ishiguro N.
  • Journal Title: Pediatr Radiol. Volume: 44(3) Pages: 340-3
  • DOI: 10.1007/s00247-013-2805-z
  • Peer Reviewed / Open Access
• [Journal Article] Biodistribution of locally or systemically transplantedosteoblast-like cells (2014)
  • Author(s): Y.T. Okabe, T. Kondo, K. Mishima, Y. Hayase, K. Kato, M. Mizuno, N. Ishiguro and H. Kitoh
  • Journal Title: Bone Joint Res. Volume: 3 Pages: 76-81
  • DOI: 10.1302/2046-3758.33.2000257
  • Peer Reviewed / Open Access
• [Journal Article] Radiographic characteristics of the hand and cervical spine in fibrodysplasia ossificans progressiva (2014)
  • Author(s): Mishima K, Kitoh H, Haga N, Nakashima Y, Kamizono J, Katagiri T, Susami T, Matsushita M, Ishiguro N.
  • Journal Title: IRDR Volume: 3(2) Issue: 2 Pages: 46-51
  • DOI: 10.5582/irdr.2014.01009
  • NAID: 130005008088
  • Peer Reviewed / Open Access
• [Journal Article] A case of severe proximal focal femoral deficiency with overlapping phenotypes of Al-Awadi-Raas-Rothschild syndrome and Fuhrmann syndrom (2014)
  • Author(s): Matsushita M, Kitoh H, Mishima K, Nishida Y, Ishiguro N
  • Journal Title: Ped Radiol Volume: 44 Pages: 1617-1619
  • DOI: 10.1007/s00247-014-3013-1
  • Peer Reviewed
• [Journal Article] Early and late fracture following extensive limb lengthening in achondroplasia and hypochondroplasia (2014)
  • Author(s): Kitoh H, Kaneko H, Mishima K, Matsushita M, Kadono I, Nishida Y, Ishiguro N.
  • Journal Title: Bone Joint J. Volume: 96-B(9) Pages: 1269-1273
  • DOI: 10.1302/0301-620x.96b9.33840
  • Peer Reviewed / Open Access
• [Journal Article] Factors associated with an unfavourable outcome after Salter innominate osteotomy in patients with unilateral developmental dysplasia of the hip: Does occult dysplasia of the contralateral hip affect the outcome? (2014)
  • Author(s): Kaneko H, Kitoh H, Mishima K, Matsushita M, Izumi K, Naoki Ishiguro, Hattori T
  • Journal Title: Bone Joint J Volume: 96 Pages: 1419-1423
  • DOI: 10.1302/0301-620x.96b10.34263
  • Peer Reviewed
• [Journal Article] Mutations in PCYT1A, encoding a key regulator of phosphatidylcholine metabolism, cause spondylometaphyseal dysplasia with cone-rod dystrophy (2014)
  • Author(s): Hoover-Fong J, Sobreira N, Jurgens J, Modaff P, Blout C, Moser A, Kim OH, Cho TJ, Cho SY, Kim SJ, Jin DK, Kitoh H, Park WY, Ling H, Hetrick KN, Doheny KF, Valle D, Pauli RM.
  • Journal Title: Am J Hum Genet. Volume: 94(1) Pages: 105-112
  • DOI: 10.1016/j.ajhg.2013.11.018
  • Peer Reviewed / Open Access
• [Journal Article] Clinically applicable antianginal agents suppress osteoblastic transformation of myogenic cells and heterotopic ossification in mice (2013)
  • Author(s): Yamamoto R, Matsushita M, Kitoh H, Masuda A, Ito M, Katagiri T, Kawai T, Ishiguro N, Ohno K
  • Journal Title: Journal of Bone and Mineral Metabolism Volume: 31 Pages: 26-33
  • DOI: 10.1007/s00774-012-0380-2
  • NAID: 10031168834
  • Peer Reviewed
• [Journal Article] Orthopaedic manifestations and diagnostic clues in children with Guillain-Barré syndrome (2013)
  • Author(s): Matsushita M, Kitoh H, Itomi K, Kitakoji T, Iwata K, Mishima K, Ishiguro N, Hattori T
  • Journal Title: J Child Orthop Volume: 7 Pages: 177-182
  • DOI: 10.1007/s11832-012-0475-2
  • Peer Reviewed
• [Journal Article] Prognostic factors for trochanteric overgrowth after containment treatment in Legg-Calve-Perthes disease (2013)
  • Author(s): Kitoh H, Kaneko H, Mishima K, Matsushita M, Ishiguro N
  • Journal Title: J Pediatr Orthop B. Volume: 22 Pages: 432-436
  • DOI: 10.1097/bpb.0b013e32835f585b
  • Peer Reviewed
• [Journal Article] Mutations in B3GALT6, which encodes a glycosaminoglycan linker region enzyme, cause a spectrum of skeletal and connective tissue disorders (2013)
  • Author(s): Masahiro Nakajima, Shuji Mizumoto et al.
  • Journal Title: Am J Hum Genet. Volume: in press Pages: 927-34
  • DOI: 10.1016/j.ajhg.2013.04.003
  • Peer Reviewed
• [Journal Article] Long-term outcome of gradual reduction using overhead traction for developmental dysplasia of the hip over six months of age. (2013)
  • Author(s): Kaneko H, Kitoh H, Mishima K, Matsushita M, Ishiguro N.
  • Journal Title: J Pediatr Orthop Volume: 33(6) Pages: 628-34
  • DOI: 10.1097/bpo.0b013e31829b2d8b
  • Peer Reviewed
• [Journal Article] A comparative study of blade plate fixation and external fixation in osteotomies for slipped capital femoral epiphysis (2013)
  • Author(s): Kitoh H, Kitakoji T, Hattori T, Kaneko H, Mishima K, Matsushita M, Ishiguro N.
  • Journal Title: J Pediatr Orthop B Volume: 22(6) Pages: 542-547
  • DOI: 10.1097/bpb.0b013e3283637070
  • Peer Reviewed
• [Journal Article] A novel SOX9 H169Q mutation in a family with overlapping phenotype of mild campomelic dysplasia and small patella syndrome. (2013)
  • Author(s): Matsushita M, Kitoh H, Kaneko H, Mishima K, Kadono I, Ishiguro N, Nishmura G
  • Journal Title: Am J Med Genet A. Volume: 161 Pages: 2528-2534
  • DOI: 10.1002/ajmg.a.36134
  • Peer Reviewed
• [Journal Article] Meclozine Facilitates Proliferation and Differentiation of Chondrocytes by Attenuating Abnormally Activated FGFR3 Signaling in Achondroplasia. (2013)
  • Author(s): Matsushita, M., Kitoh, H., Ohkawara, B., Mishima, K., Kaneko, H., Ito, M., Masuda, A., Ishiguro, N. and Ohno, K.
  • Journal Title: PLoS ONE Volume: 8(12) Pages: 81569-81569
  • DOI: 10.1371/journal.pone.0081569
  • Peer Reviewed
• [Journal Article] Perhexiline maleate in the treatment of fibrodysplasia ossificans progressiva : an open-labeled clinical trial (2013)
  • Author(s): Kitoh H, Achiwa M, Kaneko H, Mishima K, Matsushita M, Kadono I, Horowitz JD, Sallustio BC, Ohno K, Ishiguro N.
  • Journal Title: Orphanet J Rare Dis Volume: 8 Pages: 163-163
  • DOI: 10.1186/1750-1172-8-163
  • Peer Reviewed
• [Journal Article] Mutations in B3GALT6 which encodes a glycosaminoglycan linker region enzyme cause a spectrum of skeletal and connective tissue disorders (2013)
  • Author(s): Nakajima M, Mizumoto S, Miyake N, Kogawa R, Iida A, Ito H, Kitoh H, et al
  • Journal Title: Am J Hum Genet Volume: in press
  • Peer Reviewed
• [Journal Article] Novel compound heterozygous mutations in the cathepsin K gene in Japanese female siblings with pyknodysostosis (2012)
  • Author(s): Matsushita M, Kitoh H, Kaneko H, Mishima K, Itoh Y, Hattori T, Ishiguro N
  • Journal Title: Mol Syndromol Volume: (in press)(未定) Pages: 254-258
  • DOI: 10.1159/000336581
  • Peer Reviewed
• [Journal Article] Chondroblastoma of the femoral neck as a cause of hip synovitis. (2012)
  • Author(s): Kaneko H, Kitoh H, Wasa J, Nishida Y, Ishiguro N
  • Journal Title: J Pediatr Orthop B Volume: 21 Pages: 179-182
  • DOI: 10.1097/bpb.0b013e3283484c31
  • Peer Reviewed
• [Journal Article] Isolated bifid rib : clinical and radiological findings in children (2012)
  • Author(s): Kaneko H, Kitoh H, Mabuchi A, Mishima K, Matsushita M, Ishiguro N.
  • Journal Title: Pediatr Int. Volume: 54 Pages: 820-3
  • DOI: 10.1111/j.1442-200x.2012.03672.x
  • Peer Reviewed
• [Journal Article] The biomechanical effect of the sensomotor insole on a pediatric intoeing gait (2012)
  • Author(s): Mabuchi A, Kitoh H, Kaneko H, Inoue M, Hayashi M, Ishiguro N, Suzuki N
  • Journal Title: ISRN Orthop Volume: 2012 Pages: 1-5
  • DOI: 10.5402/2012/396718
  • Peer Reviewed
• [Presentation] 先天性股関節脱臼に対する選択的リーメンビューゲル法による短期治療成績 (2014)
  • Author(s): 鬼頭浩史、三島健一、松下雅樹、杉浦洋、長谷川幸、北村暁子、石黒直樹
  • Organizer: 第25回日本小児整形外科学会
  • Place of Presentation: ヒルトン東京ベイ（千葉県浦安市）
  • Year and Date: 2014-11-27 – 2014-11-28
• [Presentation] 骨髄幹細胞を用いた骨延長術 (2014)
  • Author(s): 鬼頭浩史、三島健一、松下雅樹、杉浦洋、石黒直樹
  • Organizer: 第87回日本整形外科学会
  • Place of Presentation: 神戸ポートピアホテル、神戸国際展示場、神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2014-05-22 – 2014-05-25
  • Invited
• [Presentation] 下肢骨延長後の骨折に関連する因子 (2014)
  • Author(s): 鬼頭浩史、金子浩史、三島健一、松下雅樹、西田佳弘、石黒直樹
  • Organizer: 第87回日本整形外科学会
  • Place of Presentation: 神戸ポートピアホテル、神戸国際展示場、神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2014-05-22 – 2014-05-25
• [Presentation] Early and late fracture following lower limb lengthening (2014)
  • Author(s): Hiroshi Kitoh, Hiroshi Kaneko, Kenichi Mishima, Masaki Matsushita, Naoki Ishiguro
  • Organizer: Annual meeting of Pediatric Orthopedic Society of North America
  • Place of Presentation: Los Angeles, USA
  • Year and Date: 2014-04-30 – 2014-05-03
• [Presentation] 整形外科common diseasetと骨系統疾患 (2014)
  • Author(s): 鬼頭浩史
  • Organizer: 第122回中部日本整形外科災害外科学会
  • Place of Presentation: 岡山コンベンションセンター（岡山県岡山市）
  • Year and Date: 2014-04-11
  • Invited
• [Presentation] Long-term outcome of gradual reduction with overhead traction for developmental dysplasia of the hip in children over six months of age (2013)
  • Author(s): Hiroshi Kaneko, Hiroshi Kitoh, Kenichi Mishima, Masaki Matsushita, Naoki Ishguro
  • Organizer: Annual meeting of Pediatric Orthopedic Society of North America
  • Place of Presentation: Toronto（カナダ）
• [Presentation] A novel Sox9 H169Q mutation in a family with overlapping phenotype of mild campomelic dysplasia and small patella syndrome (2013)
  • Author(s): Hiroshi Kaneko, Hioroshi Kitoh, Kenichi Mishima, Masaki Matsushita, Naoki Ishiguro
  • Organizer: International Skeletal Dysplasia Meeting
  • Place of Presentation: Bologna（イタリア）
• [Presentation] Meclozine facilitates chondrocyte proliferation and differentiation by attenuating abnormally activated fibroblast growth factor receptor 3 (FGFR3) signaling in achondroplasia (2013)
  • Author(s): Masaki Matsushita, Hiroshi Kitoh, Hiroshi Kaneko, Kenichi Mishima, Naoki Ishiguro, Kinji Ohno
  • Organizer: International Skeletal Dysplasia Meeting
  • Place of Presentation: Bologna（イタリア）
• [Presentation] Potential clinical application of meclizine, an anti-histamine drug, for short stature in FGFR3-related skeletal dysplasias (2013)
  • Author(s): Masaki Matsushita, Hiroshi Kitoh, Hiroshi Kaneko, Kenichi Mishima, Naoki Ishiguro, Kinji Ohno
  • Organizer: 第24回日本小児整形外科学会
  • Place of Presentation: パシフィコ横浜（横浜市）
• [Presentation] 先天性股関節脱臼に対する新しい適応を用いたリーメンビューゲルによる短期治療成績 (2012)
  • Author(s): 鬼頭浩史、金子浩史、松下雅樹、石黒直樹
  • Organizer: 第85回日本整形外科学会
  • Place of Presentation: 国立京都国際会館、グランドプリンスホテル京都（京都市左京区）
• [Presentation] 軟骨無形成症に対する治療の展望 (2012)
  • Author(s): 鬼頭浩史
  • Organizer: 第85回日本整形外科学会
  • Place of Presentation: 国立京都国際会館、グランドプリンスホテル京都（京都市左京区）
  • Invited
• [Presentation] 先天性股関節脱臼保存治療後の臼蓋発育についてー幼児期の補正手術の適応を再考するー (2012)
  • Author(s): 鬼頭浩史、金子浩史、三島健一、松下雅樹、石黒直樹
  • Organizer: 第51回日本小児股関節研究会
  • Place of Presentation: ホテルスプリングス幕張（千葉市美浜区）
• [Presentation] ヒト骨髄由来間葉系幹細胞の細胞増殖能および骨芽細胞分化能 (2012)
  • Author(s): 鬼頭浩史、金子浩史、三島健一、松下雅樹、石黒直樹
  • Organizer: 第23回日本小児整形外科学会
  • Place of Presentation: 九州大学医学部百年講堂（福岡市東区）
• [Presentation] 進行性骨化性線維異形成症に対するマレイン酸ペルヘキシリンの治療経験 (2012)
  • Author(s): 鬼頭浩史、金子浩史、三島健一、松下雅樹、石黒直樹
  • Organizer: 第24回日本整形外科学会骨系統疾患研究会
  • Place of Presentation: 九州大学医学部百年講堂（福岡市東区）
• [Patent(Industrial Property Rights)] 骨形成促進剤及びその用途 (2012)
  • Inventor(s): 大野欽司、石黒直樹、鬼頭浩史、三島健一
  • Industrial Property Rights Holder: 大野欽司、石黒直樹、鬼頭浩史、三島健一
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2011-185306
  • Filing Date: 2012-08-23
  • Application Year: 2012
  • Overseas