Pathophysiological investigation of bone cell communications regulated by chemokine network

2015 Fiscal Year Annual Research Report

• Project/Area Number: 26861549
• Research Institution: Ehime University
• Principal Investigator: 李 智媛 愛媛大学, プロテオサイエンスセンター, 助教(特命教員) (70711274)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Keywords: osteoclast / chemokine / CCR5 / cytoskeleton / RANKL

Outline of Annual Research Achievements

- CCR5 deficiency impairs osteoclast adhesion; Ccr5-deficient osteoclasts showed decreased bone resorption activity accompanied with disorganized cellular architecture and impaired motility. Multimodal and multidimensional super-resolution microscopy facilitates to observe irregular microtubule network and podosome arrangement in Ccr5-/- osteoclasts, suggesting malfunctions for cell polarity, cell adhesion and locomotion. Time-lapse imaging and subsequent numerical analysis of cell deformity index revealed that Ccr5-deficient osteoclasts reduced their stability of attachment to matrix as evidence by abnormal motility.

- CCR5-mediated signals involved in Focal adhesion complex and its downstream signals; Expression of integrins and signaling of FAK-Src complex were markedly reduced in Ccr5-deficient osteoclasts, which was concomitant to reduced activity of small GTPase. CCL5, a major ligand of CCR5, stimulated FAK phosphorylation not Src in wild type osteoclasts. RANKL-induced Src phosphorylation and downstream signals were enhanced by CCL5 stimuli, suggesting a cooperative role of CCR5-mediated signaling with RANKL-mediated signaling pathways. Forced expression of constitutive active forms of Rho and Rac in Ccr5-deficient osteoclasts rescued integrin expression and bone resorption. These findings suggested that CCR5-mediated signaling, with cooperating with RANKL-mediated signaling, regulate small GTPases, and thus cellular architecture and motility of differentiated osteoclasts.

Research Products

• [Journal Article] Quantitative in situ fluorescence imaging to unveil the morphological and functional heterogeneity of osteocytes (2015)
  • Author(s): Lee JW, Iimura T
  • Journal Title: Journal of Oral Biosciences Volume: 57 Pages: 76-79
  • DOI: org/10.1016/j.job.2015.02.001
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Ji-Won Lee, Hoshino Akiyoshi, Saitou Takashi, Inoue Kazuki, Uehara Shunsuke, Kobayashi Yasuhiro, Ueha Satoshi, Matsushima Kouji, Ito Masako, Yamaguchi Akira, Imai Yuuki, Iimura Tadahiro (2015)
  • Author(s): Ji-Won LeeJi-Won Lee, Hoshino Akiyoshi, Saitou Takashi, Inoue Kazuki, Uehara Shunsuke, Kobayashi Yasuhiro, Ueha Satoshi, Matsushima Kouji, Ito Masako, Yamaguchi Akira, Imai Yuuki, Iimura Tadahiro
  • Organizer: the ASBMR 2015 Annual Meeting
  • Place of Presentation: Washington StateConvention Center, Seattle, USA
  • Year and Date: 2015-10-09 – 2015-10-12
  • Int'l Joint Research
• [Presentation] 蛍光細胞イメージングと骨形態計測で見る骨代謝におけるケモカインシグナルの役割 (2015)
  • Author(s): Ji-Won Lee
  • Organizer: 第57回歯科基礎医学会学術大会
  • Place of Presentation: 新潟県新潟市 朱鷺メッセ（新潟コンベンションセンター）
  • Year and Date: 2015-09-11 – 2015-09-12
  • Invited
• [Presentation] Roles of C-C chemokine receptor 5, a co-receptor of HIV, -mediated signal in locomotion of osteoclasts and bone resorption (2015)
  • Author(s): Ji-Won Lee
  • Organizer: 第33回日本骨代謝学会
  • Place of Presentation: 東京都新宿区 京王プラザホテル
  • Year and Date: 2015-07-23 – 2015-07-25
• [Presentation] Roles of CCR5, a co-receptor of HIV, in regulation of functional motility of osteoclasts (2015)
  • Author(s): Ji-Won Lee, Hoshino Akiyoshi, Saitou Takashi, Inoue Kazuki, Uehara Shunsuke, Kobayashi Yasuhiro, Ueha Satoshi, Matsushima Kouji, Ito Masako, Yamaguchi Akira, Imai Yuuki, Iimura Tadahiro
  • Organizer: 第1回日本骨免疫学会
  • Place of Presentation: 沖縄県宮古島市 ホテルブリーズベイマリーナ
  • Year and Date: 2015-06-30 – 2015-07-02