Sost down-regulation by mechanical strain in human osteoblastic cells involves PGE2 signaling via EP4

Sclerostin is a potent inhibitor of bone formation which is down-regulated by mechanical loading. To investigate the mechanisms involved we subjected Saos2 human osteoblastic cells to short periods of dynamic strain and used quantitative reverse transcriptase polymerase chain reaction to compare their responses to unstrained controls. Strain-induced Sost down-regulation was recapitulated by cyclo-oxygenase-2-mediated PGE2, acting through the EP4 receptor, whereas strain-related up-regulation of osteocalcin was mediated by the EP2 receptor. Strain-related Sost regulation required extracellular signal-regulated kinase signaling, whereas osteocalcin required protein kinase C. These findings indicate early divergence in the signaling pathways stimulated by strain and establish PGE2/EP4 as the pathway used by strain to regulate Sost expression.