Secretion of L-glutamate from osteoclasts through transcytosis

EMBO J. 2006 Sep 20;25(18):4175-86. doi: 10.1038/sj.emboj.7601317. Epub 2006 Sep 7.


Osteoclasts are involved in the catabolism of the bone matrix and eliminate the resulting degradation products through transcytosis, but the molecular mechanism and regulation of transcytosis remain poorly understood. Upon differentiation, osteoclasts express vesicular glutamate transporter 1 (VGLUT1), which is essential for vesicular storage and subsequent exocytosis of glutamate in neurons. VGLUT1 is localized in transcytotic vesicles and accumulates L-glutamate. Osteoclasts secrete L-glutamate and the bone degradation products upon stimulation with KCl or ATP in a Ca2+-dependent manner. KCl- and ATP-dependent secretion of L-glutamate was absent in osteoclasts prepared from VGLUT1-/- knockout mice. Osteoclasts express mGluR8, a class III metabotropic glutamate receptor. Its stimulation by a specific agonist inhibits secretion of L-glutamate and bone degradation products, whereas its suppression by a specific antagonist stimulates bone resorption. Finally, it was found that VGLUT1-/- mice develop osteoporosis. Thus, in bone-resorbing osteoclasts, L-glutamate and bone degradation products are secreted through transcytosis and the released L-glutamate is involved in autoregulation of transcytosis. Glutamate signaling may play an important role in the bone homeostasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • Bone Resorption / metabolism
  • Cell Line
  • Cells, Cultured
  • Exocytosis / physiology*
  • Glutamic Acid / metabolism*
  • Homeostasis
  • In Vitro Techniques
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Immunoelectron
  • Models, Biological
  • Osteoclasts / metabolism*
  • Osteoclasts / ultrastructure
  • Receptors, Metabotropic Glutamate / agonists
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors
  • Receptors, Metabotropic Glutamate / metabolism
  • Signal Transduction
  • Vesicular Glutamate Transport Protein 1 / deficiency
  • Vesicular Glutamate Transport Protein 1 / genetics


  • Receptors, Metabotropic Glutamate
  • Slc17a7 protein, mouse
  • Vesicular Glutamate Transport Protein 1
  • metabotropic glutamate receptor 8
  • Glutamic Acid