Effects of CXCL12 expressed in adipocytes on osteoclastogenesis and orthodontic tooth movement

• Project/Area Number: 17K17306
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Orthodontics/Pediatric dentistry
• Research Institution: Tohoku University
• Principal Investigator: Shima Kazuhiro 東北大学, 大学病院, 医員 (40792148)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: CXCL12 / 破骨細胞 / LPS

Outline of Final Research Achievements

CXCL12 belongs to the family of CXC chemokines. Lipopolysaccharide (LPS) induces inflammation-induced osteoclastogenesis and bone resorption, and in recent years, stimulatory effects of CXCL12 on bone resorption have also been reported. LPS was administered with or without CXCL12 onto mouse calvariae by daily subcutaneous injection. Numbers of osteoclasts and bone resorption were significantly elevated in mice co-administered LPS and CXCL12 compared with mice administered LPS alone. These in vitro results confirmed a direct stimulatory effect of CXCL12 on RANKL- and TNF-α-induced osteoclastogenesis. Our results suggest that CXCL12 enhances LPS-induced osteoclastogenesis and bone resorption in vivo through a combination of increasing LPS-induced TNF-α production by macrophages, increasing RANKL production by osteoblasts, and direct enhancement of osteoclastogenesis.

Academic Significance and Societal Importance of the Research Achievements

近年、生活習慣病が社会的な問題となっている。その中で肥満および肥満に随伴する代謝異常によるメタボリックシンドロームが特に問題視されている。肥満の有病率は年々増加しており、矯正治療においても肥満の患者は増加してきている。肥満には脂肪細胞が関与していることが知られている。脂肪細胞は、骨髄ニッチに存在し、肥満、骨吸収の増加する骨粗鬆症、関節リウマチ、骨転移性の癌の際に著しく増加することが知られている。このことから、脂肪細胞と破骨細胞の関係を調べることは重要なことだと考えられる。

Research Products

• [Journal Article] C-X-C motif chemokine 12 enhances lipopolysaccharide-induced osteoclastogenesis and bone resorption in vivo. (2018)
  • Author(s): Shima K, Kimura K, Ishida M, Kishikawa A, Ogawa S, Qi J, Shen WR, Ohori F, Noguchi T, Marahleh A, Kitaura H.
  • Journal Title: Calcif. Tissue Int. Volume: 103 Issue: 4 Pages: 431-442
  • DOI: 10.1007/s00223-018-0435-z
  • Peer Reviewed / Open Access
• [Journal Article] The glucagon-like peptide-1 receptor agonist exendin-4 inhibits lipopolysaccharide-induced osteoclast formation and bone resorption via inhibition of TNF-α expression in macrophages. (2018)
  • Author(s): Wei-Ren Shen, Keisuke Kimura, Masahiko Ishida, Haruki Sugisawa, Akiko Kishikawa, Kazuhiro Shima, Saika Ogawa, Jiawei Qi, Hideki Kitaura
  • Journal Title: Journal of Immunology Research Volume: 2018 Pages: 5783639-5783639
  • DOI: 10.1155/2018/5783639
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Role of muramyl dipeptide for lipopolysaccharide-mediated biological activity and osteoclast activity. (2018)
  • Author(s): Kitaura, H., Ishida, M., Kimura, K., Sugisawa, H., Kishikawa A, Shima, K., Ogawa S., Qi J, Kitaura H., Shen WR
  • Journal Title: Anal. Cell. Pathol. Volume: Volume 2018 Pages: 8047610-8047610
  • DOI: 10.1155/2018/8047610
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inflammatory Effects of Nitrogen-Containing Bisphosphonates (N-BPs): Modulation by Non-N-BPs (2017)
  • Author(s): Shima K, Tsuchiya M, Oizumi T, Takano-Yamamoto T, Sugawara S, Endo Y.
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 40 Issue: 1 Pages: 25-33
  • DOI: 10.1248/bpb.b16-00521
  • NAID: 130005188786
  • ISSN: 0918-6158, 1347-5215
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of a vesicular ATP release inhibitor for the treatment of neuropathic and inflammatory pain (2017)
  • Author(s): Kato Yuri、Hiasa Miki、Ichikawa Reiko、Hasuzawa Nao、Kadowaki Atsushi、Iwatsuki Ken、Shima Kazuhiro、Endo Yasuo、Kitahara Yoshiro、Inoue Tsuyoshi、Nomura Masatoshi、Omote Hiroshi、Moriyama Yoshinori、Miyaji Takaaki
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 114 Issue: 31
  • DOI: 10.1073/pnas.1704847114
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 歯科矯正用Ni-Tiワイヤーに対する表面コーティングによる耐食性の解析 (2017)
  • Author(s): 木村桂介，杉澤晴紀，井田裕人，石田匡彦，島和弘，岸川明子，小川紗衣香，北浦英樹
  • Journal Title: 東北矯正歯科学会雑誌 Volume: 25 Pages: 9-15
  • Peer Reviewed
• [Presentation] CXCL12の破骨細胞形成、骨吸収および破骨細胞関連サイトカインの発現への影響についての検討 (2018)
  • Author(s): 島和弘、木村桂介、石田匡彦、岸川明子、小川紗衣香、斉嘉;、沈威任、大堀文俊 、野口隆弘、Aseel Marahleh 、北浦英樹
  • Organizer: 日本矯正歯科学会
• [Presentation] Inhibition of lipopolysaccharide-induced osteoclast formation and bone resorption in vivo by glucagon-like peptide-1 receptor agonist. (2018)
  • Author(s): Shen WR, Kimura K, Ishida M, Kishikawa A, Shima K, Ogawa S, Qi J, Ohori F, Noguchi T, Marahleh A, Kitaura H
  • Organizer: International Symposium for Multimodal Research and Education in IOHS-Liaison 2018
  • Int'l Joint Research
• [Presentation] Comparisons with and without retention in orthodontic relapse mouse models (2018)
  • Author(s): Qi J, Kimura K, Ishida M, Kishikawa A, Shima K, Ogawa S, Shen WR, Ohori F, Noguchi T, Marahleh A, Kitaura H.
  • Organizer: International Symposium for Multimodal Research and Education in IOHS-Liaison 2018
  • Int'l Joint Research
• [Presentation] 破骨細胞形成および骨吸収に対する 脂肪細胞に発現するケモカインCXCL12の作用の検討 (2017)
  • Author(s): 島和弘、木村桂介、石田匡彦、杉澤晴紀、越智由美子、岸川明子、小川紗衣香、セイカイ、沈威任、北浦英樹
  • Organizer: 第76回日本矯正歯科学会学術大会
• [Presentation] Exendin-4, a GLP-1 receptor agonist, suppresses inflammation-induced osteoclast formation and bone resorption. The 12th International Workshop on Biomaterials in Interface Science (2017)
  • Author(s): Shen WR, Kimura K, Ishida M, Sugisawa H, Ochi Y, Kishikawa A, Shima K, Ogawa S., Qi J, Kitaura H.
  • Organizer: Innovative Research for Biosis-Abiosis Intelligent Interface Summer Seminar 2017
  • Int'l Joint Research
• [Presentation] The effects of diabetic medicine exendin-4 for osteoclast formation and bone resorption (2017)
  • Author(s): Shen WR, Kimura K, Ishida M, Sugisawa H, Ochi Y, Kishikawa A, Shima K, Ogawa S., Qi J, Kitaura H
  • Organizer: The 76th Annual Meeting of the Japanese Orthodontic Society
• [Presentation] 脂肪酸受容体GPR120の破骨細胞形成および骨吸収との関連性の検討 (2017)
  • Author(s): 木村桂介、石田匡彦、島和弘、杉澤晴紀、越智由美子、岸川明子、小川紗衣香、セイカイ、沈威任、北浦英樹
  • Organizer: 第76回日本矯正歯科学会大会
• [Presentation] 糖尿病治療薬DPP-4阻害薬による破骨細胞形成および骨吸収への影響について (2017)
  • Author(s): 石田匡彦、木村桂介、島和弘、沈威任、北浦英樹
  • Organizer: 第76回日本矯正歯科学会大会