Glucocorticoid Induced Osteoblast Apoptosis by Increasing E4BP4 Expression via Up-regulation of Bim

Abstract

It is well known that glucocorticoid (GC)-induced bone loss is caused primarily by hypofunction and apoptosis of osteoblasts. However, the precise molecular events underlying the effect of GC on osteoblast apoptosis are not fully understood. Recent studies implicated an important role of E4BP4 in the regulation of osteoblast apoptosis and differentiation. Furthermore, E4BP4 is a GC-regulated gene required for GC-induced apoptosis in many cells. Therefore, we hypothesize that E4BP4 may be implicated in the process of GC-induced osteoblast apoptosis. Western blot, reverse-transcription-PCR, flow cytometry, and Hoechst 33258 staining were employed to investigate the role of E4BP4 in dexamethasone (DEX)-induced osteoblast apoptosis. We found that the expression of E4BP4 is significantly up-regulated in osteoblasts exposed to DEX. Furthermore, the depletion of E4BP4 significantly decreased DEX-induced osteoblast apoptosis. In addition, E4BP4 plays a crucial role in GC-evoked apoptosis of osteoblasts by enabling induction of Bim. On the basis of these results above, we can draw the conclusion that E4BP4 may contribute to the process of DEX-induced osteoblast apoptosis.

Glucocorticoid Signaling and Bone Biology

“…Excess GCs have been shown to increase the pro-apoptotic factors, Bim and Bak, and decrease the pro-survival factor, BclXL in vitro [20,21]. GCs induce the expression of E4bp4, which is a basic leucine zipper transcription factor, and upregulate Bim through E4bp4 [22]. Excess GCs also upregulate p53 protein levels, resulting in increases in p21, Noxa, and Puma [23].…”

Glucocorticoid-mediated co-regulation of RCAN1-1, E4BP4 and BIM in human leukemia cells susceptible to apoptosis

“…Although the BIM promoter lacks a traditional GRE, GCs regulate its expression via a novel intronic GR binding region [25], and through a region in the 3′UTR, by relieving miRNA mediated post-transcriptional repression [26]. GR-mediated upregulation of E4BP4 , and subsequent induction of BIM , has been reported in correlation with apoptosis in lymphoid and osteoblastic cells [9, 27]. GR has been shown to regulate E4BP4 transcription via a GR binding sequence (GBS) located ~5kb upstream of the transcription start site [28, 29].…”

Congenital adrenal hyperplasia with localized aggressive periodontitis and amelogenesis imperfecta

“…This long-term cortisone treatment was reported to have multiple sideeffects, some of them involving bone metabolism (Vegiopoulos and Herzig 2007). On cellular level, cortisone is known to affect osteo- blast production (Shi et al 2015b), increase osteoblast apoptosis (Chen et al 2014), inhibit osteoblast proliferation (Shi et al 2015a) and increase osteoclast lifespan (Weinstein et al 2002). Overall, those changes are known to affect bone turnover and cause what is known as glucocorticoid induced osteoporosis (Cooper et al 2015).…”