Glucocorticoids inhibit notch target gene expression in osteoblasts

Area of Science:

• Endocrinology
• Molecular Biology
• Bone Biology

Background:

• Glucocorticoids (GCs) are potent regulators of bone metabolism.
• Excess GCs induce osteoporosis by suppressing osteoblast function.
• GCs induce Notch receptors in osteoblasts, suggesting a role in skeletal effects.

Purpose of the Study:

• To investigate whether GCs modulate Notch signaling in bone.
• To elucidate the molecular mechanisms by which GCs affect Notch target gene expression in osteoblasts.

Main Methods:

• Gene expression analysis (mRNA, hnRNA) in mouse femoral bone and osteoblast-enriched cells.
• Treatment with prednisolone or cortisol in vivo and in vitro.
• Studies on Notch receptor activation, ligand interaction (DLL1), and downstream signaling (RBPJ).
• Analysis of mRNA stability, transactivation, and DNA-binding assays.

Main Results:

• Prednisolone administration suppressed Hey1 and HeyL expression in mouse bone.
• Cortisol inhibited DLL1-induced Hey1, Hey2, and HeyL expression transcriptionally.
• Cortisol did not affect mRNA stability or RBPJ-mediated transcription/DNA binding.
• Glucocorticoids suppress Hey gene expression via RBPJ-independent mechanisms.

Conclusions:

• Glucocorticoids inhibit Notch target genes Hey1, Hey2, and HeyL in osteoblasts.
• This suppression occurs through RBPJ-independent transcriptional repression.
• These findings provide a molecular mechanism for GC-induced osteoporosis.