期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 293, 期 23, 页码 8969-8981出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA117.001167
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资金
- NIAMS, National Institutes of Health [R01AR055655, R01AR064733, T32AR052273, F30AR066506]
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-kappa B, and C/EBP-beta. While COX-2 promoter activity was positively regulated by both AP-1 and NF-kappa B, AP-1 had no effect and NF-kappa B negatively regulated COX-2 protein levels under hyperosmotic conditions. Onthe other hand, TonEBPwas necessary for both COX-2 promoter activity and protein up-regulation in response to hyperosmotic stimuli. Ex vivo disc organ culture studies using hypomorphic TonEBP(+/-) mice confirmed that TonEBP is required for hyperosmotic induction of COX-2. Importantly, the inhibition of COX-2 activity under hyperosmotic conditions resulted in decreased cell viability, suggesting that COX-2 plays a cytoprotectiveandhomeostatic role inNPcells for their adaptation to dynamically loaded hyperosmotic niches.
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