Tmem64 modulates calcium signaling during RANKL-mediated osteoclast differentiation

Cell Metab. 2013 Feb 5;17(2):249-60. doi: 10.1016/j.cmet.2013.01.002.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Density / drug effects
  • Bone and Bones / anatomy & histology
  • Bone and Bones / drug effects
  • Calcium Signaling / drug effects*
  • Cell Differentiation / drug effects*
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Gene Deletion
  • HEK293 Cells
  • Humans
  • Male
  • Membrane Proteins / chemistry
  • Membrane Proteins / deficiency
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Models, Biological
  • Organ Size / drug effects
  • Osteoclasts / cytology*
  • Osteoclasts / drug effects
  • Osteoclasts / metabolism*
  • Osteogenesis / drug effects
  • Phosphorylation / drug effects
  • RANK Ligand / pharmacology*
  • Reactive Oxygen Species / metabolism
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism

Substances

  • Cyclic AMP Response Element-Binding Protein
  • Membrane Proteins
  • RANK Ligand
  • Reactive Oxygen Species
  • Tmem64 protein, mouse
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Atp2a2 protein, mouse