PNNL

Abstract

Fluid shear stress regulates gene expression in osteoblasts, in part by activation of the transcription factor NF-kB. We examined whether this process was under control of purinoceptor activation. MC3T3-E1 osteoblasts under static conditions expressed the NF-kB inhibitory protein IkB alpha and exhibited cytosolic localization of NF-kB. Under fluid shear stress, I?Ba levels decreased, and concomitant nuclear localization of NF-kB was observed. Cells exposed to fluid shear stress in ATP-depleted medium exhibited no significant reduction in I?Ba, and NF-kB remained within the cytosol. Similar results were found using oxidized ATP or Brilliant Blue G, P2X7 receptor antagonists, indicating that the P2X7 receptor is responsible for fluid shear-stress-induced I?Ba degradation and nuclear accumulation of NF-kB. Pharmacologic blockage of the P2Y6 receptor also prevented shear-induced IkB alpha degradation. These phenomena involved neither ERK1/2 signaling nor autocrine activation by P2X7-generated lysophosphatidic acid. Our results suggest that fluid shear stress regulates NF-kB activity through the P2Y6 and P2X7 receptor.