Bone and hematological regulation by their modulators

• Project/Area Number: 25861341
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Orthopaedic surgery
• Research Institution: Keio University
• Principal Investigator: MIYAMOTO Kana 慶應義塾大学, 医学部, 研究員 (60464997)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 腫瘍 / 骨代謝 / 腫瘍医学 / 破骨細胞 / 造血

Outline of Final Research Achievements

We found that tumor necrosis factor alpha (TNFα) is required for tumorigenesis of an osteosarcoma cell line, AX cells. AX cells were generated by transducing c-Myc oncogene into Ink4a-deficient mesenchymal stem cells. Transplantation of AX cells into wild-type mouse peritoneal cavity resulted in tumorigenesis leading to mortality within 21 days. We found that TNFα-expressing macrophages were recruited to tumor lesions, and lethal tumor development was not observed in TNFα-deficient mice, suggesting that TNFα is required for tumorigenesis of AX cells. Osteoblastic gene expression was significantly inhibited in AX cells by TNFα, and such inhibition was reversed by addition of either a TNFα-inhibitor or a MEK thereby ERK inhibitor. These results suggest that the undifferentiated state of AX cells was the TNFα-ERK pathway dependent.

Research Products

• [Journal Article] Interleukin-1 receptor-associated kinase-4 (IRAK4) promotes inflammatory osteolysis by activating osteoclasts and inhibiting formation of foreign body giant cells. (2015)
  • Author(s): Katsuyama E, Miyamoto H, Kobayashi T, Sato Y, Hao W, Kanagawa H, Fujie A, Tando T, Watanabe R, Morita M, Miyamoto K, Niki Y, Morioka H, Matsumoto M, Toyama Y, Miyamoto T.
  • Journal Title: J Biol Chem. Volume: 290 Issue: 2 Pages: 716-726
  • DOI: 10.1074/jbc.m114.568360
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Mycobacterium tuberculosis promotes arthritis development through toll-like receptor 2. (2015)
  • Author(s): Kanagawa H, Niki Y, Kobayashi T, Sato Y, Katsuyama E, Fujie A, Hao W, Miyamoto K, Tando T, Watanabe R, Morita M, Morioka H, Matsumoto M, Toyama Y, Miyamoto T.
  • Journal Title: J Bone Miner Metab. Volume: 33 Issue: 2 Pages: 135-141
  • DOI: 10.1007/s00774-014-0575-9
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Bcl6 promotes osteoblastogenesis through Stat1 inhibition. (2015)
  • Author(s): Fujie A, Funayama A, Miyauchi Y, Sato Y, Kobayashi T, Kanagawa H, Katsuyama E, Hao W, Tando T, Watanabe R, Morita M, Miyamoto K, Kanaji A, Morioka H, Matsumoto M, Toyama Y and Miyamoto T.
  • Journal Title: Biochem Biophys Res Commun. Volume: 457 Issue: 3 Pages: 451-456
  • DOI: 10.1016/j.bbrc.2015.01.012
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The Vitamin D Analogue ED71 but Not 1,25(OH)2D3 Targets HIF1α Protein in Osteoclasts. (2014)
  • Author(s): Sato Y, Miyauchi Y, Yoshida S, Morita M, Kobayashi T, Kanagawa H, Katsuyama E, Fujie A, Hao W, Tando T, Watanabe R, Miyamoto K, Morioka H, Matsumoto M, Toyama Y, Miyamoto T.
  • Journal Title: PLoS One Volume: 9 Issue: 11 Pages: e111845-e111845
  • DOI: 10.1371/journal.pone.0111845
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] TNFα promotes osteosarcoma progression by maintaining tumor cells in an undifferentiated state. (2013)
  • Author(s): Mori T
  • Journal Title: Oncogene Volume: Epub ahead of print Issue: 33 Pages: 4236-4241
  • DOI: 10.1038/onc.2013.545
  • Peer Reviewed
• [Journal Article] HIF1α is required for osteoclast activation by estrogen deficiency in postmenopausal osteoporosis. (2013)
  • Author(s): Miyauchi Y, Sato Y, Kobayashi T, Yoshida S, Mori T, Kanagawa H, Katsuyama E, Fujie A, Hao W, Miyamoto K, Tando T, Morioka H, Matsumoto M, Chambon P, Johnson RS, Kato S, Toyama Y, Miyamoto T.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 110 Issue: 41 Pages: 16568-16573
  • DOI: 10.1073/pnas.1308755110
  • Peer Reviewed