Does oral mucosal immune system contribute to Bisphosphonate-related osteonecrosis of the jaw?

• Project/Area Number: 15K20572
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Surgical dentistry
• Research Institution: Asahi University
• Principal Investigator: KANAYAMA KEIICHI 朝日大学, 歯学部, 講師 (20454275)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2017: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: ビスホスホネート関連顎骨壊死 / マウスモデル / 口腔粘膜免疫 / 顎骨壊死 / 粘膜免疫 / 口腔粘膜 / 破骨細胞 / ビスホスホネート関連骨壊死 / 免疫細胞

Outline of Final Research Achievements

The number of patients with bisphosphonate-related osteonecrosis of the jaw itself is small, symptoms are severe when it develops and there is no causal treatment. A lot of research has been done to clarify the mechanism of BRONJ and it has also been suggested that immune cells are involved in the phenotype of BRONJ symptoms. We studied using the ONJ mouse model as to which immune cell's response the BRONJ phenotype shows various symptoms.

Academic Significance and Societal Importance of the Research Achievements

2014年に米国口腔顎顔面外科学会からMRONJに関するポジションペーパーが出され、従来の定義の変更がなされた。骨露出を認めるものに加え、骨露出のない瘻孔型のものも併記された。nBP長期使用患者数は年々累積していくなかTCRD-/-での結果は、gdT細胞と瘻孔型MRONJの表出との関連を示唆している。MRONJの病態解明にはgdT細胞の動態だけでなく口腔粘膜の免疫をつかさどるT細胞、B細胞、NK細胞の働きが鍵を握ると考える。そこで、成熟したT細胞・B細胞を欠損したRag2-/-マウスを使ってMRONJ症状の変化の検討を行った。

Research Products

• [Journal Article] Parathyroid hormone (1-34) enhances bone regeneration in rats with cranial bone defects. (2018)
  • Author(s): M Mizuno, H Morinaga, K Mukai, K Kanayama, T Shibutani.
  • Journal Title: J Hard Tissue Biol Volume: 27 Pages: 303-308
  • NAID: 40021727282
  • Peer Reviewed
• [Journal Article] 重度歯周炎患者の血中サイトカインと歯周組織検査値との関係. (2018)
  • Author(s): 堀田敬史, 金山圭一, 竹内浩子, 森永啓嗣, 向井景祐, 木村洋子, 長谷川徹, 北後光信, 小足周平, 佐藤匠, 清水雄太, 伊神裕高, 澁谷俊昭.
  • Journal Title: 岐歯学誌 Volume: 45 Pages: 123-128
  • NAID: 120006538893
  • Peer Reviewed
• [Journal Article] Study of a method to prepare novel carbonate-containing apatite porous bodies. (2018)
  • Author(s): A Shibatsuji, K Kanayama, K Mukai, S Otari, H Morinaga, M Kitago, T Hasegawa, Y Kimura, H Takeuchi, Y Doi, T Shibutani.
  • Journal Title: J Gifu Dent Soc Volume: 45 Pages: 49-52
  • NAID: 120006536715
  • Peer Reviewed
• [Journal Article] Histological study of the unsintered carbonate containing apatite porous body in beagle dog dorsal muscle. (2018)
  • Author(s): A Shibatsuji, K Kanayama, K Mukai, S Otari, H Morinaga, M Kitago, T Hasegawa, Y Kimura, H Takeuchi, Y Doi, T Shibutani.
  • Journal Title: J Gifu Dent Soc Volume: 45 Pages: 53-58
  • NAID: 120006536716
  • Peer Reviewed
• [Journal Article] Plasticity of Myeloid Cells during Oral Barrier Wound Healing and the Development of Bisphosphonate-Related Osteonecrosis of the Jaw (2016)
  • Author(s): Yujie Sun, Kawaljit Kaur, Keiichi Kanayama, Kenzo Morinaga, Sil Park, Akishige Hokugo, Anna Kozlowska, William H. McBride, Jun Li, Anahid Jewett and Ichiro Nishimura
  • Journal Title: Journal of Biological Chemistry Volume: 291 Pages: 20602-20616
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] 歯槽骨欠損に対する各種人工リン酸カルシウム系材料と成長因子 (2015)
  • Author(s): 渋谷俊昭, 金山圭一
  • Journal Title: 日本歯周病学会誌 Volume: 56 Pages: 375-378
  • NAID: 130004842596
  • Peer Reviewed
• [Journal Article] Osteonecrosis of the Jaw Developed in Mice: Disease Variants Regulated by γδ T Cells in Oral Mucosal Barrier Immunity (2015)
  • Author(s): Sil Park, Keiichi Kanayama, Kawaljit Kaur, Han-Ching Helen Tseng, Sina Banankhah,Davood Talebi Quje, James W. Sayre, Anahid Jewett and Ichiro Nishimura
  • Journal Title: The Journal of Biological Chemistry Chemistry Volume: 290 Pages: 17349-17366
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Bisphosphonate-induced differential modulation of immune cell function in gingiva and bone marrow in vivo; Role in osteoclast-mediated NK cell activation (2015)
  • Author(s): Han-Ching Tseng, Keiichi Kanayama, Kawaljit Kaur, So-Hyun Park, Sil Park, Anna Kozlowska, Shuting Sun,Charles E. McKenna, Ichiro Nishimura and Anahid Jewett
  • Journal Title: Oncotarget Volume: 6 Pages: 20002-20025
  • Peer Reviewed / Int'l Joint Research
• [Presentation] 慢性歯周炎進展機序における破骨細胞の動態 (2018)
  • Author(s): 森永啓嗣、金山圭一、水野真央、北後光信、澁谷俊昭
  • Organizer: 第12回日本歯周病学会中部地区大学日本臨床歯周病学会中部支部合同研究会
• [Presentation] 歯周炎患者の血中サイトカインと歯周組織破壊の関係 (2018)
  • Author(s): 堀田 敬史，金山 圭一，竹内 浩子，水野 真央，佐藤 匠，北後 光信，渋谷 俊昭.
  • Organizer: 第60回春季日本歯周病学会学術大会
• [Presentation] Porous carbonate apatite and bFGF for the treatment of peri-implant bone defects. (2018)
  • Author(s): Keisuke Mukai, Masashi Takagi, Keiichi Kanayama, Yutaka Doi, Toshiaki Shibutani
  • Organizer: オステオロジーJAPAN
• [Presentation] Porous carbonate apatite with bFGF regenarate classⅢ furcation defects. (2018)
  • Author(s): K Kanayama, M Kitago, H Takeuchi, T Shibutani.
  • Organizer: オステオロジーJAPAN
• [Presentation] 慢性歯槽骨破壊マウスモデルの確立 (2017)
  • Author(s): 森永啓嗣, 金山圭一, 水野真央, 渋谷俊昭
  • Organizer: 先端モデル動物支援プラットフォーム成果発表会
  • Place of Presentation: 大津
  • Year and Date: 2017-02-06
• [Presentation] Optimization of chronic periodontitis mouse model. (2017)
  • Author(s): Hirotsugu Morinaga, Keiichi Kanayama, Toshiaki Shibutani.
  • Organizer: 12th Asian Pacific Society of Periodontology Meeting
  • Int'l Joint Research
• [Presentation] Humanized Mice as Model System for Osteoclast-derived Oral Immune Plasticity (2016)
  • Author(s): Keiichi Kanayama, Kawaljit Kaur, Yujie Sun, Anahid Jewett, Ichiro Nishimura
  • Organizer: 45th AADR Annual Meeting
  • Place of Presentation: ロサンゼルス
  • Year and Date: 2016-03-16
  • Int'l Joint Research
• [Presentation] UCLA長期海外研修報告 ～研究をうごかした ことば～ (2016)
  • Author(s): 金山圭一
  • Organizer: 第184回 岐阜歯科学会例会
  • Place of Presentation: 岐阜
  • Year and Date: 2016-02-20
  • Invited
• [Presentation] Effect of intermittent administration of parathyroid hormone in rat cranial bone defects (2015)
  • Author(s): Mao Mizuno, Hirotsugu Morinaga , Keisuke Mukai, Keiichi Kanayama, Toshiaki Shibutani
  • Organizer: 101st annual meeting American Academy of Periodontology
  • Place of Presentation: オーランド
  • Year and Date: 2015-11-14
  • Int'l Joint Research
• [Presentation] Synergistic activity of osteoclast with immune cell in inflammatory bone destruction (2015)
  • Author(s): Keiichi Kanayama, Toshiaki Shibutani, Ichiro Nishimura
  • Organizer: The 55th General Session of Korean Academy of Periodontology
  • Place of Presentation: ソウル
  • Year and Date: 2015-10-23
  • Int'l Joint Research