RRC ID 41484
Author Lee SE, Woo KM, Kim SY, Kim HM, Kwack K, Lee ZH, Kim HH.
Title The phosphatidylinositol 3-kinase, p38, and extracellular signal-regulated kinase pathways are involved in osteoclast differentiation.
Journal Bone
Abstract Phosphatidylinositol 3-kinase (PI 3-kinase) and mitogen-activated protein kinases (MAPKs) have been implicated in diverse cellular functions, including proliferation, migration, and survival. In this study, we examined the involvement of these kinases in osteoclast differentiation by employing specific inhibitors of the kinases. The osteoclast differentiation was assessed in three different culture systems: a coculture of mouse bone marrow cells with mouse calvarial osteoblasts, a mouse bone marrow cell culture in the presence of receptor activator of NF-kappaB ligand (RANKL) and macrophage-colony stimulating factor (M-CSF), and a culture of bone-resident osteoclast precursor cells driven by RANKL and M-CSF. LY294002, a specific inhibitor of PI 3-kinase, potently inhibited osteoclast differentiation in all culture systems when assessed by both tartrate-resistant acid phosphatase (TRAP) staining and dentine resorption assays. Inhibition of p38 MAPK by SB202190 resulted in a strong suppression in the exogenous RANKL dependent mouse bone marrow and bone resident precursor cell cultures. Another MAPK pathway inhibitor (PD98059), which blocks the activation of extracellular signal-regulated kinase (ERK) by inhibiting the upstream kinase MAPK-ERK kinase (MEK) 1, exerted an inhibitory effect on osteoclast differentiation only at the highest concentration tested (30 micromol/L) in many cases. Whether the signaling pathways involving these kinases are activated by RANKL was also examined. The RANKL-stimulated phosphorylation of Akt, a downstream target of PI 3-kinase, and that of ERK were observed. RANKL also stimulated the activity of p38. These results suggest that PI 3 kinase, p38, and ERK play roles in osteoclast differentiation, at least in part, by participating in RANKL signaling.
Volume 30(1)
Pages 71-7
Published 2002-1-1
DOI 10.1016/s8756-3282(01)00657-3
PII S8756328201006573
PMID 11792567
MeSH Animals Carrier Proteins / metabolism Cell Differentiation / drug effects Cell Line Chromones / pharmacology Coculture Techniques Enzyme Inhibitors / pharmacology Flavonoids / pharmacology Humans Imidazoles / pharmacology MAP Kinase Kinase 1 Macrophage Colony-Stimulating Factor / pharmacology Membrane Glycoproteins / metabolism Mice Mice, Inbred ICR Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors Mitogen-Activated Protein Kinase Kinases / metabolism Mitogen-Activated Protein Kinases / antagonists & inhibitors Mitogen-Activated Protein Kinases / metabolism* Morpholines / pharmacology Osteoblasts / cytology Osteoclasts / cytology* Osteoclasts / drug effects Osteoclasts / metabolism Phosphatidylinositol 3-Kinases / metabolism* Phosphoinositide-3 Kinase Inhibitors Protein-Serine-Threonine Kinases / antagonists & inhibitors Protein-Serine-Threonine Kinases / metabolism Pyridines / pharmacology RANK Ligand Receptor Activator of Nuclear Factor-kappa B Signal Transduction Stem Cells / cytology Stem Cells / drug effects Stem Cells / metabolism p38 Mitogen-Activated Protein Kinases
IF 4.36
Times Cited 228
Human and Animal Cells