Elucidation of molecular mechanisms for osteoclast polarization through Wnt5a-Ror2 signaling

• Project/Area Number: 25462904
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Functional basic dentistry
• Research Institution: Matsumoto Dental University
• Principal Investigator: Uehara Shunsuke 松本歯科大学, 歯学部, 講師 (90434480)
• Co-Investigator(Kenkyū-buntansha): KOBAYASHI Yasuhiro 松本歯科大学, 総合歯科医学研究所, 教授 (20264252)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 破骨細胞 / Wnt / 非古典経路 / 骨吸収 / Rho / 極性化 / Wnt非古典経路 / Wnt5a / Ror2

Outline of Final Research Achievements

Polarization of osteoclasts (formation of actin rings and ruffled borders) is necessary to resorb bone. We examined the molecular mechanisms regulating osteoclast polarization through the cytokine Wnt5a and co-receptor Ror2 in osteoclasts.
We revealed that Wnt5a-Ror2 signaling regulates the bone-resorbing activity of osteoclasts through the activation of Rho-Pkn3 pathways, and that Daam2, an adaptor molecule, is involved in activation of Rho under the Ror2 signaling.

Research Products

• [Journal Article] Wnt16 regulates osteoclast differentiation in conjunction with Wnt5a. (2015)
  • Author(s): Kobayashi Y, Thirukonda GJ, Nakamura Y, Koide M, Yamashita T, Uehara S, Kato H, Udagawa N, Takahashi N
  • Journal Title: Biochem Biophys Res Commun Volume: 463 Issue: 4 Pages: 1278-1283
  • DOI: 10.1016/j.bbrc.2015.06.102
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The regulation of osteoclast differentiation by Wnt signals (2015)
  • Author(s): Kobayashi Y, Uehara S, Koide M, Takahashi N
  • Journal Title: Bonekey Rep Volume: 4 Issue: 4 Pages: 713-713
  • DOI: 10.1093/jb/mvv124
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] Roles of cathelicidin-related antimicrobial peptide in murine osteoclastogenesis (2013)
  • Author(s): Horibe K, Kobayashi Y, Takahashi N, Udagawa N(他4名)
  • Journal Title: Immunology Volume: 140 Issue: 3 Pages: 344-351
  • DOI: 10.1111/imm.12146
  • Peer Reviewed / Open Access
• [Presentation] Rho-Pkn3 pathway regulates the bone-resorbing activity of osteoclasts under Wnt5a-Ror2 signaling (2015)
  • Author(s): Uehara S, Mukai H, Yamashita T, Nakamura T, Kato S, Kikuchi A, Nishita M, Minami Y, Udagawa N, Takahashi N, Kobayashi Y
  • Organizer: 第37回アメリカ骨代謝学会(ASBMR)
  • Place of Presentation: ワシントン州コンベンションセンター アメリカ シアトル
  • Year and Date: 2015-10-10
  • Int'l Joint Research
• [Presentation] Wnt5a-Ror2シグナルの下流で骨吸収機能を調節するPKN3 (2015)
  • Author(s): 上原俊介，山下照仁，中村貴，加藤茂明，宇田川信之，高橋直之，小林泰浩
  • Organizer: 第33回日本骨代謝学会学術集会
  • Place of Presentation: 京王プラザホテル 東京 新宿
  • Year and Date: 2015-07-23
• [Presentation] Wnt5a-Ror2シグナルは、Daam2-Rhoを介して骨吸収機能を促進する (2014)
  • Author(s): 上原俊介、山下照仁、中村貴、加藤茂明、宇田川信之、高橋直之、小林泰浩
  • Organizer: 第32回日本骨代謝学会学術集会
  • Place of Presentation: 京王プラザホテル 東京 新宿
  • Year and Date: 2014-07-28
• [Presentation] Wnt5a-Ror2 signal regulates function of osteoclasts through Daam2-Rho pathway (2014)
  • Author(s): Uehara S, Ishihara A, Maeda K, Yamashita T, Nakamura T, Kato S, Kikuchi A, Nishita M, Minami Y, Udagawa N, Takahashi N, Kobayashi Y
  • Organizer: 第5回International conference on osteoimmunology
  • Place of Presentation: へロナリゾート ギリシャ コス島
  • Year and Date: 2014-06-16
• [Presentation] Wnt5a enhances Wnt/-catenin signaling through the up-regulation of Lrp5/6 during osteogenesis
  • Author(s): Okamoto M, Udagawa N, Yamashita T, Uehara S, Kato H, Saito N, Minami Y, Takahashi N and Kobayashi Y
  • Organizer: 第35回アメリカ骨代謝学会(ASBMR)
  • Place of Presentation: ボルチモアコンベンションセンター（アメリカ メリーランド州ボルチモア）
• [Presentation] 破骨細胞の機能を制御するWnt5a-Ror2シグナルによるRho活性化
  • Author(s): 上原俊介、山下照仁、宇田川信之、高橋直之、小林泰浩
  • Organizer: 第55回歯科基礎医学会
  • Place of Presentation: 岡山コンベンションセンター（岡山市）
• [Presentation] 破骨細胞の分化に必須な因子NFATc1の転写活性を抑制するアルクチゲニンの作用メカニズム
  • Author(s): 山下照仁，李峰，上原俊介，小林泰浩，宇田川信之，門田重利，高橋直之
  • Organizer: 第76回松本歯科大学学会例会
  • Place of Presentation: 松本歯科大学（塩尻市）
• [Presentation] Wnt5a-Ror2 signal regulates osteoclast polarization through Daam2 and Rho
  • Author(s): Uehara S, Ishihara A, Maeda K, Yamashita T, Nakamura T, Imai Y, Kato S, Kikuchi A, Nishita M, Minami Y, Udagawa N, Takahashi N, Kobayashi Y
  • Organizer: 国際骨代謝学会(IBMS)・日本骨代謝学会第2回合同学術集会
  • Place of Presentation: 神戸コンベンションセンター（神戸市）
• [Presentation] Wnt5a-Ror2シグナルはDaam2とRhoを介して破骨細胞機能を制御する
  • Author(s): 上原俊介
  • Organizer: 第12回松本ボーンフォーラム
  • Place of Presentation: 信州大学医学部（松本市）
  • Invited