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Analysis of signal transduction of inflammatory cytokines in bone destruction

Research Project

Project/Area Number 12470393
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Functional basic dentistry
Research InstitutionMATSUMOTO DENTAL UNIVERSITY (2001)
Showa University (2000)

Principal Investigator

TAKAHASHI Naoyuki  Institute for Dental Science, Professor, 総合歯科医学研究所, 教授 (90119222)

Co-Investigator(Kenkyū-buntansha) MIZOGUCHI Toshihide  Dental Material, Research Assistant, 総合歯科医学研究所, 助手 (90329475)
HIRAOKA Yukihiro  Biochemistry, Associate Professor, 歯学部, 助教授 (20097512)
UDAGAWA Nobuyuki  Biochemistry, Professor, 歯学部, 教授 (70245801)
SASAKI Takahisa  Department of Oral Histology, School of Dentistry, Showa University, 医学部, 教授 (50129839)
Project Period (FY) 2000 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥16,500,000 (Direct Cost: ¥16,500,000)
Fiscal Year 2001: ¥4,700,000 (Direct Cost: ¥4,700,000)
Fiscal Year 2000: ¥11,800,000 (Direct Cost: ¥11,800,000)
KeywordsOsteoclasts / Macrophage / Osteoblast / Inflammatory cytokine / p38 MAP kinase / Lipopolysaccharide / ERK / RANKL
Research Abstract

The mechanism of osteoclastogenesis induced by lipopolysaccharide (LPS) was studied in cocultures of mouse osteoblasts and bone marrow cells. LPS stimulated osteoclastogenesis and prostaglandin E_2 (PGE_2) production in the cocultures, both of which were inhibited by NS398, a cyclooxygenase-2 inhibitor. LPS stimulated receptor activator of NF-κB ligand (RANKL) mRNA expression, and inhibited osteoprotegerin (OPG) mRNA expression in osteoblasts. NS398 inhibited only LPS-induced down-regulation of OPG mRNA expression, suggesting that LPS-stimulated PGE_2 production is important for the down-regulation of OPG. Indeed, NS398 failed to inhibit LPS-induced osteoclastogenesis in cocultures containing OPG knockout mouse-derived osteoblasts. Calcium/protein kinase C (PKC) inhibitors and PD98059 [mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor] suppressed RANKL mRNA expression in osteoblasts, and inhibited osteoclastogenesis in the cocultures treated with LPS. LPS induced phosphorylation of MEK and ERK in osteoblasts, and this induction was inhibited by calcium/PKC inhibitors. In addition, PD98059 and NS398 inhibited interleukin 1 (IL-1)-induced osteoclastogenesis in the cocultures, but only PD98059 suppressed RANKL mRNA expression induced by IL-1 in osteoblasts. These results suggest that LPS and IL-1 similarly promote osteoclastogenesis through two parallel events : enhancement of RANKL expression through calcium/PKC signals followed by MEK/ERK signals, and suppression of OPG production mediated by PGE_2.

Report

(2 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • Research Products

    (23 results)

All Other

All Publications (23 results)

  • [Publications] Kotake S, Udagawa N, Hakoda M, Mogi M, Yano K, Tsuda E, Takahashi K, Furuya T, Ishiyama S, Kim KJ, Saito S, Nishikawa T, Takahashi N, Togari A, Tomatsu T, Suda T, Kamatani N: "Activated human T cells directly induce osteoclastogenesis from human monocytes : possible role of T cells in bone destruction in rheumatoid arthritis patients"Arthritis Rheum. 44. 1003-1012 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Itoh K, Udagawa N, Katagiri T, Iemura S, Ueno N, Yasuda H, Higashio K, Quinn JMW, Gillespie MT, Martin TJ, Suda T, Takahashi N.: "Bone morphogenetic protein 2 stimulates osteoclast differentiation and survival supported by receptor activator of nuclear factor-kB ligand"Endocrinology. 142. 3656-3662 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Quinn JM, Itoh K, Udagawa N, Hausler K, Yasuda H, Shima N, Mizuno A, Higashio K, Takahashi N, Suda T, Martin TJ, Gillespie MT: "Transforming growth factor b effects on osteoclast differentiation via direct and indirect actions"J. Bone Miner. Res.. 16. 1787-1794 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yanai T, Katagiri T, Akiyama S, Imada M, Yamashita T, Chiba H, Takahashi N, Suda T: "Expression of mouse osteocalcin transcripts, OG1 and OG2, is differently regulated in bone tissues and osteoblast cultures"J. Bone Mineral Metab.. 19. 345-351 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Katagiri T, Takahashi N: "Regulatory mechanisms of osteoblast and osteoclast differentiation"Oral Diseases. (in press). (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Takahashi N, Udagawa N, Suda T: "Principles of Bone Biology, ed by Raisz LG, Rodan GA, Bilezikian JP [Cells of bone : Osteoclast generation]"Academic Press. 1695(109-126) (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kotake, S. et al.: "Activated human T cells directly induce osteoclastogenesis from human monocytes : possible role of T celIs in bone destruction in rheumatoid arthritis patients."Arthritis Rheum. 44. 1003-1012 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Quinn, J.M.W. et al.: "Transforming growth factor-β affects osteoclast differentiation via direct and indirect actions."J. Bone Miner. Res.. 16. 1787-1794 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Itoh, K. et al.: "Bone morphogenetic protein 2 stimulates osteoclast differentiation and survival supported by receptor activator of nuclear factor-κB ligand."Endocrinology. 142. 3656-3662 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Murase, Y. et al.: "Possible involvement of protein kinases and Smad2 signaling pathways on osteoclast differentiation enhanced by activin A."J. Cell. Physiol.. 188. 236-242 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kim, K.J. et al.: "Osteoprotegerin inhibits in vitro mouse osteoclast formation induced by joint fluid from failed total hip arthroplasty."J. Biomed Master Res.. 58. 393-400 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Suda, N. et al.: "Parathyroid hormone-related protein is required for normal intramembranous bone development."J. Bone Miner. Res.. 16. 2182-2191 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Wang. X. et al.: "Effects of geranylgeranoic acid in bone : induction of osteoblast differentiation and inhibition of osteoclast formation."J. Bone Miner. Res.. 17. 91-100 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Takahashi, N. et al.: "Cells of bone : osteoclast generation."Principles of Bone Biology, Second Edition, Volume 1, eds. Billezikian, J.P., Raisz, LG., Rodan. G. A. Academic press. 109-126 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Udagawa, N. et al.: "The molecular mechanism of osteoclastogenesis in rheumatoid arthritis"Arthritis Res.. (in press). (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Udagawa, N.: "Mechanisms involved in bone resorption."Biogerontology. (in press). (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Takahashi, N. et al.: "Generation of murine osteoclasts from bone marrow."Bone Res. Protocols. (in press). (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kotake S, Udagawa N, Hakoda M, Mogi M, Yano K, Tsuda E, Takahashi K, Furuya T, Ishiyama S, Kim KJ, Saito S, Nishikawa T, Takahashi N, Togari A, Tomatsu T, Suda T, Kamatani N: "Activated human T cells directly induce osteoclastogenesis from human monocytes : possible role of T cells in bone destruction in rheumatoid arthritis patients"Arthritis Rheum. 44. 1003-1012 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Itoh K, Udagawa N, Katagiri T, Iemura S, Ueno N, Yasuda H, Higashio K, Quinn JMW, Gillespie MT, Martin TJ, Suda T, Takahashi N.: "Bone morphogenetic protein 2 stimulates osteoclast differentiation and survival supported by receptor activator of nuclear factor-kB ligand"Endocrinology. 142. 3656-3662 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Quinn JM, Itoh K, Udagawa N, Hausler K, Yasuda H, Shima N, Mizuno A, Higashio K, Takahashi N, Suda T, Martin TJ, Gillespie MT: "Transforming growth factor b effects on osteoclast differentiation via direct and indirect actions"J. Bone Miner. Res.. 16. 1787-1794 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yanai T, Katagiri T, Akiyama S, Imada M, Yamashita T, Chiba H, Takahashi N. Suda T: "Expression of mouse osteocalcin transcripts, OG1 and OG2, is differently regulated in bone tissues and osteoblast cultures"J. Bone Mineral Metab.. 19. 345-351 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Katagiri T, Takahashi N:, , 2002: "Regulatory mechanisms of osteoblast and osteoclast differentiation"Oral Diseases. (in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Takahashi N, Udagawa N, Takami N, Suda T: "Principles of Bone Biology, ed by Raisz LG, Rodan GA, Bilezikian JP [Cells of bone : Osteoclast generation. pp109-126]"Academic Press. 1695 (2002)

    • Related Report
      2001 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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