The dysfunction of macrophages/osteoclast precursors in bone metabolism after transplantation with RelA-deficient HSC.

• Project/Area Number: 25462392
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Tokyo Medical and Dental University (2015); Institute of Physical and Chemical Research (2013)
• Principal Investigator: Mise-Omata Setsuko 東京医科歯科大学, 医歯(薬)学総合研究科, 非常勤講師 (00269052)
• Co-Investigator(Kenkyū-buntansha): Doi S. Takahiro 独立行政法人理化学研究所, 生体情報統合技術開発チーム, 研究員 (60227684)
• 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: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 骨芽細胞 / 造血幹細胞移植 / マクロファージ / 炎症 / 骨代謝 / 放射線 / 造血幹細胞ニッチ / NF-kB / 炎症性サイトカイン / オステオマック

Outline of Final Research Achievements

Lethal radiation of mice before HSC transplantation induces eradication of hematopoietic cells, but its effect on osteogenic cells may be less considered. The mice transferred with RelA-deficient fetal liver cells developed severe osteoporosis, and even the mice transferred with wild type cells reduced trabecular bones, suggesting that lethal radiation may damage to osteogenic cells. In contrast to wound healing M2 type macrophages reducing in bone marrow of the mice transferred with RelA-deficient HSCs, inflammatory M1 type macrophages were aberrantly activated. Co-transplantation of wild type macrophages have recovered osteoporosis which occurs in the mice transferred with RelA-deficient fetal liver cells, indicating that the dysfunction of RelA-deficient macrophages cause the uncoupling of bone metabolism.

Research Products

• [Journal Article] Delivery of RANKL-Binding Peptide OP3-4 Promotes BMP-2-Induced Maxillary Bone Regeneration. (2016)
  • Author(s): Uehara T, Mise-Omata S, Matsui M, Tabata Y, Murali R, Miyashin M, Aoki K.
  • Journal Title: J Dent Res. Volume: 95 Issue: 6 Pages: 665-672
  • DOI: 10.1177/0022034516633170
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Peptide-induced de novo bone formation after tooth extraction prevents alveolar bone loss in a murine tooth extraction model. (2016)
  • Author(s): Arai Y, Aoki K, Shimizu Y, Tabata Y, Ono T, Murali R, Mise-Omata S, Wakabayashi N
  • Journal Title: Eur J Pharmacol Volume: 782 Pages: 89-97
  • DOI: 10.1016/j.ejphar.2016.04.049
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The inhibitory effects of a RANKL-binding peptide on articular and periarticular bone loss in a murine model of collagen-induced arthritis: A bone histomorphometric study. (2015)
  • Author(s): Kato G, Shimizu Y, Arai Y, Suzuki N, Sugamori Y, Maeda M, Takahashi M, Tamura Y, Wakabayashi N, Murali R, Ono T, Ohya K, Mise-Omata S, Aoki K.
  • Journal Title: Arthritis Research & Therapy Volume: Sep 12 Issue: 1 Pages: 251-264
  • DOI: 10.1186/s13075-015-0753-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] A pharmacological role of metallothionein in zinc-treated cartilage-progenitor cells. (2016)
  • Author(s): Yukihiko Tamura, Setsuko Mise, Yasutaka Sugamori, Md. Zahirul Haq Bhuyan, Mariko Takahashi, Tomoki Uehara, Yuki Arai, Michiyo Miyashin, Noriyuki Wakabayashi, Kazuhiro Aoki.
  • Organizer: APFP 2016(The 13th Asia Pacific Federation of Pharmacologists Meeting)
  • Place of Presentation: Bangkok(Thailand)
  • Year and Date: 2016-02-01
  • Int'l Joint Research
• [Presentation] 亜鉛処理による軟骨前駆細胞(ATDC5)におけるメタロチオンネインの発現について (2015)
  • Author(s): 32.田村幸彦、三瀬節子、菅森泰隆、Md Zahirul Haque Bhuyan、高橋真理子、上原智己、新井祐貴、宮新美智世、若林則幸、青木和広.
  • Organizer: 第133回日本薬理学会関東部会
  • Place of Presentation: 千葉(柏市、柏の葉カンファレンスセンター)
  • Year and Date: 2015-10-10
• [Presentation] マウス抜歯窩に局所適用したRANKL結合ペプチドとBMP-2の併用による骨形成促進作用の評価. (2015)
  • Author(s): 新井祐貴、青木和広、三瀬節子、清水康広、小野卓史、若林則幸.
  • Organizer: 第35回日本骨形態計測学会
  • Place of Presentation: 倉敷（倉敷市芸文館）
  • Year and Date: 2015-06-04
• [Presentation] A rankl-binding peptide accelerates BMP-induced bone regeneration in murine maxilla by subperiosteal injections.: (2015)
  • Author(s): Uehara T, Mise S, Arai Y, Sugamori Y, Kato G, Tamura Y, Tabata Y, Murali R, Wakabayashi N, Miyashin M, Aoki K.
  • Organizer: 13th Congress of the Internatitonal Society of Bone Morphometry.
  • Place of Presentation: 東京（東京ガーデンパレスホテル）
  • Year and Date: 2015-04-27
  • Int'l Joint Research
• [Presentation] NF-kappaB, rela-deficient bone marrow macrophages fail to support bone formation and maintain HSC niche after lethal irradiation and HSC tranplantation. (2013)
  • Author(s): Setsuko Mise－Omata, Neil Alles, Taro Fukazawa, Kazuhiro Aoki, Keiichi Ohya, Eijiro Jimi, Yuichi Obata, Takahiro Doi
  • Organizer: The joint international meeting of the 78th meeting of the japanese society of interferon and cytokine research and The 21st international symposium on Molecular cell biology of macrophages 2013
  • Place of Presentation: 東京 日本
• [Presentation] NF-kaｐpaB rela-deficient macrophages fail to support bone formation and maintain the microenvironment for hematopoiesis after X-ray irradiation and HSC transplantation. (2013)
  • Author(s): Setsuko Mise-Omata,Taro Fukazawa, Yuichi Obata, Takahiro Doi
  • Organizer: 15th International Congress of Immunology
  • Place of Presentation: Milan, Italy
• [Book] Biology in Stem Cell Niche. (2015)
  • Author(s): Mise-Omata, S., Doi, TS, Aoki K., Obata Y.
  • Total Pages: 14
  • Publisher: Springer Humana Press