COX-2 expression mediated by calcium-TonEBP signaling axis under hyperosmotic conditions serves osmoprotective function in nucleus pulposus cells.
The nucleus pulposus (NP) of intervertebral discs experiences dynamic changes in tissue osmolarity because of diurnal loading of the spine. TonEBP/NFAT5 is a transcription factor that is critical in osmoregulation as well as survival of NP cells in the hyperosmotic milieu. The goal of this study was to investigate whether cyclooxygenase-2 (COX-2) expression is osmoresponsive and dependent on TonEBP, and whether it serves an osmoprotective role. NP cells up-regulated COX-2 expression in hyperosmotic media. The induction of COX-2 depended on elevation of intracellular calcium levels and p38 MAPK pathway, but independent of calcineurin signaling as well as MEK/ERK and JNK pathways. Under hyperosmotic conditions, both COX-2 mRNA stability and its proximal promoter activity were increased. The proximal COX-2 promoter (-1840/+123 bp) contained predicted binding sites for TonEBP, AP-1, NF-κB, and C/EBP-β. While COX-2 promoter activity was positively regulated by both AP-1 and NF-κB, AP-1 had no effect and NF-κB negatively regulated COX-2 protein levels under hyperosmotic conditions. On the other hand, TonEBP was necessary for both COX-2 promoter activity and protein up-regulation in response to hyperosmotic stimuli.
Choi, Hyowon; Chaiyamongkol, Weera; Doolittle, Alexandra C.; Johnson, Zariel I.; Gogate, Shilpa S.; Schoepflin, Zachary R.; Shapiro, Irving M.; and Risbud, Makarand V., "COX-2 expression mediated by calcium-TonEBP signaling axis under hyperosmotic conditions serves osmoprotective function in nucleus pulposus cells." (2018). Department of Orthopaedic Surgery Faculty Papers. Paper 113.
This research was originally published in Journal of Biological Chemistry. Choi, H., Chaiyamongkol, W., Doolittle, A. C., Johnson, Z. I., Gogate, S. S., Schoepflin, Z. R., Shapiro, I.M., & Risbud, M. V.. COX-2 expression mediated by calcium-TonEBP signaling axis under hyperosmotic conditions serves osmoprotective function in nucleus pulposus cells. Journal of Biological Chemistry. 2018; 293(23):869-898. © the American Society for Biochemistry and Molecular Biology