A transmembrane osteoclastic protein-tyrosine phosphatase regulates osteoclast activity in part by promoting osteoclast survival through c-Src-dependent activation of NFkappaB and JNK2.
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.
Amoui
Mehran
M
The Musculoskeletal Disease Center, Jerry L. Pettis Memorial VA Medical Center, 11201 Benton Street, Loma Linda, CA 92357, USA.
Sheng
Matilda H-C
MH
Chen
Shin-Tai
ST
Baylink
David J
DJ
Lau
K-H William
KH
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001862:Bone Resorption / Q000503:physiopathology; D002454:Cell Differentiation; D002470:Cell Survival / Q000502:physiology*; D051379:Mice; D048056:Mitogen-Activated Protein Kinase 9 / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology*; D010010:Osteoclasts / Q000502:physiology*; D019000:Phosphotyrosine / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000502:physiology*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology
D016328:NF-kappa B; D034741:RNA, Small Interfering; D019000:Phosphotyrosine; D048056:Mitogen-Activated Protein Kinase 9; D016392:Proto-Oncogene Proteins pp60(c-src); D017027:Protein Tyrosine Phosphatases