title: Tmem64 modulates calcium signaling during RANKL-mediated osteoclast differentiation.
abstract: 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 ([Ca(2+)](i)) oscillation. However, the coordination mechanism that mediates Ca(2+) oscillation during osteoclastogenesis remains ill defined. Here, we identified transmembrane protein 64 (Tmem64) as a regulator of Ca(2+) 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 Ca(2+) ATPase 2 (SERCA2) and modulates its activity. Consequently, Tmem64 deficiency significantly diminishes RANKL-induced [Ca(2+)](i) oscillation, which results in reduced Ca(2+)/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 Ca(2+) signaling.
authors: Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors: Hyunsoo
authors: H
authors: Kim
authors: Taesoo
authors: T
authors: Kim
authors: Byung-Chul
authors: BC
authors: Jeong
authors: Il-Taeg
authors: IT
authors: Cho
authors: Daehee
authors: D
authors: Han
authors: Noriko
authors: N
authors: Takegahara
authors: Takako
authors: T
authors: Negishi-Koga
authors: Hiroshi
authors: H
authors: Takayanagi
authors: Jae Hee
authors: JH
authors: Lee
authors: Jai-Yoon
authors: JY
authors: Sul
authors: Vikram
authors: V
authors: Prasad
authors: Seoung Hoon
authors: SH
authors: Lee
authors: Yongwon
authors: Y
authors: Choi
mesh_terms: D000818:Animals; D015519:Bone Density / Q000187:drug effects; D001842:Bone and Bones / Q000033:anatomy & histology / Q000187:drug effects; D020013:Calcium Signaling / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017353:Gene Deletion; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D009929:Organ Size / Q000187:drug effects; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D053245:RANK Ligand / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D008565:Membrane Proteins; D053245:RANK Ligand; D017382:Reactive Oxygen Species; C583521:Tmem64 protein, mouse; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506947:Atp2a2 protein, mouse
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