Morphometrical and quantitative transcriptome analyses of C-C chemokine receptor 5 in functional structure of osteoclasts

2018 Fiscal Year Annual Research Report

• Project/Area Number: 16K20412
• 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(特定教員) (70711274)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: chemokine / osteoclast / bone / CCR5 / RANKL

Outline of Annual Research Achievements

C-C chemokine receptor (CCR5) is a critical co-receptor for macrophage-tropic HIV, and Maraviroc, an inhibitor against CCR5, has significantly increased the lifespan of patients with HIV infection through blocking HIV transmission. Simultaneously age-related comorbidities including bone diseases have been needed to prevent in patients with HIV. Epidermiological and pathological findings in human studies reported that functional loss in CCR5 were correlated with the resistance to bone destruction diseases such as rheumatoid arthritis and osteoporosis. This possible association between loss of CCR5 and resistance to bone loss has been largely interpreted by the changes in the inflammatory and immunomodulatory responses caused by functional loss of CCR5 in bone metabolism have not been experimentally well documented. This study demonstrated that the blockade of CCR5 using its specific antibodies impaired in vitro human osteoclastogenesis with disorganized actin rings, but not osteoblastogenesis. Ccr5-deficient mice with dysfunctional osteoclasts were resistant to osteoporotic stimulation via the administration of receptor activator of nuclear factor kappaB ligand (RANKL), which induces osteoporosis independently of the inflammatory and immunomodulatory responses. Furthermore, CCL5, a ligand for CCR5, enhanced the integrin- and chemokine-mediated pathways in osteoclast. The present study experimental provides through the functional regulation of osteoclasts, thus suggesting a skeletal benefit of the CCr5-targeting therapy.

Research Products

• [Journal Article] PV1, a novel Plasmodium falciparum merozoite dense granule protein, interacts with exported protein in infected erythrocytes. (2018)
  • Author(s): Morita M, Nagaoka H, Ntege E, Kanoi B, Ito D, Nalata T, Lee JW, Tokunaga T, Torii M, Tsuboi T, Takashima E.
  • Journal Title: Scientific Reports Volume: 8 Pages: 3696
  • DOI: 10.1038/s41598-018-22026-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Harmine promotes molar root development via SMAD1/5/8 phosphorylation. (2018)
  • Author(s): Fujiwara N, Lee JW, Kumakami-Sakano M, Otsu K, Woo JT, Iseki S, Ota MS.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 497 Pages: 924-929
  • DOI: 10.1016/j.bbrc.2017.12.062
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Uhrf1 is indispensable for normal limb growth by regulating chondrocyte differentiation through specific gene expression. (2018)
  • Author(s): Yamashita M, Inoue K, Saeki N, Ideta-Otsuka M, Yanagihara Y, Sawada Y, Sakakibara I, Lee JW, Ichikawa K, Kamei Y, Iimura T, Imai Y.
  • Journal Title: Development Volume: 145 Pages: 157412
  • DOI: 10.1242/dev.157412
  • Peer Reviewed / Int'l Joint Research
• [Presentation] HIV, co-receptor, CCR5 plays an essential role in bone-destructive conditions through the functional regulation of osteoclast (2018)
  • Author(s): Lee JW
  • Organizer: The 36th annual meeting of the Japanese society for bone and mineral research
  • Invited
• [Presentation] CCR5, a therapeutic target of HIV infection, is required for osteoclast differentiation and function, suggesting a skeletal merit of the CCR5 targeting HIV therapy. (2018)
  • Author(s): Lee JW
  • Organizer: BioForum@Dental School, Okayama University
  • Invited
• [Presentation] The HIV co-receptor CCR5 regulates cellular pathways required for osteoclast function (2018)
  • Author(s): Lee JW
  • Organizer: The 370th Matsumoto University
  • Invited
• [Presentation] CCR5 is required for osteoclast function through regulating lysosomal vesicle trafficking (2018)
  • Author(s): LEe JW, Iami Y, Iimura T
  • Organizer: Annual meeting of American Society for Bone and Mineral Research, Montreal, Canada
  • Int'l Joint Research