Analysis of bone remodeling mechanism between osteoblasts and osteoclasts for the alveolar bone regeneration

• Project/Area Number: 24390417
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Functional basic dentistry
• Research Institution: Matsumoto Dental University
• Principal Investigator: UDAGAWA Nobuyuki 松本歯科大学, 歯学部, 教授 (70245801)
• Co-Investigator(Kenkyū-buntansha): KOIDE Masanori 松本歯科大学, 総合歯科医学研究所, 講師 (10367617) ; NAKAMURA Midori 松本歯科大学, 歯学部, 准教授 (90278177) ; NAKAMICHI Yuko 松本歯科大学, 総合歯科医学研究所, 講師 (20350829) ; UEHARA Syunsuke 松本歯科大学, 歯学部, 講師 (90434480) ; TAGUCHI Akira 松本歯科大学, 歯学部, 教授 (70243582)
• Co-Investigator(Renkei-kenkyūsha): ABIKO Yoshimitu 日本大学, 歯学部, 教授 (70050086) ; SHIMODAIRA Shigetaka 信州大学, 医学部, 教授 (80345751)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥18,330,000 (Direct Cost: ¥14,100,000、Indirect Cost: ¥4,230,000); Fiscal Year 2014: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2013: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2012: ¥8,970,000 (Direct Cost: ¥6,900,000、Indirect Cost: ¥2,070,000)
• Keywords: 骨芽細胞 / 破骨細胞 / 骨代謝共役 / 歯槽骨 / 歯周病 / 骨粗鬆症 / RANKL / RANK / W9ペプチド / BMP-2 / OPG / μCT / 皮質骨

Outline of Final Research Achievements

OPG-deficient mice (OPG KO) exhibited severe osteoporosis due to enhanced osteoclastogenesis when they grew to be adults. In RANKL-Tg mice, a soluble form of RANKL is expressed under the control of the human serum amyloid P component promoter. RANKL-Tg mice exhibit osteopenia characterized by excessive bone resorption. Alveolar bone loss in OPG KO mice and RANKL-Tg mice was evaluated using micro computed tomography and histological techniques. We show that OPG KO but not RANKL-Tg mice exhibit severe alveolar bone destruction. OPG was highly expressed in osteocytes in the alveolar bone, suggesting that OPG secreted from osteocytes prevents the alveolar bone loss induced by the excess amount of RANKL in RANKL-Tg mice. Treatment with an anti-RANKL antibody as well as risedronate, a bisphosphonate, significantly inhibited the alveolar bone loss in OPG KO mice. These results suggest that OPG KO mice are a useful model for screening therapeutic agents in periodontology.

Research Products

• [Journal Article] The dynamin inhibitor dynasore inhibits bone resorption by rapidly disrupting actin rings of osteoclasts. (2015)
  • Author(s): Thirkonda, G.J., Uehara, S., Nakayama, T., Yamashita, T., Nakamura, Y., Mizoguchi, T., Yagami, K., Takahashi, N., Udagawa, N., Kobayashi, Y.
  • Journal Title: J. Bone Miner. Metab. Volume: 33
  • Peer Reviewed
• [Journal Article] Noncanonical Wnt5a enhances Wnt/-catenin signaling during osteogenesis. (2014)
  • Author(s): Okamoto, M., Udagawa, N., Yamashita, T., Nakamichi, Y., Uehara, S., Kato, H., Saito, N., Minami, Y., Takahashi, N., Kobayashi, Y.
  • Journal Title: Sci. report Volume: 4 Issue: 1 Pages: 4493-4493
  • DOI: 10.1038/srep04493
  • Peer Reviewed / Open Access
• [Journal Article] Arctigenin inhibits osteoclast differentiation and function by suppressing both calcineurin-dependent and osteoblastic cell-dependent NFATc1 pathways. (2014)
  • Author(s): Yamashita T, Uehara S, Udagawa N, Li F, Kadota S, Esumi H, Kobayashi Y, Takahashi N
  • Journal Title: PLoS One Volume: 9 Issue: 1 Pages: 85878-85878
  • DOI: 10.1371/journal.pone.0085878
  • Peer Reviewed / Open Access
• [Journal Article] VitaminD endocrine system and osteoclasts. (2014)
  • Author(s): Takahashi N, Udagawa N, Suda T
  • Journal Title: BoneKEy Reports Volume: 3 Pages: 495-495
  • Peer Reviewed
• [Journal Article] Stimulation of bone formation in cortical bone of mice treated with a receptor activator of nuclear factor-κB ligand (RANKL)-binding peptide that possesses osteoclastogenesis inhibitory activity. (2013)
  • Author(s): Furuya Y, Inagaki A, Khan M, Mori K, Penninger JM, Nakamura M, Udagawa N, Aoki K, Ohya K, Uchida K, Yasuda H
  • Journal Title: J Biol Chem Volume: 288 Issue: 8 Pages: 5562-5571
  • DOI: 10.1074/jbc.m112.426080
  • Peer Reviewed
• [Journal Article] Osteoprotegerin-deficient male mice as a model for severe alveolar bone loss: Comparison with RANKL-overexpressing transgenic male mice. (2013)
  • Author(s): Koide M et al.
  • Journal Title: Endocrinology Volume: 190 Issue: 2 Pages: 773-782
  • DOI: 10.1210/en.2012-1928
  • Peer Reviewed / Open Access
• [Journal Article] Wnt5a-Ror2 signaling between osteoblasts and osteoclast precursors enhances osteoclastogenesis (2012)
  • Author(s): Maeda, K., Kobayashi, Y., Udagawa, N., Uehara, S., Ishihara, A., Mizoguchi, T., Kikuchi, Y., Takada, I., Kato, S., Kani, S., Nishita, M., Marumo, K., Martin, T.J., Minami, Y., Takahashi, N.
  • Journal Title: Nat.Med. Volume: (印刷中) Issue: 3 Pages: 405-12
  • DOI: 10.1038/nm.2653
  • Peer Reviewed
• [Journal Article] Spleen serves as a reservoir of osteoclast precursors through vitamin D-induced IL-34 expression in osteopetrotic op/op mice. (2012)
  • Author(s): Nakamichi Y et al.
  • Journal Title: Proc Natl Acad Sci USA Volume: 109 Issue: 25 Pages: 10006-10011
  • DOI: 10.1073/pnas.1207361109
  • Peer Reviewed
• [Journal Article] c-Fos plays an essential role in the up-regulation of RANK expression in osteoclast precursors within the bone microenvironment (2012)
  • Author(s): Arai A, et al
  • Journal Title: J Cell Sci Volume: (印刷中) Pages: 2910-2917
  • DOI: 10.1242/jcs.099986
  • Peer Reviewed
• [Presentation] Bone tissue as systemic organ supporting a life-correlation between periodontitis and osteoporosis. (2014)
  • Author(s): Udagawa N
  • Organizer: The 2nd Bio-Rheumatology International Congress（BRIC 2014）& The 9th GARN Meeting Moscow ～Eurasia Rheumatology Congress～
  • Place of Presentation: Russian Federation
  • Year and Date: 2014-06-06
  • Invited
• [Presentation] 骨の再生を目指した破骨細胞・骨芽細胞・歯髄細胞に関する橋渡し研究 (2012)
  • Author(s): 宇田川信之
  • Organizer: 第89回日本生理学会シンポジウム
  • Place of Presentation: 長野県松本文化会館(松本市)
  • Year and Date: 2012-03-30
• [Presentation] 生命を支えている臓器としての骨－歯周疾患と骨粗鬆症の関連－
  • Author(s): 宇田川信之
  • Organizer: 第55回歯科基礎医学会学術大会・総会（日本学術会議シンポジウム）
  • Place of Presentation: 岡山(岡山コンベンションセンター)
  • Invited
• [Book] Encyclopedia of Human Body 3rd Edition (2015)
  • Author(s): Takahashi, N., Mizoguchi, T., Nakamichi, Y., Kobayashi, Y., Nakamura, M., Hofstetter, W., Udagawa, N.
• [Book] がん骨転移のバイオロジーとマネージメント (2012)
  • Author(s): 宇田川信之, 溝口利英, 中村美どり
  • Total Pages: 400
  • Publisher: 医薬ジャーナル社