A transmembrane osteoclastic protein-tyrosine phosphatase regulates osteoclast activity in part by promoting osteoclast survival through c-Src-dependent activation of NFkappaB and JNK2

Arch Biochem Biophys. 2007 Jul 1;463(1):47-59. doi: 10.1016/j.abb.2007.02.025. Epub 2007 Mar 15.

Abstract

This study evaluated the effects of overexpression of wild-type (WT) or phosphatase-deficient (PD) mutant of an osteoclastic protein-tyrosine phosphatase (PTP-oc) in RAW/C4 cells. Osteoclast-like cells derived from WT-PTP-oc overexpressing clones increased, while those derived from PD-PTP-oc expressing clones decreased, their resorption activity. WT-PTP-oc clones had lower apoptosis, lower caspase 3/7 activity, reduced c-Src tyr-527 phosphorylation (PY527) and IkappaBalpha cellular levels, and increased NFkappaB activation and JNK phosphorylation. Overexpression of PD-PTP-oc or PTP-oc siRNA treatment increased apoptosis, caspase 3/7 activity, PY527 and IkappaBalpha levels, and decreased NFkappaB and JNK2 activation. Inhibition of the c-Src kinase blocked the PTP-oc-mediated NFkappaB and JNK2 activation. Blocking the NFkappaB activation had no effect on the JNK2 activation. Inhibiting the NFkappaB and/or JNK2 pathway prevented the PTP-oc-mediated reduction in apoptosis. In conclusion, PTP-oc activates osteoclast activity in part by promoting osteoclast survival through the PTP-oc-mediated c-Src-dependent activation of NFkappaB and JNK2.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Bone Resorption / physiopathology
  • Cell Differentiation
  • Cell Survival / physiology*
  • Mice
  • Mitogen-Activated Protein Kinase 9 / physiology*
  • NF-kappa B / physiology*
  • Osteoclasts / physiology*
  • Phosphotyrosine / metabolism
  • Protein Tyrosine Phosphatases / physiology*
  • Proto-Oncogene Proteins pp60(c-src) / physiology*
  • RNA, Small Interfering / pharmacology

Substances

  • NF-kappa B
  • RNA, Small Interfering
  • Phosphotyrosine
  • Mitogen-Activated Protein Kinase 9
  • Proto-Oncogene Proteins pp60(c-src)
  • Protein Tyrosine Phosphatases