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2011 Fiscal Year Final Research Report

Analysis of acid extrusion mechanism through new regulatory protein during bone resorption

Research Project

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Project/Area Number 21592381
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Functional basic dentistry
Research InstitutionFukuoka Dental College

Principal Investigator

KAJIYA Hiroshi  福岡歯科大学, 歯学部, 講師 (80177378)

Co-Investigator(Kenkyū-buntansha) OKAMOTO Fujio  福岡歯科大学, 歯学部, 講師 (60153938)
OKABE Kouji  福岡歯科大学, 歯学部, 教授 (80224046)
Project Period (FY) 2009 – 2011
Keywords骨代謝 / 酸分泌 / Clcn7型Cl-輸送体 / 破骨細胞 / メバロン酸経路
Research Abstract

The Clcn7 transporter is crucial for osteoclastic bone resorption and its deficiency or mutations suppress bone resorption and lead to severe osteopetrosis. Farnesyl diphosphate synthase(Fdps) catalyses the formation of an important cellular intermediate in mevalonic acid metabolism. Furthermore, Fdps is inhibited by nitrogen-containing bisphosphonate in mature osteoclasts. Here we describe a novel role for the enzyme in Clcn7 Cl-transporter activity in osteoclasts. Using yeast two-hybrid and co-immunoprecipitation methods, we demonstrate the binding of Fdps to Clcn7 in mouse osteoclasts and Fdps and Clc7 overexpressing HEK cells. Bisphosphonates have been attributed to directly inhibit bone resorption and to promote apoptosis of mature osteoclasts. Furthermore, the main pharmacological mechanism of nitrogen-containing bisphosphonates is to inhibit Fdps. Thus, we examined the effects of an Fdps inhibitor zoledronic acid on the Clcn7 extrusion activity in osteoclasts. Extracellular acidification induced Cl-currents associated with Clcn7, which were upregulated in according to osteoclast differentiation. Zoledronic acid inhibited the acid-activated Cl-current in dose-dependent manner. In contrast a non-nitrogen bisphosphonate etidronic acid has no effects on the acid-activated Cl-current. The tetracycline-induced Fdps silencing significantly decreased the Cl-current. Furthermore, the Cl-current also suppressed the inhibitor of geranylgeranyl transferase. In contrast, zoledronic inhibitory effect was rescued by the addition geranylgeranyl acid a derivative of mebalonic acid. Although extracellular acidification decreased[Cl-] i zoledronic acid significantly suppressed the decrease in[Cl-] i. The results suggest that nitrogen-containing bisphosphonates not only suppress resorbing osteoclast cytoskeleton structure but also inhibit acid extrusion transporter through inhibition of Fdps in mature osteoclasts.

  • Research Products

    (17 results)

All 2011 2010 2009

All Journal Article (12 results) (of which Peer Reviewed: 12 results) Presentation (5 results)

  • [Journal Article] Effects of oxdative stress on the expression of 8-oxoguanine and its eliminating enzymes in human keratinocytes and squamous carcinoma cells2011

    • Author(s)
      Nakayama S, Kajiya H, Okabe K, Ikebe T
    • Journal Title

      Oral Science Inter

      Volume: 8 Pages: 11-16

    • Peer Reviewed
  • [Journal Article] Hyperocclusion stimulated osteoclastogenesis via CCL2 expression2011

    • Author(s)
      Goto-T K, Kajiya H, Nemoto T, Tsutumi T, Tsuzuki T, Sato H, Okabe K
    • Journal Title

      J Dent Res

      Volume: 90 Pages: 793-798

    • Peer Reviewed
  • [Journal Article] Zoledronic acid inhibits RANK expression and migration of osteoclast precursors during osteoclastogenesis2011

    • Author(s)
      Kimachi K, Kajiya H, Nakayama S, Ikebe T, Okabe K
    • Journal Title

      Naunyn Schmiedebergs

      Volume: 383 Pages: 297-308

    • Peer Reviewed
  • [Journal Article] Oral Epithelial Cells are Activated via TRP Channels2011

    • Author(s)
      Wang B, Danjo A, Kajiya H, Okabe K, Kido MA
    • Journal Title

      J Dent Res

      Volume: 90 Pages: 163.-167

    • Peer Reviewed
  • [Journal Article] Antibodies against ClC7 inhibit extracellular acidification-induced Cl-currents and bone resorption activity in mouse osteoclasts2011

    • Author(s)
      Ohgi K, Okamoto F, Kajiya H, Sakagami R, Okabe K
    • Journal Title

      Naunyn Schmiedebergs

      Volume: 383 Pages: 79-90

    • Peer Reviewed
  • [Journal Article] Pro-inflammatory cytokines induce suppressor of cytokine signaling-3 in human periodontal ligament cells2011

    • Author(s)
      Fukushima A, Kajiya H, Izumi T, Shigeyama C, Okabe K, Anan H
    • Journal Title

      J Endod

      Volume: 36 Pages: 1004-1008

    • Peer Reviewed
  • [Journal Article] Ca^<2+> extrusion via Na^+-Ca^<2+> exchangers in rat odontoblasts2011

    • Author(s)
      Tsumura M, Okumura R, Tatsuyama S, Ichikawa H, Muramatsu T, Matsuda T, Baba A, Suzuki K, Kajiya H, Sahara Y, Tokuda M, Momose Y, Tazaki M, Shimono M, Shibukawa Y
    • Journal Title

      J Endod

      Volume: 36 Pages: 668-674

    • Peer Reviewed
  • [Journal Article] PTHrP induces Notch signaling in periodontal ligament cells2011

    • Author(s)
      Nakao A, Kajiya H, Fukushima H, Fukushima A, Anan H, Ozeki S, Okabe K
    • Journal Title

      J Dent Res

      Volume: 88 Pages: 551-556

    • Peer Reviewed
  • [Journal Article] Oral squamous cell carcinoma cells modulate osteoclast function by RANKL-dependent and-independent mechanisms2011

    • Author(s)
      Tada T, Shin M, Fukushima H, Okabe K, Ozeki S, Okamoto M, Jimi E.
    • Journal Title

      Cancer Letters

      Volume: 274 Pages: 126-13

    • Peer Reviewed
  • [Journal Article] RANKL-induced TRPV2 expression regulates osteoclastogenesisvia calcium oscillations2010

    • Author(s)
      Kajiya H, Okamoto F, Nemoto T, Kimachi K, Toh-Goto K, Nakayana S, Okabe K
    • Journal Title

      Cell Calcium

      Volume: 48 Pages: 260-269

    • Peer Reviewed
  • [Journal Article] Differential induction of collagens by mechanical stress in human periodontal ligament cells2010

    • Author(s)
      Nemoto T, Kajiya H, Tsuzuki T, Takahashi Y, Okabe K
    • Journal Title

      Arch Oral Biol

      Volume: 55 Pages: 981-987

    • Peer Reviewed
  • [Journal Article] Characteristics of ClC7 Cl-channels and their inhibition in mutant(G215R) associated with autosomal dominant osteopetrosis type II in native osteoclasts and hClcn7 gene-expressing cells2009

    • Author(s)
      Kajiya H, Okamoto F, Ohgi K, Nakao A, Fukushima H, Okabe K
    • Journal Title

      Pflugers Arch

      Volume: 458 Pages: 1049-1059

    • Peer Reviewed
  • [Presentation] Zoledronic acid inhibits TNF-a-induced RANK expression and migration in osteoclast precursors2010

    • Author(s)
      Kajiya H, Kimachi K, Nakayama S, Okamoto F, Ikebe T, Okabe K
    • Organizer
      第32回米国骨代謝学会
    • Place of Presentation
      Toronto, Canada
    • Year and Date
      2010-11-16
  • [Presentation] Hyper-occlusion stimulated osteoclast recruitment through chemokines expression2010

    • Author(s)
      Goto-T K, Kajiya H, Nemoto N, Tsuzuki T, Okabe K, Sato H
    • Organizer
      第32回米国骨代謝学会
    • Place of Presentation
      Toronto, Canada
    • Year and Date
      2010-10-16
  • [Presentation] Hyperocclusion Stimulates Collagen type XII in periodontal ligament2010

    • Author(s)
      Tsuzuki-T, Kajiya H, Goto-T K, Nemoto T, Okabe K Takahashi H
    • Organizer
      第32回米国骨代謝学会
    • Place of Presentation
      Toronto, Canada
    • Year and Date
      2010-10-16
  • [Presentation] RANKL-induced expression of transient receptor potential(TRP) V2 is involved in osteoclastogenesis via calcium oscillations2009

    • Author(s)
      Kajiya H, Okamoto F, Okabe K
    • Organizer
      36th International Congress of Physiological Sciences(IUPS2009)
    • Place of Presentation
      Kyoto
    • Year and Date
      20090727-0801
  • [Presentation] Charactaristics of acid-activated outwardly rectifying Cl-channels in mouse osteoclasts2009

    • Author(s)
      Ohgi K, Okamoto F, Nemoto T, Kajiya H, Sakagami R, Okabe K.
    • Organizer
      36th International Congress of Physiological Sciences(IUPS2009)
    • Place of Presentation
      Kyoto
    • Year and Date
      20090727-0801

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Published: 2013-07-31  

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