Lyn inhibits osteoclast differentiation by interfering with PLCgamma1-mediated Ca2+ signaling

FEBS Lett. 2009 Apr 2;583(7):1164-70. doi: 10.1016/j.febslet.2009.03.005. Epub 2009 Mar 12.

Abstract

Osteoclasts differentiate from macrophage-lineage cells to become specialized for bone resorption function. By a proteomics approach, we found that Lyn was down-regulated by the osteoclast differentiation factor, receptor activator of NF-kappaB ligand (RANKL). The forced reduction of Lyn caused a striking increase in the RANKL-induced PLCgamma1, Ca(2+), and NFATc1 responses during differentiation. These data suggest that Lyn plays a negative role in osteoclastogenesis by interfering with the PLCgamma1-mediated Ca(2+) signaling that leads to NFATc1 activation. Consistent with the in vitro results, in vivo injection of Lyn specific siRNA into mice calvariae provoked a fulminant bone resorption. Our study provides the first evidence of the involvement of Lyn in the negative regulation of osteoclastogenesis by RANKL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Resorption / genetics
  • Bone Resorption / metabolism
  • Calcium / metabolism
  • Calcium Signaling / drug effects
  • Calcium Signaling / physiology*
  • Cell Differentiation / drug effects
  • Cell Differentiation / physiology*
  • Cell Line
  • Down-Regulation / drug effects
  • Down-Regulation / physiology
  • Humans
  • Mice
  • NFATC Transcription Factors / genetics
  • NFATC Transcription Factors / metabolism
  • Osteoclasts / cytology
  • Osteoclasts / enzymology*
  • Phospholipase C gamma / genetics
  • Phospholipase C gamma / metabolism*
  • Proteomics
  • RANK Ligand / genetics
  • RANK Ligand / metabolism*
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / pharmacology
  • Skull / cytology
  • Skull / metabolism
  • src-Family Kinases / antagonists & inhibitors
  • src-Family Kinases / biosynthesis*

Substances

  • NFATC Transcription Factors
  • Nfatc1 protein, mouse
  • RANK Ligand
  • RNA, Small Interfering
  • Tnfsf11 protein, mouse
  • lyn protein-tyrosine kinase
  • src-Family Kinases
  • Phospholipase C gamma
  • Plcg1 protein, mouse
  • Calcium