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BDNF alters ERK/p38 MAPK activity ratios to promote differentiation in growth plate chondrocytes

Michele R Hutchison1

  • 1Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9063, USA. michele.hutchison@utsouthwestern.edu

Molecular Endocrinology (Baltimore, Md.)
|June 16, 2012
PubMed

Insights

The ERK and p38 MAPK pathways oppositely affect chondrocyte proliferation but are essential for differentiation. BDNF signaling reduces the ERK/p38 ratio, promoting differentiation by p38-dependent raf-1 inhibition.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Skeletal Biology

Background:

  • Extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) pathways regulate cell proliferation and differentiation.
  • The precise roles and interactions of ERK and p38 pathways in growth plate chondrocyte development remain unclear.
  • Conflicting reports exist regarding ERK's role in chondrocyte development.

Purpose of the Study:

  • To elucidate the distinct and interactive roles of ERK and p38 MAPK pathways in growth plate chondrocyte proliferation and differentiation.
  • To investigate the signaling mechanisms by which factors like BDNF and IGF-I modulate these pathways.

Main Methods:

  • Primary bovine growth plate chondrocytes and murine ATDC5 cells were utilized.
  • Analysis of ERK and p38 pathway activity under various stimulation conditions.
  • Investigation of raf-1 inhibition by p38 using purified proteins and cell lysates.

Main Results:

  • ERK and p38 pathways exhibit opposing effects on chondrocyte proliferation but are both critical for differentiation.
  • Brain-derived neurotrophic factor (BDNF) and C-type natriuretic peptide enhance p38 activity while decreasing ERK activity.
  • p38 directly inhibits raf-1 kinase activity, mediating BDNF-induced ERK attenuation.
  • Insulin-like growth factor-I (IGF-I) suppresses p38 activation, favoring proliferation.

Conclusions:

  • A model is proposed where high ERK/p38 ratios driven by IGF-I promote proliferation.
  • BDNF signaling shifts the balance towards differentiation by reducing the ERK/p38 ratio via direct p38-mediated raf-1 inhibition.
  • This study clarifies the opposing yet essential roles of ERK and p38 in chondrogenesis.

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