Analysis of new therapeutic target molecules for osteoporosis based on the chromatin information

• Project/Area Number: 17K19728
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Research Field: Surgery related to the biological and sensory functions and related fields
• Research Institution: Ehime University
• Principal Investigator: Imai Yuuki 愛媛大学, プロテオサイエンスセンター, 教授 (10423873)
• Research Collaborator: Yanagihara Yuta ; Iimura Tadahiro ; Saeki Noritaka ; Lee Jiwon
• Project Period (FY): 2017-06-30 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2018: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2017: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 破骨細胞 / Zscan10 / 転写因子 / RNA-seq / Haptoglobin / DNase-seq / 骨粗鬆症 / クロマチン情報

Outline of Final Research Achievements

Zinc finger and SCAN domain containing 10 (Zscan10) was identified as a novel transcription factor that is involved in osteoclast differentiation in our previous report. However, the biological functions of Zscan10 are not fully understood. First, Zscan10 KO RAW264 (KO) cells were established by genome editing using CRISPR/Cas9 and single cell sorting. Zscan10 might regulate transcription of the genes that negatively control osteoclastogenesis. To understand gene expression profiles controlled by Zscan10, RNA-seq was performed and stringent analyses identified the haptoglobin gene (Hp) as a possible target of Zscan10. rHp treatment suppressed TRAP activity of KO cells without affecting cell viability. Furthermore, it has been reported that Hp KO mice exhibit decreased bone mass and increased osteoclast number. Taken together, this study suggests that Zscan10 negatively regulates osteoclast differentiation through transcription of Hp.

Academic Significance and Societal Importance of the Research Achievements

新規破骨細胞転写因子Zscan10の同定から、統合的ゲノムワイド解析により明らかとなったハプトグロビン（Hp）が骨代謝制御の標的分子になりうることが明らかとなった。これまでにHp KOマウスでは骨量の減少及び破骨細胞数の増加を呈し、Hpが破骨細胞分化の抑制に関与すること、Hpが低値を示す溶血性貧血の患者では、骨量の減少を引き起こすことが報告されている。以上のような報告から、生体においてもHpが骨代謝に対し保護的作用を示すことが示唆された。

Research Products

• [Journal Article] Zscan10 Suppresses Osteoclast Differentiation by Regulating Expression of Haptoglobin. (2019)
  • Author(s): Yanagihara Y, Inoue K, Saeki N, Sawada Y, Yoshida S, Lee JW, Iimura T and Imai Y.
  • Journal Title: Bone Volume: 122 Pages: 93-100
  • DOI: 10.1016/j.bone.2019.02.011
  • Peer Reviewed / Open Access
• [Journal Article] The effects of resistance training on bone mineral density and bone quality in type 2 diabetic rats (2019)
  • Author(s): Ikedo Aoi, Kido Kohei, Ato Satoru, Sato Koji, Lee Ji‐Won, Fujita Satoshi, Imai Yuuki
  • Journal Title: Physiological Reports Volume: 7 Issue: 6 Pages: e14046-e14046
  • DOI: 10.14814/phy2.14046
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] DANFIN functions as an inhibitor of transcription factor NF-κB and potentiates the antitumor effect of bortezomib in multiple myeloma (2018)
  • Author(s): Uematsu Atsushi、Kido Kohki、Manabe Erika、Takeda Hiroyuki、Takahashi Hirotaka、Hayashi Minoru、Imai Yuuki、Sawasaki Tatsuya
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 495 Issue: 3 Pages: 2289-2295
  • DOI: 10.1016/j.bbrc.2017.12.142
  • Peer Reviewed / Open Access
• [Journal Article] Uhrf1 is indispensable for normal limb growth by regulating chondrocyte differentiation through specific gene expression (2017)
  • Author(s): Yamashita Michiko、Inoue Kazuki、Saeki Noritaka、Ideta-Otsuka Maky、Yanagihara Yuta、Sawada Yuichiro、Sakakibara Iori、Lee Jiwon、Ichikawa Koichi、Kamei Yoshiaki、Iimura Tadahiro、Igarashi Katsuhide、Takada Yasutsugu、Imai Yuuki
  • Journal Title: Development Volume: 145 Issue: 1 Pages: 157412-157412
  • DOI: 10.1242/dev.157412
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The HIV co-receptor CCR5 regulates osteoclast function. (2017)
  • Author(s): Lee JW, Hoshino A, Inoue K, Saitou T, Uehara S, Kobayashi Y, Ueha S, Matsushima K, Yamaguchi A, Imai Y, Iimura T.
  • Journal Title: Nat Commun Volume: 8 Issue: 1 Pages: 2226-2226
  • DOI: 10.1038/s41467-017-02368-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genome-wide Association Study of Idiopathic Osteonecrosis of the Femoral Head (2017)
  • Author(s): Sakamoto Y, Yamamoto T, Sugano N, Takahashi D, Watanabe T, Atsumi T, Nakamura J, Hasegawa Y, Akashi K, Narita I, Miyamoto T, Takeuchi T, Ikari K, Amano K, Fujie A, Kubo T, Tada Y, Kaneuji A, Nakamura H, Miyamura T, Kabata T, Yamaji K, Okawa T, Sudo A, Ohzono K, Tanaka Y, Yasunaga Y, Matsuda S, Imai Y
  • Journal Title: Sci Rep. Volume: 7 Issue: 1 Pages: 15035-15035
  • DOI: 10.1038/s41598-017-14778-y
  • NAID: 120006817606
  • Peer Reviewed / Open Access
• [Presentation] Zscan10 Suppresses Osteoclast Differentiation through Expression of Haptoglobin. (2018)
  • Author(s): Yuta Yanagihara, Kazuki Inoue, Noritaka Saeki, Yuichiro Sawada, Jiwon Lee, Tadahiro Iimura, Yuuki Imai
  • Organizer: The American Society for Bone and Mineral Research 2018 Annual Meeting
  • Int'l Joint Research
• [Presentation] Zscan10 Suppresses Osteoclast Differentiation by Regulating Expression of Haptoglobin (2018)
  • Author(s): Yuta Yanagihara, Kazuki Inoue, Noritaka Saeki, Yuichiro Sawada, Jiwon Lee, Tadahiro Iimura, Yuuki Imai
  • Organizer: Protein Island Matsuyama 2018 International Symposium
  • Int'l Joint Research
• [Presentation] Zscan10はHaptoglobinの転写を介して破骨細胞分化を負に制御する (2018)
  • Author(s): 柳原裕太,井上和樹,佐伯法学,沢田雄一郎,李智媛,飯村忠浩,今井祐記
  • Organizer: 第36回日本骨代謝学会学術集会
• [Presentation] Zscan10 Suppresses Osteoclast Differentiation through Expression of Haptoglobin. (2018)
  • Author(s): Yuta Yanagihara, Kazuki Inoue, Jiwon Lee, Tadahiro Iimura, Yuuki Imai
  • Organizer: ASBMR2018
  • Int'l Joint Research
• [Presentation] Zscan10は抑制因子の転写を介して破骨細胞分化を負に制御する (2018)
  • Author(s): 柳原 裕太, 佐伯法学, 沢田雄一郎, 今井祐記
  • Organizer: 第36回日本骨代謝学会学術集会
• [Remarks] 愛媛大学プロテオサイエンスセンター病態生理解析部門
  • URL: https://www.m.ehime-u.ac.jp/school/imailab
• [Remarks] 愛媛大学プロテオサイエンスセンター
  • URL: http://www.pros.ehime-u.ac.jp/
• [Remarks] 愛媛大学プロテオサイエンスセンター病態生理解析部門
  • URL: https://www.m.ehime-u.ac.jp/school/imailab/
• [Patent(Industrial Property Rights)] 骨増強作用を示すフラボノイド (2018)
  • Inventor(s): 今井祐記 菅原卓也 西脇寿
  • Industrial Property Rights Holder: 愛媛大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2018-175813
  • Filing Date: 2018