Cortisol regulates the expression of Notch in osteoblasts

Abstract

Glucocorticoids have important effects on osteoblastic replication, differentiation, and function, and the Notch family of receptors is considered to play a role in osteoblastic cell differentiation. We postulated that cortisol could regulate Notch and Notch ligand expression in osteoblastic cells, providing an additional mechanism by which glucocorticoids could regulate osteoblastic differentiation. We examined the expression and regulation of Notch1, 2, 3, and 4 and their ligands Jagged 1 and 2 and Delta 1 and 3 by cortisol in cultures of osteoblastic MC3T3-E1 cells. Cortisol caused a time-dependent increase in Notch1 and 2 mRNA levels in MC3T3 cells. Notch3 and 4 were not detected in the presence or absence of cortisol. MC3T3 cells expressed Delta 1 and Jagged 1 but not Jagged 2 or Delta 3 mRNAs, and cortisol did not have a substantial effect on the expression of any of these ligands. Cortisol increased the rate of Notch1 and 2 transcription and, in transcriptionally arrested cells, did not modify the decay of the transcripts, indicating a transcriptional level of control. In conclusion, cortisol stimulates Notch1 and 2 transcription in osteoblasts. Since Notch signaling appears to play a negative role in osteoblastic differentiation, its increased expression could be relevant to the actions of cortisol in bone.

Nuclear Factor of Activated T-cells (NFAT)c2 Inhibits Notch Receptor Signaling in Osteoblasts

“…Previously, we had shown that cortisol, an inducer of Notch1 and Notch2 expression in osteoblasts, stabilizes collagenase 3 transcripts by inducing the formation of cytosolic protein complexes with the 3Ј-untranslated region (UTR) of the collagenase 3 mRNA (42,43). Activation of Notch signaling might stabilize Nfatc2 mRNA levels by a similar mechanism.…”

Glucocorticoid and Growth Factor Synergism Requirement for Notch4 Chromatin Domain Activation

“…Glucocorticoids exert extensive physiological and pathological activities, including the direct regulation of endothelial cell functions (16,17,40,53,68). It was reported that cortisol induced Notch1 and Notch2, but not Notch4, mRNA in osteoblast MC3T3 cells (52). However, mechanisms of cortisol-induced Notch1 and Notch2 expression are unknown.…”

Osteoblastic cells regulate the haematopoietic stem cell niche

“…By changing the balance of daughter cell self-renewal versus differentiation, Notch signalling has been shown to increase stem cell numbers without expanding mature cells in a manner reminiscent of the phenotype observed here 13,16 . Furthermore, the Notch ligand jagged 1 (Jag1) has been shown to be expressed by marrow stromal cells 16,18 and by murine osteoblasts 19 . Notch activation plus cytokine receptor signalling has a combinatorial effect on haematopoietic cells 14 .…”