How does zinc signal control development and function of musculoskeletal organs?

• Project/Area Number: 26462324
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Tokushima Bunri University (2015-2016); Showa University (2014)
• Principal Investigator: Fukada Toshiyuki 徳島文理大学, 薬学部, 教授 (70373363)
• Co-Investigator(Renkei-kenkyūsha): Kimura Toru 杏林大学, 医学部, 講師 (30433725)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: シグナル伝達 / 亜鉛 / トランスポーター / 運動器 / 骨軟骨 / 結合組織 / 亜鉛シグナル / 亜鉛トランスポーター / ZIP7 / ZIP13 / ZIP14 / エーラス・ダンロス症候群

Outline of Final Research Achievements

We have revealed the role of zinc transporter ZIP13 in musculoskeletal organs, and molecular features of ZIP13 protein. We also found that proteasome pathways readily degrade the pathogenic ZIP13 mutants, showing the molecular basis of ZIP13-madiated regulation of musculoskeletal organs such as bone and cartilage.
We also assessed the role of ZIP7, a closest molecular relative of ZIP13, revealing that ZIP7 is also required for development of bone and cartilage, however, the molecular mechanisms were distinct between ZIP7 and ZIP13, indicating that each zinc signal possesses the specificity to control unique pathways and/or phenomena. Further research on these zinc transporters as molecular models will uncover the biological significance of zinc signaling, especially for the molecular mechanisms by which how each zinc signal contributes to regulate the development and functions of musculoskeletal organs.

Research Products

• [Journal Article] Physiological roles of zinc transporters: molecular and genetic importance in zinc homeostasis (2017)
  • Author(s): Hara T, Takeda T, Takagishi T, Fukue K, Kambe T, Fukada T
  • Journal Title: J Physiol Sci Volume: 67 Issue: 2 Pages: 283-301
  • DOI: 10.1007/s12576-017-0521-4
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Critical involvement of ZEB2 in collagen fibrillogenesis: the molecular reminiscent of Mowat-Wilson syndrome with Ehlers-Danlos syndrome. (2017)
  • Author(s): Teraishi M, Takaishi M, Nakajima K, Ikeda M, Higashi Y, Shimoda S, Asada Y, Hijikata A, Ohara O, Hirai Y, Mizuno S, Fukada T, Furukawa T, Wakamatsu N, Sano S.
  • Journal Title: Scientific Report Volume: 7:46565 Issue: 1 Pages: 1-10
  • DOI: 10.1038/srep46565
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Requirement of zinc transporter SLC39A7/ZIP7 for dermal development to fine-tune endoplasmic reticulum function by regulating protein disulfide isomerase. (2017)
  • Author(s): Bin BH, J. Bhin, J. Seo, SY. Kim, E. Lee, K. Park, DH. Choi, T. Takagishi, T. Hara, D. Hwang, H. Koseki, Y. Asada, S. Shimoda, K. Mishima, T. Fukada
  • Journal Title: Journal of Investigative Dermatology Volume: 印刷中
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Role of Zinc Transporter ZIP13 in Degenerative Changes in Periodontal Ligament and Alveolar Bone (2016)
  • Author(s): Idaira, Y., T. Munemasa, T. Fukada, S. Shimoda, and Y. Asada.
  • Journal Title: Journal of Hard Tissue Biology Volume: 25 Issue: 1 Pages: 49-56
  • DOI: 10.2485/jhtb.25.49
  • NAID: 130005119558
  • ISSN: 1341-7649, 1880-828X
  • Peer Reviewed
• [Journal Article] Hyperactivation of JAK1 tyrosine kinase induces stepwise, progressive pruritic dermatitis (2016)
  • Author(s): Yasuda T, Fukada T, Nishida K, Nakayama M, Matsuda M, Miura I, Dainichi T, Fukuda S, Kabashima K, Nakaoka S, Bin BH, Kubo M, Ohno H, Hasegawa T, Ohara O, Koseki H, Wakana S, Yoshida H
  • Journal Title: J. Clin. Invest Volume: 126(6) Issue: 6 Pages: 2064-76
  • DOI: 10.1172/jci82887
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Zinc transporter SLC39A7/ZIP7 promotes intestinal epithelial self-renewal by resolving ER stress. (2016)
  • Author(s): Ohashi, W., Kimura, S., Iwanaga, T., Furusawa, Y., Irie, T., Izumi, H., Watanabe, T., Hijikata, A., Hara, T., Ohara, O., Koseki, H., Sato, T., Robine, S., Mori, H., Hattori, Y., Watarai, H., Mishima, K., Ohno, H., Hase, K., Fukada, T.
  • Journal Title: PLoS Genetics Volume: 12 Issue: 10 Pages: e1006349-e1006349
  • DOI: 10.1371/journal.pgen.1006349
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] An acrodermatitis enteropathica-associated Zn transporter, ZIP4, regulates human epidermal homeostasis. (2016)
  • Author(s): Bin BH, J. Bhin, NH. Kim, SH. Lee, HS. Jung, J. Seo, DK. Kim, D. Hwang, T. Fukada, AY. Lee, TR. Lee, EG. Cho.
  • Journal Title: Journal of Investigative Dermatology Volume: 137 Issue: 4 Pages: 874-883
  • DOI: 10.1016/j.jid.2016.11.028
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] SLC39A14 Is Required for the Development of Hepatocellular Iron Overload in Murine Models of Hereditary Hemochromatosis. (2015)
  • Author(s): Jenkitkasemwong, S., C-Y Wang, R. Coffey, W. Zhang, A. Chan, T. Biel, J-S. Kim, S. Hojyo, T. Fukada, and M. Knutson
  • Journal Title: Cell Metabolism Volume: 22 Issue: 1 Pages: 138-150
  • DOI: 10.1016/j.cmet.2015.05.002
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Comparative study of dermal components and plasma TGF-β1 levels in <i>Slc39a13/Zip13</i>-KO mice (2015)
  • Author(s): Hirose, T., T. Ogura, K. Tanaka, J. Minaguchi, T. Yamauchi, T. Fukada, Y. Koyama, and K. Takehana.
  • Journal Title: Journal of Veterinary Medical Science Volume: 77 Issue: 11 Pages: 1385-1389
  • DOI: 10.1292/jvms.15-0015
  • NAID: 130005112093
  • ISSN: 0916-7250, 1347-7439
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Comparing Gene Expression during Cadmium Uptake and Distribution: Untreated vs Oral Cd-Treated Wild-Type and ZIP14 Knockout Mice. (2014)
  • Author(s): Jorge-Nebert, LF., M. Galvez-Peralta, JL. Figueroa, M. Somarathna, S. Hojyo, T. Fukada, and DW. Nebert.
  • Journal Title: Toxicological Sciences Volume: 204 Issue: 1 Pages: 26-35
  • DOI: 10.1093/toxsci/kfu204
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] B-cell receptor signal strength and zinc signaling: unraveling the role of zinc transporter ZIP10 in humoral immunity. (2014)
  • Author(s): Hojyo, S., T. Miyai, and Fukada T.
  • Journal Title: Receptors & Clinical Investigation Volume: 2 Pages: 1-4
  • DOI: 10.14800/rci.387
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Spondylocheirodysplastic Ehlers-Danlos syndrome (SCD-EDS) and the mutant zinc transporter ZIP13 (2014)
  • Author(s): Bin, BH., S. Hojyo, and Fukada T.
  • Journal Title: Rare Diseases Volume: 2 Issue: 1 Pages: e974982-e974982
  • DOI: 10.4161/21675511.2014.974982
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Zinc transporter SLC39A10/ZIP10 controls humoral immunity by modulating B-cell receptor signal strength. (2014)
  • Author(s): Hojyo S., T. Miyai, H. Fujishiro, M. Kawamura, T. Yasuda, A. Hijikata, B-H Bin, T. Irie, J. Tanaka, T. Atsumi, M. Murakami, M. Nakayama, O. Ohara, S. Himeno, H. Yoshida, H. Koseki, T. Ikawa, K. Mishima, and T. Fukada.
  • Journal Title: Proc Natl Acad Sci USA Volume: 111 Issue: 32 Pages: 11786-11791
  • DOI: 10.1073/pnas.1323557111
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Molecular pathogenesis of spondylocheirodysplastic Ehlers-Danlos syndrome caused by mutant ZIP13 proteins. (2014)
  • Author(s): Bin et al.
  • Journal Title: EMBO Molecular Medicine Volume: 6 Issue: 8 Pages: 1028-1042
  • DOI: 10.15252/emmm.201303809
  • Peer Reviewed
• [Journal Article] Zinc transporter SLC39A10/ZIP10 facilitates antiapoptotic signaling during early B-cell development (2014)
  • Author(s): Miyai T, Hojyo S, Ikawa T, Kawamura M, Irie T, Ogura H, Hijikata A, Bin BH, Yasuda T, Kitamura H, Nakayama M, Ohara O, Yoshida H, Koseki H, Mishima K, Fukada T
  • Journal Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 111 Issue: 32 Pages: 11780-11785
  • DOI: 10.1073/pnas.1323549111
  • Peer Reviewed / Open Access
• [Journal Article] Histological Analysis of Dentinogenesis Imperfecta in Slc39a13/Zip13 Knockout Mice (2014)
  • Author(s): Munemasa, T., Y.Idaira, T.Fukada, S.Shimoda, and Y. Asada.
  • Journal Title: Journal of Hard Tissue Biology Volume: 23 Issue: 2 Pages: 163-168
  • DOI: 10.2485/jhtb.23.163
  • NAID: 130004480648
  • ISSN: 1341-7649, 1880-828X
  • Peer Reviewed / Open Access
• [Presentation] Zinc homeostasis and signaling in health and disease (2017)
  • Author(s): 深田俊幸
  • Organizer: 第94回日本生理学会 大会シンポジウム
  • Place of Presentation: 浜松
  • Invited
• [Presentation] 亜鉛シグナル：個体恒常性の維持に関わる新しい制御機構 (2017)
  • Author(s): 深田俊幸
  • Organizer: 第２７回生物試料分析科学会 年次集会
  • Place of Presentation: 新潟
  • Invited
• [Presentation] 亜鉛シクナリング：生体恒常性と病気への関与 (2016)
  • Author(s): 深田俊幸
  • Organizer: 第136回日本薬学会シンポジウム「免疫制御による疾病予防・治療の最前線」
  • Place of Presentation: 横浜
  • Year and Date: 2016-03-28
  • Invited
• [Presentation] "Zinc signaling": An emerging player for epithelial tissue homeostasis. (2016)
  • Author(s): Toshiyuki Fukada
  • Organizer: The 5th Bizan Immunology Symposium: BISUT 5
  • Place of Presentation: 徳島
  • Year and Date: 2016-03-04
  • Int'l Joint Research / Invited
• [Presentation] なぜ亜鉛が必要なのか？：“亜鉛シグナル”研究からのアプローチ (2016)
  • Author(s): 深田俊幸
  • Organizer: 日本歯科人間ドック学会 第19回学術大会
  • Place of Presentation: 徳島
  • Invited
• [Presentation] Molecular and Physiological Basis of Zinc Signaling in vivo and in vitro (2016)
  • Author(s): 深田俊幸
  • Organizer: 第39回日本分子生物学会 年会
  • Place of Presentation: 横浜
  • Invited
• [Presentation] 亜鉛の役割:この10年で分かつたこと、次の10年で解明したいこと (2016)
  • Author(s): 深田俊幸
  • Organizer: 亜鉛栄養治療研究会 中国・四国支部総会
  • Place of Presentation: 広島
  • Invited
• [Presentation] 亜鉛シグナリング (2015)
  • Author(s): 深田俊幸
  • Organizer: 第6回福岡薬理・生理系研究会
  • Place of Presentation: 福岡
  • Year and Date: 2015-12-24
  • Invited
• [Presentation] Zinc signaling: Overview (2015)
  • Author(s): Toshiyuki Fukada
  • Organizer: 第38回日本分子生物学会・第88回日本生化学会合同大会「Zinc Signal Workshop」
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-01
  • Int'l Joint Research / Invited
• [Presentation] 亜鉛シグナリング：その生体恒常性と疾患における意義 (2015)
  • Author(s): 深田俊幸
  • Organizer: 第55回日本臨床化学会年次学術集会 ランチョンセミナー
  • Place of Presentation: 大阪
  • Year and Date: 2015-10-31
  • Invited
• [Presentation] 亜鉛はなぜ必要なのか？：健康と病気に関わる亜鉛トランスポーターと亜鉛シグナル (2015)
  • Author(s): 深田俊幸
  • Organizer: 衛生薬学・環境トキシコロジー若手研究者の会 フォーラム2015プレシンポジウム
  • Place of Presentation: 神戸
  • Year and Date: 2015-09-16
  • Invited
• [Presentation] Zinc signaling in physiology and pathogenesis (2015)
  • Author(s): Toshiyuki Fukada
  • Organizer: The 5th International Symposium on Metallomics: Metallomics-2015
  • Place of Presentation: 北京
  • Year and Date: 2015-09-10
  • Int'l Joint Research / Invited
• [Presentation] 亜鉛シグナリング 生命機能と病態形成に関わる新しい制御機構 (2015)
  • Author(s): 深田俊幸
  • Organizer: 第158回日本獣医学会・微生物学分科会（免疫）シンポジウム
  • Place of Presentation: 青森
  • Year and Date: 2015-09-07
  • Invited
• [Presentation] Zinc signaling: An emerging regulatory system in health and disease (2015)
  • Author(s): Toshiyuki Fukada
  • Organizer: 第25回 金属の関与する生体関連反応シンポジウム
  • Place of Presentation: 長崎
  • Year and Date: 2015-05-31
  • Invited
• [Presentation] 細胞内亜鉛シグナル (2015)
  • Author(s): 深田俊幸
  • Organizer: 第29回日本医学会総会サテライトシンポジウム「亜鉛と医学」
  • Place of Presentation: 京都
  • Year and Date: 2015-04-10
  • Invited
• [Presentation] 新たな技術・概念が切り拓くメタロミクス研究―金属の関わる生命現象のパラダイムシフトを目指して (2015)
  • Author(s): 深田俊幸
  • Organizer: 日本薬学会第135年会シンポジウム
  • Place of Presentation: 神戸
  • Year and Date: 2015-03-27
  • Invited
• [Presentation] 亜鉛シグナルの生命科学：細胞機能と病態形成を司る新しい制御機構 (2015)
  • Author(s): 深田俊幸
  • Organizer: 第120回日本解剖学会総会・全国学術集会／第92回日本生理学会大会合同大会 シンポジウム
  • Place of Presentation: 神戸
  • Year and Date: 2015-03-21
  • Invited
• [Presentation] 「亜鉛の基礎知識」 (2015)
  • Author(s): 深田俊幸
  • Organizer: 日本抗加齢医学会講習会
  • Place of Presentation: 東京
  • Year and Date: 2015-01-11
  • Invited
• [Presentation] 亜鉛シグナルから理解する細胞機能と病態形成 (2014)
  • Author(s): 深田俊幸
  • Organizer: 第87回日本生化学会大会シンポジウム
  • Place of Presentation: 京都
  • Year and Date: 2014-10-17
  • Invited
• [Presentation] 亜鉛による情報伝達：健康と病気への関与 (2014)
  • Author(s): 深田俊幸
  • Organizer: 第56回歯科基礎医学会学術大会・総会 シンポジウム
  • Place of Presentation: 福岡
  • Year and Date: 2014-09-26
  • Invited
• [Presentation] Zinc transporters; from structure to function (2014)
  • Author(s): Toshiyuki Fukada
  • Organizer: International Society for Zinc Biology 2014 Symposium
  • Place of Presentation: USA
  • Year and Date: 2014-09-15
  • Invited
• [Presentation] Zinc signaling in health and diseases (2014)
  • Author(s): Toshiyuki Fukada
  • Organizer: International Society for Zinc Biology 2014 Symposium
  • Place of Presentation: Asilomar, CA USA
  • Year and Date: 2014-09-14
  • Invited
• [Presentation] 亜鉛シグナル：B細胞の恒常性を司る新しい制御機構 (2014)
  • Author(s): 深田俊幸、宮井智浩、北條慎太郎、美島健二
  • Organizer: 心血管膜輸送研究会2014
  • Place of Presentation: 岡崎
  • Year and Date: 2014-09-05
  • Invited
• [Presentation] 亜鉛シグナル：生体恒常性を統御する新しい情報伝達機構 (2014)
  • Author(s): 深田俊幸
  • Organizer: 第87回日本内分泌学会学術総会 教育講演
  • Place of Presentation: 福岡
  • Year and Date: 2014-04-26
  • Invited
• [Book] Molecular, Genetic, and Nutritional Aspects of Major and Trace Minerals (2017)
  • Author(s): Fukada, T
  • Total Pages: 558
  • Publisher: ELSEVIER London
• [Book] Genetic study of zinc transporters and zinc signaling (2016)
  • Author(s): Fukada, T
  • Publisher: ELSEVIER
• [Book] Zinc Signals in Cellular Functions and Disorders (2014)
  • Author(s): Fukada, T, Hojyo, S., and Bin, B.H.
  • Total Pages: 343
  • Publisher: Springer
• [Remarks] 徳島文理大学薬学部 病態分子薬理学研究室ホームページ
  • URL: http://p.bunri-u.ac.jp/lab22/