Glutamate suppresses osteoclastogenesis through the cystine/glutamate antiporter

Am J Pathol. 2007 Apr;170(4):1277-90. doi: 10.2353/ajpath.2007.061039.


Previous studies have demonstrated functional expression of different glutamate receptor subtypes (GluRs) in both osteoblasts and osteoclasts. In the present study, we investigated the possible functional expression by osteoclasts of different glutamatergic signaling machineries including GluRs. In disagreement with the aforementioned prevailing view, no mRNA expression was found for all GluRs examined in primary cultured mouse osteoclasts differentiated from bone marrow precursors. Constitutive expression of mRNA was seen with glutamate transporters, such as excitatory amino acid transporters and cystine/glutamate antiporter, in primary osteoclasts. Glutamate significantly inhibited osteoclastogenesis at a concentration over 500 mumol/L in both primary osteoclasts and preosteoclastic RAW264.7 cells without affecting the cell viability in a manner sensitive to the antiporter inhibitor. In RAW264.7 cells stably overexpressing the cystine/glutamate antiporter, the inhibition by glutamate was more conspicuous than in cells transfected with empty vector alone. The systemic administration of glutamate significantly prevented the decreased bone mineral density in both femur and tibia in addition to increased osteoclastic indices in ovariectomized mice in vivo. These results suggest that glutamate may play a pivotal role in mechanisms associated with osteoclastogenesis through the cystine/glutamate antiporter functionally expressed by osteoclasts devoid of any GluRs cloned to date.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport System y+ / genetics
  • Animals
  • Antiporters / genetics
  • Antiporters / metabolism
  • Antiporters / physiology*
  • Bone Density / drug effects
  • Cell Differentiation / drug effects*
  • Cell Line
  • Cells, Cultured
  • Cystine / metabolism
  • Dose-Response Relationship, Drug
  • Excitatory Amino Acid Transporter 3 / genetics
  • Excitatory Amino Acid Transporter 3 / metabolism
  • Gene Expression / drug effects
  • Glutamic Acid / metabolism
  • Glutamic Acid / pharmacology*
  • Luciferases / genetics
  • Luciferases / metabolism
  • Macrophage Colony-Stimulating Factor / pharmacology
  • Male
  • Mice
  • Osteoclasts / cytology
  • Osteoclasts / drug effects*
  • Osteoclasts / metabolism
  • Ovariectomy
  • Promoter Regions, Genetic / genetics
  • Protein Subunits / genetics
  • Protein Subunits / metabolism
  • Protein Subunits / physiology
  • RANK Ligand / pharmacology
  • Receptors, Glutamate / genetics
  • Receptors, Glutamate / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Time Factors
  • Transfection


  • Amino Acid Transport System y+
  • Antiporters
  • Excitatory Amino Acid Transporter 3
  • Protein Subunits
  • RANK Ligand
  • Receptors, Glutamate
  • Slc1a1 protein, mouse
  • Slc7a11 protein, mouse
  • Glutamic Acid
  • Cystine
  • Macrophage Colony-Stimulating Factor
  • Luciferases