The phosphatidylinositol 3-kinase, p38, and extracellular signal-regulated kinase pathways are involved in osteoclast differentiation

Bone. 2002 Jan;30(1):71-7. doi: 10.1016/s8756-3282(01)00657-3.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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


  • Carrier Proteins
  • Chromones
  • Enzyme Inhibitors
  • Flavonoids
  • Imidazoles
  • Membrane Glycoproteins
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • Pyridines
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • TNFRSF11A protein, human
  • TNFSF11 protein, human
  • Tnfrsf11a protein, mouse
  • Tnfsf11 protein, mouse
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Macrophage Colony-Stimulating Factor
  • Protein-Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 1
  • MAP2K1 protein, human
  • Map2k1 protein, mouse
  • Mitogen-Activated Protein Kinase Kinases
  • 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one