The elucidation of the between PTH and COX-2 in bone reconstruction

• Project/Area Number: 21592513
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Surgical dentistry
• Research Institution: Tokyo Medical University (2011); The University of Tokyo (2009-2010)
• Principal Investigator: CHIKAZU Daichi 東京医科大学, 医学部, 教授 (30343122)
• Co-Investigator(Kenkyū-buntansha): 矢野 文子 東京大学, 医学部附属病院, 特任助教 (80529040) ; 緒方 直史 東京大学, 医学部附属病院, 特任助教 (10361495)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2011: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2009: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: PTH / COX-2

Research Abstract

Murine MC3T3-E1 and MC-4 cells were stably transfected with-371/+70 bp of the murine cyclooxygenase-2(COX-2) promoter fused to a luciferase reporter(Pluc371) or with Pluc371 carrying site-directed mutations. Mutations were made in(1) the cAMP response element(CRE) at-57/-52 bp,(2) the activating protein-1(AP-1)-binding site at-69/-63 bp,(3) the nuclear factor of activated T-cells(NFAT)-binding site at-77/-73 bp, and(4) both the AP-1 and NFAT sites, which comprise a composite consensus sequence for NFAT/AP-1.Single mutation of CRE, AP-1, or NFAT sites decreased parathyroid hormone(PTH)-stimulated COX-2 promoter activity 40% to 60%, whereas joint mutation of NFAT and AP-1 abrogated the induction. On electrophoretic mobility shift analysis, PTH stimulated binding of phosphorylated CREB to an oligonucleotide spanning the CRE and binding of NFATc1, c-Fos, and c-Jun to an oligonucleotide spanning the NFAT/AP-1 composite site. Mutation of the NFAT site was less effective than mutation of the AP-1 site in competing binding to the composite element, suggesting that cooperative interactions of NFATc1 and AP-1 are more dependent on NFAT than on AP-1.Both PTH and forskolin, an activator of adenylyl cyclase, stimulated NFATc1 nuclear translocation. PTH-and forskolin-stimulated COX-2 promoter activity was inhibited 56% to 80% by calcium chelation or calcineurin inhibitors and 60% to 98% by protein kinase A(PKA) inhibitors. These results indicate an important role for the calcium-calcineurin-NFAT signaling pathway in the PTH induction of COX-2 and suggest that cross-talk between the cAMP/PKA pathway and the calcium-calcineurin-NFAT pathway may play a role in other functions of PTH in osteoblasts.

Research Products

• [Journal Article] Cyclooxygenase-2 activity is important in craniofacial fracture repair (2011)
  • Author(s): Daichi Chikazu, Yumiko Fujikawa, Hisako Fujihara, Hideyuki Suenaga, Hideto Saijo, Kazumi Ohkubo, Toru Ogasawara, Yoshiyuki Mori, Mitsuyoshi Iino, and Tsuyoshi Takato
  • Journal Title: Int J Oral Maxillofac Surg Volume: 40(3) Pages: 322-326
• [Journal Article] A novel method for designing and fabricating custom-made artificial bones (2011)
  • Author(s): Hideto Saijo, Yuki Kanno, Yoshiyuki Mori, Shigeki Suzuki, Kazumi Ohkubo, Daichi Chikazu, Yoshiyuki Yonehara, Ung-il Chung, and Tsuyoshi Takato
  • Journal Title: Int J Oral Maxillofac Surg Volume: 40(9) Pages: 955-960
• [Journal Article] 咬合機能の回復-インプラント治療と骨造成について- (2011)
  • Author(s): 近津大地
  • Journal Title: 東京医科大学雑誌 Volume: 69(4) Pages: 450-455
  • NAID: 10029806354
• [Journal Article] Improvement in wound healing by a novel synthetic collagen-gel dressing in genetically diabetic mice (2010)
  • Author(s): Daichi Chikazu, Tetsushi Taguchi, Hiroyuki Koyama, Hisako Hikiji, Hisako Fujihara, Hideyuki Suenaga, Hideto Saijo, Yoshiyuki Mori, Ichiro Seto, Mitsuyoshi Iino, and Tsuyoshi Takato
  • Journal Title: Asian J Oral Maxillofac Surg Volume: 22(2) Pages: 61-67
• [Journal Article] Evaluation and analysis of formation of bone at the palate in patients with cleft lip and palate after palatoplasty based on computed tomograms and three-dimensional data (2010)
  • Author(s): Hideto Saijo, Yoshiyuki Mori, Hisako Fujihara, Yuki Kanno, Daichi Chikazu, Kazumi Ohkubo, Hisako Hikiji, Mitsuyoshi Iino, Yoshiyuki Yonehara, and Tsuyoshi Takato
  • Journal Title: J Plast Surg Hand Surg Volume: 44(1) Pages: 21-25
• [Journal Article] A bone harvesting method involving a surgical template prepared using a three-dimensional model (2010)
  • Author(s): Hideto Saijo, Yuki Kanno, Yoshiyuki Mori, Daichi Chikazu, Mitsuyoshi Iino, and Tsuyoshi Takato
  • Journal Title: Asian J Oral Maxillofac Surg Volume: 22(1) Pages: 20-22
• [Journal Article] Tumor-induced osteomalacia associated with a maxillofacial tumor producing fibroblast growth factor 23 : report of a case and review of the literature (2010)
  • Author(s): Yoshiyuki Mori, Toru Ogasawara, Toru Motoi, Yuichiro Shimizu, Daichi Chikazu, Kazumi Tamura, Seiji Fukumoto, and Tsuyoshi Takato
  • Journal Title: Oral Surg Oral Med Oral Pathol Oral Radiol Endod Volume: 109(3)
• [Journal Article] Improvement in wound healing by a novel synthetic collagen-gel dressing in genetically diabetic mice (2010)
  • Author(s): Chikazu D, Taguchi T, Koyama H, Hikiji H, Fujihara H, Suenaga H, Saijo H, Mori Y, Seto I, Iino M, Takato T
  • Journal Title: Asian J Oral Maxillofac Surg Volume: 22 Pages: 61-67
  • Peer Reviewed
• [Journal Article] Parathyroid hormone induction of cyclooxygenase-2 in murine osteoblasts : Role of the calcium-calcineurin-NFAT pathway (2009)
  • Author(s): Hechang Huang, Daichi Chikazu, Olga S. Voznesensky, Harvey R. Herschman, Barbara E. Kream, Hicham Drissi, and Carol C. Pilbeam
  • Journal Title: Bone Miner Res Volume: 25 Pages: 819-829
• [Journal Article] Evaluation of 15 mandibular reconstructions with Dumbach Titan Mesh-System and particulate cancellous bone and marrow harvested from bilateral posterior ilia (2009)
  • Author(s): Mitsuyoshi Iino, Masayuki Fukuda, Hirokazu Nagai, Yoshiki Hamada, Hiroyuki Yamada, Kazutoshi Nakaoka, Yoshiyuki Mori, Daichi Chikazu, Hideto Saijo, Ichiro Seto, Kazumi Ohkubo, and Tsuyoshi Takato
  • Journal Title: Oral Surg Oral Med Oral Pathol Oral Radiol Endod Volume: 107
• [Journal Article] Unilateral expansion of a narrow mandibular dental arch combined with bimaxillary osteotomies in a patient with hypoglossia (2009)
  • Author(s): Yoshiyuki Mori, Takafumi Susami, Daichi Chikazu, Hideto Saijo, Miyuki Sakiyama, Masako Matsuzaki, Masako Abe, Mamiko Wada, Mitsuyoshi Iino, and Tsuyoshi Takato
  • Journal Title: Int J Oral Maxillofac Surg Volume: 38 Pages: 689-693
• [Journal Article] Transforming growth factor-b1 in combination with fibroblast growth factor-2 and insulin-like growth factor-I for chondrocyte proliferation culture and cartilage regenerative medicine (2009)
  • Author(s): Toru Ogasawara, Shinsuke Ohba, Yuko Fujihara, Tsuguharu Takahashi, Guangyao Liu, Daichi Chikazu, Hideyuki Suenaga, Ung-Il Chung, Tetsuya Yoda, Yoshiyuki Mori, Takafumi Susami, Tsuyoshi Takato, and Kazuto Hoshi
  • Journal Title: Asian J Oral Maxillofac Surg Volume: 21 Pages: 18-26
• [Journal Article] Maxillofacial reconstruction using custom-made artificial bones fabricated by inkjet printing technology (2009)
  • Author(s): Hideto Saijo, Kazuyo Igawa, Yuki Kanno, Yoshiyuki Mori, Kayoko Kondo, Koutaro Shimizu, Shigeki Suzuki, Daichi Chikazu, Mitsuyoshi Iino, Masahiro Anzai, Nobuo Sakai, Ung-il Chung, and Tsuyoshi Takato
  • Journal Title: J Artif Organs Volume: 12 Pages: 200-205
  • NAID: 10025351463
• [Journal Article] Evaluation of 15 mandibular reconstructions with Dumbach Titan Mesh-System and particulate cancellous bone and marrow harvested from bilateral poster for ilia (2009)
  • Author(s): Iino M, Fukuda M, Nagai H, Hamada Y, Yamada H, Nakaoka K, Mori Y, Chikazu D, Saijo H, Seto I, Ohkubo K, Takato T
  • Journal Title: Oral Surg.Oral Med.Oral Pathol.Oral Radiol.Endod. 107 Pages: 1-8
  • Peer Reviewed
• [Journal Article] Transforming growth factor-β1 in combination with fibroblast growth factor-2 and insulin-like growth factor-I for chondrocyte proliferation culture and cartilage regenerative medicine (2009)
  • Author(s): Ogasawara T, Ohba S, Fujihara Y, Takahashi T, Liu G, Chikazu D, Suenaga H, Chung U, Yoda T, Mori Y, Susami T, Takato T, Hoshi K
  • Journal Title: Asian.J.Oral.Maxillofac.Surg. 21 Pages: 18-26
  • Peer Reviewed
• [Presentation] 咬合機能の回復-インプラント治療と骨造成について- (2011)
  • Author(s): 近津大地
  • Organizer: 第167回医学会総会特別講演
  • Place of Presentation: 東京医科大学、東京
  • Year and Date: 2011-06-04
• [Presentation] Are implants a risk factor for osteonecrosis in intravenous bisphosphonate (2011)
  • Author(s): Akira Matsuo, Hayato Hamada, Eriko Tsuji, Ayako Okamoto, Daichi Chikazu, Hiroshi Kaise, and Norio Kohno
  • Organizer: 20th Annual Scientific Meeting Europian Association for Osseointegration(EAO)
  • Place of Presentation: Megaron Congress Center, Athens
• [Presentation] 間葉系細胞においてNanogはBMPシグナルを増強する (2010)
  • Author(s): 斎藤忠仁、小笠原徹、森良之、近津大地、阿部雅修、末永英之、白土博司、高戸毅、米原啓之
  • Organizer: 第64回NPO法人日本口腔科学会学術集会
  • Place of Presentation: 札幌プリンスホテル国際館パミール、札幌
• [Presentation] 間葉系細胞においてNanogはBMPシグナルを増強する (2010)
  • Author(s): 齊藤忠仁、小笠原徹、森良之、近津大地、阿部雅修、末永英之, ほか
  • Organizer: 第64回NPO法人日本口腔科学会学術集会
  • Place of Presentation: 札幌
• [Presentation] Cyclooxygenase-2 Activity is important for Membrane Bone Fracture Healing (2009)
  • Author(s): Daichi Chikazu, Yumiko Fujikawa, Naoshi Ogata, Fumiko Yano, Toru Ogasawara, Hideto Saijo, Yoshiyuki Mori, Mitsuyoshi Iino, and Tsuyoshi Takato
  • Organizer: 31th ASBMR Annual Meeting
• [Presentation] Regulator of G Protein Signaling(RGS)-2 Enhances Bone Anabolic Action of PTH through Inhibition of Gaq/PKC Pathway in Osteoblasts (2009)
  • Author(s): Naoshi Ogata, Fumiko Yano, Daichi Chikazu, Ung-il Chung, Kozo Nakamura, and Hiroshi Kawaguchi
  • Organizer: 31th ASBMR Annual Meeting
• [Presentation] Cyclooxygenase-2は膜性骨の骨折治癒におけるkey factorである (2009)
  • Author(s): 近津大地、藤川由美子、末永英之、杉山円、古賀陽子、阿部雅修、西條英人、森良之、飯野光喜、高戸毅
  • Organizer: 第54回日本口腔外科学会総会
• [Presentation] Cyclooxygenase-2 Activity is important for Membrane Bone Fracture Healing (2009)
  • Author(s): Chikazu D, Fujikawa Y, Ogata N, Yano F, Ogasawara T, Saijo H, Mori Y, Iino M, Takato T
  • Organizer: 31th ASBMR Annual Meeting
  • Place of Presentation: Montreal, Quebec, Canada
• [Presentation] Regulator of G Protein Signaling(RGS)-2 Enhances Bone Anabolic Action of PTH through Inhibition of Gαq/PKC Pathway in Osteoblasts (2009)
  • Author(s): Ogata N, Yano F, Chikazu D, Chung U, Nakamura K, Kawaguchi H
  • Organizer: 31th ASBMR Annual Meeting
  • Place of Presentation: Montreal, Quebec, Canada