Circadian factors BMAL1 and RORα control HIF-1α transcriptional activity in nucleus pulposus cells: implications in maintenance of intervertebral disc health

Apr 7, 2016Oncotarget

Body Clock Proteins BMAL1 and RORα Regulate Oxygen Response in Spine Disc Cells, Affecting Disc Health

AI simplified

Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

Stable silencing of BMAL1 or inhibition of RORα decreased expression of select HIF-1 target genes, including VEGF, PFKFB3, and Eno1.

BMAL1 and RORα are identified as key regulators of HIF-1-dependent transcriptional responses in nucleus pulposus (NP) cells.
Co-transfection with BMAL1 or RORα enhances HIF-1-dependent reporter activity.
Inhibition of RORα affects HIF1α transcriptional activity, but no direct binding between these regulators and HIF-1α was found in NP cells.
BMAL1-null mice exhibited decreased lumbar disc height and altered vertebral bone quality parameters.
In BMAL1-null animals, an increased ratio of cells to matrix in NP tissue and hyperplasia of the annulus fibrosus were observed.
BMAL1 and RORα may form a regulatory loop influencing NP cell adaptation to their environment.

AI simplified

BMAL1 and RORα are major regulators of the circadian molecular oscillator. Since previous work in other cell types has shown cross talk between circadian rhythm genes and hypoxic signaling, we investigated the role of BMAL1 and RORα in controlling HIF-1-dependent transcriptional responses in NP cells that exist in the physiologically hypoxic intervertebral disc. HIF-1-dependent HRE reporter activity was further promoted by co-transfection with either BMAL1 or RORα. In addition, stable silencing of BMAL1 or inhibition of RORα activity resulted in decreased HRE activation. Inhibition of RORα also modulated HIF1α-TAD activity. Interestingly, immunoprecipitation studies showed no evidence of BMAL1, CLOCK or RORα binding to HIF-1α in NP cells. Noteworthy, stable silencing of BMAL1 as well as inhibition of RORα decreased expression of select HIF-1 target genes including VEGF, PFKFB3 and Eno1. To delineate if BMAL1 plays a role in maintenance of disc health, we studied the spinal phenotype of BMAL1-null mice. The lumbar discs of null mice evidenced decreased height, and several parameters associated with vertebral trabecular bone quality were also affected in nulls. In addition, null animals showed a higher ratio of cells to matrix in NP tissue and hyperplasia of the annulus fibrosus. Taken together, our results indicate that BMAL1 and RORα form a regulatory loop in the NP and control HIF-1 activity without direct interaction. Importantly, activities of these circadian rhythm molecules may play a role in the adaptation of NP cells to their unique niche.

Full Text

We can’t show the full text here under this license. Use the link below to read it at the source.

View full text ↗

Circadian factors BMAL1 and RORα control HIF-1α transcriptional activity in nucleus pulposus cells: implications in maintenance of intervertebral disc health

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief