Activation of p38 and Smads mediates BMP-2 effects on human trabecular bone-derived osteoblasts

Exp Cell Res. 2003 Nov 15;291(1):201-11. doi: 10.1016/s0014-4827(03)00386-0.


The bone morphogenetic proteins (BMPs) are potent osteoinductive factors that accelerate osteoblast maturation, accompanied by increased cell-substrate adhesion. BMP-2 treatment of osteoblastic cells increases phosphorylation of the cytoplasmic BMP-2 signaling molecules, Smad1 and Smad5. We have previously reported that BMP-2 treatment increase cytoskeletal organization of human trabecular bone-derived osteoblast-like cells (osteoblasts), which is also accompanied by an activation of the focal adhesion kinase p125(FAK). We report here that activation of p125(FAK) occurs with the same kinetics as the phosphorylation of Smad1, suggesting that BMP-2 initiates cross-talk between Smad signaling and the adhesion-mediated signaling pathway. As an adjunct to these effects, we examined activation of mitogen-activated protein (MAP) kinase family members in response to focal adhesion contact formation. Although phosphorylated forms of all three kinases were apparent, only SAPK2alpha/p38 (p38) was activated in response to BMP-2 treatment. Inhibition of p38 kinase activity suppressed BMP-2 induced Smad1 phosphorylation, as well as its translocation to the nucleus, suggesting the integration of p38 activation with Smad1 signaling. Finally, inhibition of p38 in osteoblasts also led to the complete abrogation of BMP-2 induced osteocalcin gene expression and matrix mineralization. These findings suggest that BMP-2 must activate p38 in order to mediate osteogenic differentiation and maturation.

Publication types

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

MeSH terms

  • Bone Density / drug effects
  • Bone Density / genetics
  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Proteins / metabolism*
  • Bone Morphogenetic Proteins / pharmacology
  • Bone and Bones / cytology
  • Bone and Bones / drug effects
  • Bone and Bones / enzymology*
  • Cell Adhesion / drug effects
  • Cell Adhesion / physiology
  • Cell Differentiation / drug effects
  • Cell Differentiation / genetics
  • Cells, Cultured
  • DNA-Binding Proteins / drug effects
  • DNA-Binding Proteins / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Focal Adhesion Kinase 1
  • Focal Adhesion Protein-Tyrosine Kinases
  • Humans
  • Imidazoles / pharmacology
  • Mitogen-Activated Protein Kinases / drug effects
  • Mitogen-Activated Protein Kinases / metabolism*
  • Osteoblasts / drug effects
  • Osteoblasts / enzymology*
  • Osteocalcin / biosynthesis
  • Osteocalcin / genetics
  • Osteogenesis / drug effects
  • Osteogenesis / physiology
  • Phosphorylation / drug effects
  • Protein-Tyrosine Kinases / drug effects
  • Protein-Tyrosine Kinases / metabolism
  • Pyridines / pharmacology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Smad Proteins
  • Smad1 Protein
  • Trans-Activators / drug effects
  • Trans-Activators / metabolism*
  • Transforming Growth Factor beta*
  • p38 Mitogen-Activated Protein Kinases


  • BMP2 protein, human
  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Proteins
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Imidazoles
  • Pyridines
  • SMAD1 protein, human
  • Smad Proteins
  • Smad1 Protein
  • Trans-Activators
  • Transforming Growth Factor beta
  • Osteocalcin
  • Protein-Tyrosine Kinases
  • Focal Adhesion Kinase 1
  • Focal Adhesion Protein-Tyrosine Kinases
  • PTK2 protein, human
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • SB 203580