Defective microtubule-dependent podosome organization in osteoclasts leads to increased bone density in Pyk2(-/-) mice

J Cell Biol. 2007 Sep 10;178(6):1053-64. doi: 10.1083/jcb.200701148.

Abstract

The protein tyrosine kinase Pyk2 is highly expressed in osteoclasts, where it is primarily localized in podosomes. Deletion of Pyk2 in mice leads to mild osteopetrosis due to impairment in osteoclast function. Pyk2-null osteoclasts were unable to transform podosome clusters into a podosome belt at the cell periphery; instead of a sealing zone only small actin rings were formed, resulting in impaired bone resorption. Furthermore, in Pyk2-null osteoclasts, Rho activity was enhanced while microtubule acetylation and stability were significantly reduced. Rescue experiments by ectopic expression of wild-type or a variety of Pyk2 mutants in osteoclasts from Pyk2(-/-) mice have shown that the FAT domain of Pyk2 is essential for podosome belt and sealing zone formation as well as for bone resorption. These experiments underscore an important role of Pyk2 in microtubule-dependent podosome organization, bone resorption, and other osteoclast functions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Density / physiology*
  • Bone Resorption / metabolism
  • Bone Resorption / pathology
  • Cells, Cultured
  • Focal Adhesion Kinase 2 / genetics
  • Focal Adhesion Kinase 2 / metabolism*
  • Mice
  • Mice, Knockout
  • Microtubules / metabolism*
  • Osteoclasts / metabolism
  • Osteoclasts / ultrastructure*
  • Osteopetrosis / metabolism
  • Osteopetrosis / pathology
  • Signal Transduction
  • rho GTP-Binding Proteins / metabolism

Substances

  • Focal Adhesion Kinase 2
  • Ptk2b protein, mouse
  • rho GTP-Binding Proteins