Oxidative stress in bone regulates skeletal homeostasis in mice

• Project/Area Number: 26462283
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Chiba University
• Principal Investigator: Shimizu Takahiko 千葉大学, 大学院医学研究院, 特任准教授 (40301791)
• Co-Investigator(Renkei-kenkyūsha): NOJIRI Hidetoshi 順天堂大学, 医学部, 准教授 (10317456)
• 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: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 骨 / 酸化ストレス / 老化 / SOD / 骨格筋

Outline of Final Research Achievements

Superoxide dismutase 2 (Sod2) is a mitochondrial antioxidant enzyme that plays a pivotal role in the maintenance of mitochondrial function to regulate redox balance. However, the physiological function of Sod2 in bone metabolism has not been fully elucidated. In order to address this question, mice lacking Sod2 in osteocytes were generated by crossbreeding mice harboring a Sod2 conditional allele with Dmp1-Cre transgenic mice (Dmp1-Sod2-/-). The Sod2 ablation in osteocytes significantly caused bone loss and fragility in an age-dependent manner. In addition, histomorphometric analyses also revealed that Sod2 loss markedly disorganized bone canaliculi in the cortical bones, indicating osteocyte dysfunction. Interestingly, we found specific up-regulation of Sost and Rankl genes in bone. These findings demonstrated that mitochondrial SOD in osteocytes regulates osteocyte fate and RANKL- and Sclerostin-mediated bone metabolism in mice.

Research Products

• [Journal Article] Balfour Sartor, John P Iredale, Jack Satsangi. MDR1-deficiency impairs mitochondrial homeostasis and promotes intestinal inflammation. (2017)
  • Author(s): Gwo-Tzer Ho, Rhona E Aird, Bo Liu, Nicholas A Kennedy, David A Dorward, Colin L Noble, Takahiko Shimizu, Nicholas M Morton, Adriano G Rossi, R. Balfour Sartor, John P Iredale, Jack Satsangi.
  • Journal Title: Mucosal Immunology Volume: - Issue: 1 Pages: 120-130
  • DOI: 10.1038/mi.2017.31
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Manganese superoxide dismutase influences the extent of noise-induced hearing loss in mice. (2017)
  • Author(s): Tuerdi A, Kinoshita M, Kamogashira T, Fujimoto C, Iwasaki S, Shimizu T, Yamasoba T
  • Journal Title: Neurosci Lett Volume: 642 Pages: 123-128
  • DOI: 10.1016/j.neulet.2017.02.003
  • Peer Reviewed / Open Access
• [Journal Article] EGCG, a green tea catechin, attenuates the progression of heart failure induced by the heart/muscle-specific deletion of MnSOD in mice. (2017)
  • Author(s): Oyama, J.*, Shirakihara, A., Nishikido, T., Maeda, T., Komoda, H., Shimizu, T., Makino, N., Node, K.
  • Journal Title: J Cardiol. Volume: 69 Issue: 2 Pages: 417-427
  • DOI: 10.1016/j.jjcc.2016.05.019
  • Peer Reviewed / Open Access
• [Journal Article] Effects of Korean ginseng berry on skin anti-pigmentation and anti-aging via FoxO3a activation. (2016)
  • Author(s): Juewon Kim, Si Young Cho, Su Hwan Kim, Donghyun Cho, Sunmi Kim, Chan-Woong Park, Shimizu, T., Jae Youl Cho, Dae Bang Seo*, Song Seok Shin*.
  • Journal Title: J. Ginseng Res. Volume: - Issue: 3 Pages: 277-283
  • DOI: 10.1016/j.jgr.2016.05.005
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Monoclonal antibody with conformational specificity for a toxic conformer of amyloid β42 and its application toward the Alzheimer's disease diagnosis (2016)
  • Author(s): Kazuma Murakami, Maki Tokuda, Takashi Suzuki, Yumi Irie, Mizuho Hanaki, Naotaka Izuo, Yoko Monobe, Ken-ichi Akagi, Ryotaro Ishii, Harutsugu Tatebe, Takahiko Tokuda, Masahiro Maeda, Toshiaki Kume, Takahiko Shimizu, Kazuhiro Irie
  • Journal Title: Sci. Rep. Volume: 6 Issue: 1 Pages: 29038-29038
  • DOI: 10.1038/srep29038
  • NAID: 120005774689
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Mitochondrial superoxide in osteocytes perturbs canalicular networks in the setting of age-related osteoporosis. (2015)
  • Author(s): Kobayashi K1, Nojiri H2, Saita Y2, Morikawa D1, Ozawa Y3, Watanabe K3, Koike M1, Asou Y4, Shirasawa T5, Yokote K6, Kaneko K2, Shimizu T3.
  • Journal Title: Scientific Reports Volume: Mar 16;5 Issue: 1 Pages: 9148-9148
  • DOI: 10.1038/srep09148
  • Peer Reviewed / Open Access
• [Journal Article] Mechanical overloading causes mitochondrial superoxide and SOD2 imbalance in chondrocytes resulting in cartilage degeneration (2015)
  • Author(s): Koike, M., Nojiri, H., Ozawa, Y., Watanabe, K., Muramatsu, Y., Kaneko, H., Morikawa, D., Kobayashi, K., Saita, Y., Sasho, T., Shirasawa, T., Yokote, K., Kaneko, K., Shimizu, T.
  • Journal Title: Sci. Rep. Volume: 5 Issue: 1 Pages: 11722-11722
  • DOI: 10.1038/srep11722
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The effects of 2% rebapimide ophthalmic solution on the tear functions and ocular surface of the superoxide dismutase-1 (Sod1) knockout mice. (2015)
  • Author(s): Kojima, T., Dogru, M.*, Ibrahim, O. M., Wakamatsu, T. H., Ito, M., Igarashi, A., Inaba, T., Shimizu, T., Shirasawa, T. Shimazaki, J., Tsubota, K.
  • Journal Title: Invest. Ophthalmol. Vis. Sci. Volume: 54 Issue: 12 Pages: 7793-7802
  • DOI: 10.1167/iovs.13-13128
  • Peer Reviewed
• [Journal Article] Aging-induced changes in sex-steroidogenic enzymes and sex-steroid receptors in the cortex, hypothalamus and cerebellum (2015)
  • Author(s): Munetomo A, Hojo Y, Higo S, Kato A, Yoshida K, Shirasawa T, Shimizu T, Barron A, Kimoto T and Kawato S
  • Journal Title: J Physiol. Sci Volume: 65 Issue: 3 Pages: 253-263
  • DOI: 10.1007/s12576-015-0363-x
  • Peer Reviewed
• [Journal Article] Brain-specific superoxide dismutase 2 deficiency causes perinatal death with spongiform encephalopathy in mice. (2015)
  • Author(s): Izuo, N., Nojiri, H., Uchiyama, S., Noda, Y., Kawakami, S., Kojima, S., Sasaki, T., Shirasawa, T., Shimizu, T.
  • Journal Title: Oxid. Med. Cell. Longev. Volume: 2015 Pages: 238914-238914
  • DOI: 10.1155/2015/238914
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Mitochondrial respiration deficits driven by reactive oxygen species in experimental temporal lobe epilepsy. (2015)
  • Author(s): Rowley, S., Liang, LP., Fulton, R., Shimizu, T., Day, B., Patel, M.
  • Journal Title: Neurobiol. Dis. Volume: 75 Pages: 151-158
  • DOI: 10.1016/j.nbd.2014.12.025
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Resveratrol derivative-rich melinjo seed extract attenuates skin atrophy in Sod1-deficient mice. (2015)
  • Author(s): Watanabe, K., Shibuya, S., Ozawa, Y., Izuo, N., Shimizu, T.
  • Journal Title: Oxid. Med. Cell. Longev. Volume: 2015 Pages: 391075-391075
  • DOI: 10.1155/2015/391075
  • Peer Reviewed / Open Access
• [Journal Article] Brain-specific superoxide dismutase 2 deficiency causes perinatal death with spongiform encephalopathy in mice. (2015)
  • Author(s): Izuo, N., Nojiri, H., Uchiyama, S., Noda, Y., Kawakami, S., Kojima, S., Sasaki, T., Shirasawa, T., Shimizu, T.
  • Journal Title: Oxid. Med. Cell. Longev Volume: 2015 Pages: 238914-238914
  • Peer Reviewed / Open Access
• [Journal Article] Superoxide dismutase 1 loss disturbs intracellular redox signaling, resulting in global age-related pathological changes. (2014)
  • Author(s): Watanabe, K., Shibuya, S., Ozawa, Y., Nojiri, H., Izuo, N., Yokote, K., and Shimizu, T.
  • Journal Title: BioMed. Res. Int. Volume: 2014 Pages: 140165-140165
  • DOI: 10.1155/2014/140165
  • Peer Reviewed / Open Access
• [Presentation] Mitochondrial SOD in osteocytes plays a pivotal role in maintaining bone metabolism in mice. (2017)
  • Author(s): Takahiko Shimizu, Keiji Kobayashi, Hidetoshi Nojiri.
  • Organizer: Asian Society of Aging Research Symposium 2017
  • Place of Presentation: 札幌グランドホテル（北海道札幌市）
  • Year and Date: 2017-03-02
  • Int'l Joint Research / Invited
• [Presentation] Mechanical overloading causes mitochondrial superoxide and SOD2 imbalance in chondrocytes resulting in cartilage degeneration. (2016)
  • Author(s): Takahiko Shimizu, Masato Koike, Hidetoshi Nojiri.
  • Organizer: Cell symposia Aging & Metabolism
  • Place of Presentation: Melia Stiges（スペイン）
  • Year and Date: 2016-07-10
  • Int'l Joint Research
• [Presentation] Identification of the “Toxic Conformer” of Amyloid β and its Pathogenic Contribution of Alzheimer’s Disease. (2016)
  • Author(s): Naotaka Izuo, Kazuma Murakami, Toshiaki Kume, Masahiro Maeda, Kazuhiro Irie, Takahiko Shimizu
  • Organizer: The Japan-Korea Joint Aging Symposium
  • Place of Presentation: Daegu（韓国）
  • Year and Date: 2016-06-15
  • Int'l Joint Research / Invited
• [Presentation] Pathological significance of telomere in a model mouse for Werner syndrome. (2016)
  • Author(s): Shuichi Shibuya, Koutaro Yokote, Takahiko Shimizu.
  • Organizer: RecQ helicase symposium 2016
  • Place of Presentation: Seattle（米国）
  • Year and Date: 2016-05-28
  • Int'l Joint Research
• [Presentation] Apple polyphenols protect cartilage degeneration through modulating mitochondrial function in mice. (2016)
  • Author(s): Isao Masuda, Masato Koike, Yusuke Ozawa, Kenji Watanabe, Shohei Nakashima, Hiroshi Sugiyama, Tomomasa Kanda Hidetoshi Nojiri, Takahiko Shimizu.
  • Organizer: 2016 World Congress of Osteoarthritis Research Society International
  • Place of Presentation: Amsterdam（オランダ）
  • Year and Date: 2016-04-01
  • Int'l Joint Research
• [Presentation] Mitochondrial superoxide regulation in chondrocytes suppresses mechanical overloading-induced cartilage degeneration. (2016)
  • Author(s): Masato Koike, Hidetoshi Nojiri, Haruka Kaneko, Daichi Morikawa, Keiji Kobayashi, Yoshitomo Saita, Kazuo Kaneko, Takahiko Shimizu.
  • Organizer: Orthopaedic Research Society (ORS) Annual Meeting 2016
  • Place of Presentation: Orlando (USA)
  • Year and Date: 2016-03-05
  • Int'l Joint Research
• [Presentation] SOD2 loss in osteocytes perturbs canalicular networks associated with impairment of bone remodeling in age-related osteoporosis. (2015)
  • Author(s): Takahiko Shimizu, Keiji Kobayashi, Hidetoshi Nojiri, Koutaro Yokote
  • Organizer: Biology of Ageing Conference
  • Place of Presentation: Singapore
  • Year and Date: 2015-10-22
  • Int'l Joint Research
• [Presentation] Mn-SOD loss in osteocytes causes age-related bone loss associated with impairment of bone remodeling. (2015)
  • Author(s): Takahiko Shimizu, Keiji Kobayashi, Hidetoshi Nojiri
  • Organizer: The 10th IAGG (International Association of Gerontology and Geriatrics) Asia/Oceania 2015 Congress
  • Place of Presentation: Chiang Mai (Thailand)
  • Year and Date: 2015-10-19
  • Int'l Joint Research
• [Presentation] Contribution of mitochondrial superoxide and SOD2 imbalance to the locomotive syndrome. (2015)
  • Author(s): Hidetoshi Nojiri, Daichi Morikawa, Keiji Kobayashi, Masato Koike, Yoshitomo Saita, Kazuo Kaneko, Takahiko Shimizu
  • Organizer: The 2nd International Academy of Sportology
  • Place of Presentation: 順天堂大学（東京都文京区）
  • Year and Date: 2015-09-15
  • Int'l Joint Research
• [Presentation] Mitochondrial superoxide in chondrocytes regulates age-related osteoarthritis. (2014)
  • Author(s): Takahiko Shimizu
  • Organizer: The 4th International Symposium of Asian Association of Aging Research (AAAR) 2014
  • Place of Presentation: Beijing (China)
  • Year and Date: 2014-11-07 – 2014-11-09
  • Invited
• [Presentation] Superoxide dismutase 2 deficiency in osteocytes causes age-related bone loss associated with impairment of bone remodeling. (2014)
  • Author(s): Takahiko Shimizu, Keiji Kobayashi, Hidetoshi Nojiri.
  • Organizer: The Japan-Korea Joint Symposium 2014
  • Place of Presentation: Jeju (Korea)
  • Year and Date: 2014-06-20 – 2014-06-21
  • Invited