Glucocorticoid receptor-mediated cis -repression of osteogenic genes requires BRM-SWI/SNF

Abstract

Glucocorticoids are an effective therapy for a variety of severe inflammatory and autoimmune disorders; however, the therapeutic use of glucocorticoids is severely limited by their negative side effects, particularly on osteogenesis. Glucocorticoids regulate transcription by binding to the glucocorticoid receptor (GR), which then binds the promoters of target genes to induce either activation or repression. The gene activation effects of nuclear hormone receptors broadly require the cooperation of the chromatin remodeling complex known as SWI/SNF, which is powered by an ATPase core. The well-studied SWI/SNF ATPase, BRG1, is required for gene activation by a spectrum of nuclear hormone receptors including GR. However, glucocorticoid-induced side effects specifically related to impaired osteogenesis are mostly linked with GR-mediated repression. We have considered whether cis-repression of osteogenic genes by GR may be mediated by a distinct subclass of SWI/SNF powered by the alternative ATPase, BRM. BRM does not have an essential role in mammalian development, but plays a repressor role in osteoblast differentiation and favors adipogenic lineage selection over osteoblast commitment, effects that mirror the repressor effects of GR. The studies reported here examine three key GR cis-repression gene targets, and show that GR association with these promoters is sharply reduced in BRM deficient cells. Each of these GR-targeted genes act in a different way. Bglap encodes osteocalcin, which contributes to normal maturation of osteoblasts from committed pre-osteoblasts. The Per3 gene product acts in uncommitted mesenchymal stem cells to influence the osteoblast/adipocyte lineage selection point. Fas ligand, encoded by FasL, is a means by which osteoblasts can modulate bone degradation by osteoclasts. Repression of each of these genes by glucocorticoid favors bone loss. The essential role of BRM in cooperation with GR at each of these control points offers a novel mechanistic understanding of the role of GR in bone loss.

Cytoplasmic Interactions between the Glucocorticoid Receptor and HDAC2 Regulate Osteocalcin Expression in VPA-Treated MSCs

“…In addition, it is to be noted that osteocalcin, although poorly expressed, does not compromise bone formation. These results are consistent with previous genetic evidence showing that OC-deficient mice develop a phenotype that is characterized by increased bone formation [59]. Until now, the role of osteocalcin is still unknown.…”

“…Thus, we identified GR as being responsible for this downregulation. Pico et al demonstrated that GR acts on OC genes by direct cis -repression [59]. Therefore, we decided to analyze the expression of GR in dental pulp stem cells after treatment with VPA and in shHDAC2 DPSCs.…”

Deciphering the potential pharmaceutical mechanism of Guzhi Zengsheng Zhitongwan on rat bone and kidney based on the “kidney governing bone” theory

“…Finally, we analyzed the differentially expressed genes with consistent patterns in both the kidney and bone, of which 15 genes were significantly upregulated and 39 genes were significantly downregulated in both the kidney and bone under GZZSZTW. Among the upregulated genes in both the kidney and bone, Per3, Junb, Bcl6, and Fos have been reported to be involved in the regulation of bone formation and resorption by controlling osteoblast and osteoclast activities [30][31][32][33]. Among the downregulated genes in both the kidney and bone, Col6a2, Mmp2, Col5a1, Olfml3, Igfbp4, Dcn, Sepp1, Col1a1, Slc16a1, Slit3, Alox15, Igfbp3, Col3a1, and Omd have been reported to be involved in the regulation of bone formation and resorption by controlling osteoblast and osteoclast activities [34][35][36][37][38][39][40][41][42][43][44][45][46][47].…”

Comparison of Myosepta Development and Transcriptome Profiling between Blunt Snout Bream with and Tilapia without Intermuscular Bones

“…The runx2 gene can promote the differentiation of multipotent mesenchymal cells into osteoblasts [ 21 , 51 ]. Besides, runx2 induces the expression of bgp , encoding osteocalin, to induce the differentiation of preosteoblasts into mature osteoblasts [ 52 , 53 ]. The entpd5 gene plays an important role in phosphate homeostasis and has been demonstrated to be essential for skeletal mineralization in zebrafish [ 54 , 55 ].…”