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Skeletal Phenotype Analysis of a Conditional Stat3 Deletion Mouse Model
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Skeletal Phenotype Analysis of a Conditional Stat3 Deletion Mouse Model

Published on: July 3, 2020

Protein kinase A regulates caspase-1 via Ets-1 in bone stromal cell-derived lesions: a link between cyclic AMP and

Madson Q Almeida1, Kit Man Tsang, Chris Cheadle

  • 1PDEGEN, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.

Human Molecular Genetics
|October 14, 2010
PubMed

Insights

Genetic defects in cyclic adenosine monophosphate (cAMP) signaling and neonatal-onset multisystem inflammatory disease (NOMID) both cause bone lesions. This study reveals a link between abnormal cAMP signaling and inflammasome activation, suggesting new therapeutic targets.

Area of Science:

  • Molecular biology
  • Cellular signaling
  • Inflammasome biology

Background:

  • Patients with genetic defects in cyclic adenosine monophosphate (cAMP) signaling and neonatal-onset multisystem inflammatory disease (NOMID) exhibit similar tumor-like bone lesions.
  • The underlying molecular mechanisms connecting these conditions remain unclear.
  • NOMID pathogenesis involves dysregulated caspase-1 activity and inflammasome activation.

Purpose of the Study:

  • To elucidate the molecular basis for the shared bone pathology in NOMID and cAMP-signaling pathway defects.
  • To investigate the role of protein kinase A (PKA) and caspase-1 in the development of these bone lesions.
  • To identify potential therapeutic targets for these conditions.

Main Methods:

  • Comparative analysis of osteoblast progenitor cells from NOMID patients and individuals with aberrant cAMP/PKA signaling.
  • Assessment of caspase-1 activity, PKA levels, prostaglandin E2 (PGE2) production, and Wnt signaling.
  • Inhibition studies targeting caspase-1 and PGE2 to evaluate effects on cell proliferation.

Main Results:

  • NOMID bone lesions originate from osteoblast progenitor cells similar to those forming tumors in mice and humans with elevated cAMP-dependent protein kinase A (PKA) signaling.
  • NOMID tumor cells exhibit high PKA activity, which drives caspase-1 activation, partly via Ets-1.
  • Increased PKA activity and prostaglandin E2 (PGE2) contribute to elevated cAMP levels and Wnt signaling activation in both conditions.
  • Inhibition of caspase-1 and PGE2 reduced cell proliferation in both NOMID and PKA-dysregulated cells.

Conclusions:

  • A novel link exists between aberrant cAMP signaling and dysregulated inflammasome activity.
  • Caspase-1 and PGE2 represent potential therapeutic targets for bone lesions associated with defects in these pathways.

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