한빛사논문
전남대학교 치과대학, University of Pennsylvania Perelman School of Medicine
Abstract
Hyunsoo Kim1, 8, Taesoo Kim3, 8, Byung-Chul Jeong1, 4, 8, Il-Taeg Cho1, Daehee Han1, Noriko Takegahara1, Takako Negishi-Koga5, Hiroshi Takayanagi5, Jae Hee Lee2, Jai-Yoon Sul2, Vikram Prasad6, Seoung Hoon Lee7, Yongwon Choi1,*
1 Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
2 Department of Pharmacology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
3 TKM-Based Herbal Drug Research Group, Korea Institute of Oriental Medicine, Daejeon 305-811, Korea
4 Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University, Gwangju 500-757, Korea
5 Department of Cell Signaling, Tokyo Medical and Dental University, Tokyo 113-8549, Japan
6 Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
7 Departments of Oral Microbiology and Immunology, Wonkwang University School of Dentistry, Iksan 570-749, Korea
8 These authors contributed equally to this work
*Corresponding author : Yongwon Choi
Summary
Osteoclast maturation and function primarily depend on receptor activator of NF-κB ligand (RANKL)-mediated induction of nuclear factor of activated T cells c1 (NFATc1), which is further activated via increased intracellular calcium ([Ca2+]i) oscillation. However, the coordination mechanism that mediates Ca2+ oscillation during osteoclastogenesis remains ill defined. Here, we identified transmembrane protein 64 (Tmem64) as a regulator of Ca2+ oscillation during osteoclastogenesis. We found that Tmem64-deficient mice exhibit increased bone mass due in part to impaired osteoclast formation. Using in vitro osteoclast culture systems, we show here that Tmem64 interacts with sarcoplasmic endoplasmic reticulum Ca2+ ATPase 2 (SERCA2) and modulates its activity. Consequently, Tmem64 deficiency significantly diminishes RANKL-induced [Ca2+]i oscillation, which results in reduced Ca2+/calmodulin-dependent protein kinases (CaMK) IV and mitochondrial ROS, both of which contribute to achieving the CREB activity necessary for osteoclast formation. These data demonstrate that Tmem64 is a positive modulator of osteoclast differentiation via SERCA2-dependent Ca2+ signaling.
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