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

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K20412
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Morphological basic dentistry
• Research Institution: Ehime University
• Principal Investigator: LEE JIWON 愛媛大学, プロテオサイエンスセンター, 助教(特定教員) (70711274)
• Research Collaborator: Iimura Tadahiro
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: osteoclast / osteoblast / chemokine receptor 5 / bone metabolism

Outline of Final Research Achievements

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 kappa-B 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 experimentally provides further evidence that CCR5 plays an essential role in bone destructive diseases through the functional regulation of osteoclasts, thus suggesting a skeletal benefit of the CCR5-targeting therapy.

Free Research Field

骨代謝・細胞生物学

Academic Significance and Societal Importance of the Research Achievements

HIV感染治療薬の標的分子であるCCR5が骨の代謝も調節していることを解明した。抗CCR5治療薬はHIV感染患者の延命に大きく貢献しますが、高齢化に伴う運動器疾患への影響が懸念されていた。今回の研究でCCR5が骨を吸収する破骨細胞にも存在し、CCR5の機能抑制は破骨細胞の骨吸収能を抑えることを解明した。さらに、動物実験では、CCR5の機能抑制が骨粗鬆症を抑えることを発見された。これらの実験観察は、抗CCR5治療薬はHIV感染症のみならず、骨粗鬆症を始めとする骨吸収性疾患に対してもメリットをもたらす可能性を明らかにした。