Clarification of the mechanism of bone degradation by methylglyoxal and development of methods to prevent it

• Project/Area Number: 18K09528
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 57010:Oral biological science-related
• Research Institution: Showa University
• Principal Investigator: Yoshimura Kentaro 昭和大学, 歯学部, 講師 (10585699)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 最終糖化産物 / 骨 / メチルグリオキサール / 活性イオウ分子種 / 骨芽細胞 / 硫化水素 / 糖化ストレス / 石灰化

Outline of Final Research Achievements

Methylglyoxal (MG), a by-product of glycolysis, is one of the precursors of advanced glycation end-products. We had reported that MG degrades physicochemical properties of mineralized nodules produced by osteoblasts through glycation of bridges between collagen molecules. Since MG is a nucleophilic compound, we studied the effects of reactive sulfur species having strong electrophilic properties on the degradation of mineralized nodules by MG. Suppression of the expression of RSS-producing enzyme in osteoblasts reduced their mineralization. Also, NaHS, an RSS donor, improved the osteoblastic mineralization in the presence of MG. These results suggest that RSS can prevent degradation of the bone matrix by MG.

Academic Significance and Societal Importance of the Research Achievements

骨の強度は骨密度と骨質に依存する。種々の要因で、骨密度あるいは骨質が低下し、骨粗鬆症を引き起こす。2型糖尿病でも骨が脆弱になり骨折リスクが高まるが、この場合は、骨密度の低下に比較し、骨質の劣化が著しい。我々は、骨質劣化の原因の一つとしてMGによる骨基質タンパク質の糖化変性を見出した。本研究は、RSSがMGの反応性を低下させることで、２型糖尿病に伴う骨粗鬆症を予防できる可能性を示すもので、今後の治療薬開発の基礎となるものである。

Research Products

• [Journal Article] Zoledronate promotes inflammatory cytokine expression in human CD14-positive monocytes among peripheral mononuclear cells in the presence of γδ T cells. (2021)
  • Author(s): Takimoto R, Suzawa T, Yamada A, Sasa K, Miyamoto Y, Yoshimura K, Sasama Y, Tanaka M, Kinoshita M, Ikezaki K, Ichikawa M, Yamamoto M, Shirota T, Kamijo R
  • Journal Title: Immunology Volume: 162(3) Issue: 3 Pages: 306-313
  • DOI: 10.1111/imm.13283
  • Peer Reviewed / Open Access
• [Journal Article] Functional analysis of PTH1R variants found in primary failure of eruption. (2020)
  • Author(s): Izumida E, Suzawa T, Miyamoto Y, Yamada A, Takimoto R, Otsu M, Saito T, Yamaguchi T, Nishimura K, Ohtaka M, Nakanishi M, Yoshimura K, Sasa K, Takimoto R, Uyama R, Shirota T, Maki K, Kamijo R.
  • Journal Title: Journal of Dental Research Volume: 99 Issue: 4 Pages: 429-436
  • DOI: 10.1177/0022034520901731
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] モノカルボン酸トランスポーターによる骨・軟骨代謝の調節 (2020)
  • Author(s): 笹清人、吉村健太郎、宮本洋一、上條竜太郎
  • Journal Title: 口腔組織培養学会誌 Volume: 29 Pages: 49-56
  • Peer Reviewed
• [Journal Article] Lipopolysaccharide (LPS) Inhibits Ectopic Bone Formation Induced by Bone Morphogenetic Protein-2 and TGF-β1 through IL-1β Production. (2020)
  • Author(s): Matsumoto A, Takami M, Urano E, Nakamachi T, Yoshimura K, YamadaA, Suzawa T, Miyamoto Y, Baba K, Kamijo R.
  • Journal Title: Journal of Oral Biosciences Volume: 62 Issue: 1 Pages: 44-51
  • DOI: 10.1016/j.job.2020.01.004
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Possible involvement of elastase in enhanced osteoclast differentiation by neutrophils through degradation of osteoprotegerin. (2020)
  • Author(s): Sugisaki R, Miyamoto Y, Yoshimura K, Sasa K, Kaneko K, Tanaka M, Itose M, Inoue S, Baba K, Shirota T, Chikazu D, Kamijo R
  • Journal Title: Bone Volume: 132 Pages: 115216-115216
  • DOI: 10.1016/j.bone.2019.115216
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Roles of monocarboxylate transporter subtypes in promotion and suppression of osteoclast differentiation and survival on bone. (2019)
  • Author(s): Imai H, Yoshimura K, Miyamoto Y, Sasa K, Sugano M, Chatani M, Takami M, Yamamoto M, Kamijo R
  • Journal Title: Sci Rep Volume: 9 Issue: 1 Pages: 15608-15608
  • DOI: 10.1038/s41598-019-52128-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Production of 8-nitro-cGMP in osteocytic cells and its upregulation by parathyroid hormone and prostaglandin E2. (2019)
  • Author(s): Nagayama K, Miyamoto Y, Kaneko K, Yoshimura K, Sasa K, Akaike T, Fujii S, Izumida E, Uyama R, Chikazu D, Maki K, Kamijo R.
  • Journal Title: In Vitro Cell Dev Biol Anim Volume: 55 Issue: 1 Pages: 45-51
  • DOI: 10.1007/s11626-018-0304-0
  • Peer Reviewed
• [Journal Article] Nephronectin Expression is Inhibited by Inorganic Phosphate in Osteoblasts (2018)
  • Author(s): Kato Tadashi、Yamada Atsushi、Sasa Kiyohito、Yoshimura Kentaro、Morimura Naoko、Ogata Hiroaki、Sakashita Akiko、Kamijo Ryutaro
  • Journal Title: Calcified Tissue International Volume: 104 Issue: 2 Pages: 201-206
  • DOI: 10.1007/s00223-018-0484-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Monocarboxylate transporter-1 promotes osteoblast differentiation via suppression of p53, a negative regulator of osteoblast differentiation. (2018)
  • Author(s): Sasa K, Yoshimura K, Yamada A, Suzuki D, Miyamoto Y, Imai H, Nagayama K, Maki K, Yamamoto M, Kamijo R
  • Journal Title: Sci. Rep. Volume: 8(1) Issue: 1 Pages: 10579-10579
  • DOI: 10.1038/s41598-018-28605-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The inhibition of malignant melanoma cell invasion of bone by the TLR7 agonist R848 is dependent upon pro-inflammatory cytokines produced by bone marrow macrophages (2018)
  • Author(s): Manome Yoko、Suzuki Dai、Mochizuki Ayako、Saito Emi、Sasa Kiyohito、Yoshimura Kentaro、Inoue Tomio、Takami Masamichi、Inagaki Katsunori、Funatsu Takahiro、Kamijo Ryutaro
  • Journal Title: Oncotarget Volume: 9 Issue: 52 Pages: 29934-29943
  • DOI: 10.18632/oncotarget.25711
  • Peer Reviewed / Open Access
• [Journal Article] 8-Nitro-cGMP is a promoter of osteoclast differentiation induced by RANKL (2018)
  • Author(s): Kaneko K.、Miyamoto Y.、Tsukuura R.、Sasa K.、Akaike T.、Fujii S.、Yoshimura K.、Nagayama K.、Hoshino M.、Inoue S.、Maki K.、Baba K.、Chikazu D.、Kamijo R.
  • Journal Title: Nitric Oxide Volume: 72 Pages: 46-51
  • DOI: 10.1016/j.niox.2017.11.006
  • Peer Reviewed / Open Access
• [Presentation] モノカルボン酸トランスポーター1は骨芽細胞分化の負の調節因子p53の抑制を介して骨芽細胞分化を促進する. (2020)
  • Author(s): 笹清人, 吉村健太郎, 宮本洋一, 上條竜太郎
  • Organizer: 第62回 歯科基礎医学会学術大会
• [Presentation] ゾレドロン酸による末梢血単球の破骨細胞分化抑制． (2020)
  • Author(s): 瀧本玲子，田中元博，山田 篤，宮本洋一，笹 清人，須澤徹夫，吉村健太郎，高見正道，代田達夫，上條竜太郎
  • Organizer: 第62回 歯科基礎医学会学術大会
• [Presentation] Trehalose suppresses osteoclast formation (2020)
  • Author(s): 根岸宗一郎，吉村健太郎
  • Organizer: 令和2年度スチューデント・クリニシャン・リサーチ・プログラム（SCRP）日本代表選抜大会
• [Presentation] Trehalose, a natural sweetening compound, suppresses osteoclast differentiation. Department of Biochemistry, Showa University School of Dentistry (2020)
  • Author(s): S. NEGISHI, K. YOSHIMURA, R. KAMIJO
  • Organizer: 第68回国際歯科研究学会日本部会［JADR］総会・学術大会
  • Int'l Joint Research
• [Presentation] Respiration using hydrogen sulfide promotes chondrocyte proliferation and bone growth. (2019)
  • Author(s): Sasama Y, Yoshimura K, Miyamoto Y, Sasa K, Akaike T, Morita M, Matsunaga T, Shirota T, Kamijo R
  • Organizer: 第67回JADR総会・学術大会／（第4回IADR APR（Asia Pacific Region）学術大会
  • Int'l Joint Research
• [Presentation] Gelated ozone suppresses osteoclast d1ifferentiation and periodontal bone loss. (2019)
  • Author(s): Oshio A, Miyamoto Y, Sasa K, Yamada A, Yoshimura K, Kamijo R
  • Organizer: 第67回JADR総会・学術大会／（第4回IADR APR（Asia Pacific Region）学術大会
  • Int'l Joint Research
• [Presentation] 歯周病性骨破壊に対するオゾンジェルの効果 (2019)
  • Author(s): 吉村健太郎、宮本洋一、笹清人、 山田篤、茶谷昌宏、高見正道、上條竜太郎
  • Organizer: 第2回 オゾン医療・審美学会総会・学術大会
• [Presentation] モノカルボン酸輸送担体は骨形成と骨吸収の両者を調節する (2019)
  • Author(s): 笹 清人、吉村健太郎、今井裕子、山本松男、上條竜太郎
  • Organizer: 第56回日本口腔組織培養学会学術大会
• [Presentation] モノカルボン酸トランスポーター（MCT）は新規骨代謝調節因子である (2019)
  • Author(s): 笹 清人、吉村健太郎、今井裕子、山本松男、上條竜太郎
  • Organizer: 第37回日本ヒト細胞学会
• [Presentation] Zoledronate inhibits differentiation of human CD14+ monocytes into osteoclasts induced by RANKL through upregulation of IRF8 expression. (2019)
  • Author(s): Takimoto R, Tanaka M, Sasa K, Yamada A, Miyamoto Y, Suzawa T, Yoshimura K, Kamijo R
  • Organizer: 第61回歯科基礎医学会学術大会
• [Presentation] ゾレドロン酸は末梢血単球の破骨細胞分化を抑制する． (2019)
  • Author(s): 瀧本玲子，田中元博，笹 清人，山田 篤，宮本洋一，須澤徹夫，吉村健太郎，代田達夫，上條竜太郎
  • Organizer: 第19回東京骨関節フォーラム
• [Presentation] 破骨細胞におけるモノカルボン酸トランスポーター(MCT)の役割について (2019)
  • Author(s): 今井 裕子、吉村 健太郎、宮本 洋一、茶谷 昌宏、高見 正道、上條 竜太郎、山本 松男
  • Organizer: 第65回 昭和大学学士会総会
• [Presentation] 破骨細胞におけるモノカルボン酸トランスポーター（MCT）の役割について． (2018)
  • Author(s): 今井裕子、吉村健太郎、宮本洋一、茶谷昌宏、高見正道、上條竜太郎、山本松男
  • Organizer: 第65回昭和大学学士会総会
• [Presentation] Sucrose suppressed osteoclast differentiation. (2018)
  • Author(s): S.UEDA, K.YOSHIMURA, R.KAMIJO
  • Organizer: The 66th Annual Meeting of Japanese Association for Dental Redearch.
  • Int'l Joint Research
• [Presentation] α-Cyano-4-hydroxycinnamic acid suppresses bone resorption. (2018)
  • Author(s): HIROKO IMAI, KENTARO YOSHIMURA, YOICHI MIYAMOTO, MASAHIRO CHATANI, MASAMICHI TAKAMI, RYUTARO KAMIJO, MATSUO YAMAMOTO
  • Organizer: American Academy of Periodontlogy 104th Annual Meeting
  • Int'l Joint Research
• [Presentation] モノカルボン酸トランスポーター阻害剤α-Cyano-4- hydroxycinnamic acidは破骨細胞の骨吸収を抑制する. (2018)
  • Author(s): 今井裕子,吉村健太郎,宮本洋一,茶谷昌宏,高見正道,山本松男,上條竜太郎
  • Organizer: 第60回歯科基礎医学会学術大会
• [Presentation] モノカルボン酸トランスポーターを介した骨代謝調節． (2018)
  • Author(s): 吉村健太郎,笹 清人,今井裕子,宮本洋一,山本松男,上條竜太郎
  • Organizer: 第18回東京骨関節フォーラム
• [Presentation] α-cyano-4-hydroxycinnamic acid は破骨細胞の骨吸収を抑制する (2018)
  • Author(s): 今井裕子,吉村健太郎,宮本洋一,山田篤,笹清人,茶谷昌宏,高見正道,山本松男,上條竜太郎
  • Organizer: 第4回日本骨免疫学会