Glucocorticoid receptor and Histone deacetylase 6 mediate the differential effect of dexamethasone during osteogenesis of mesenchymal stromal cells (MSCs)

Abstract

Lineage commitment and differentiation of mesenchymal stromal cells (MSCs) into osteoblasts in vitro is enhanced by a potent synthetic form of glucocorticoid (GC), dexamethasone (Dex). Paradoxically, when used chronically in patients, GCs exert negative effects on bone, a phenomenon known as glucocorticoid-induced osteoporosis in clinical practice. The mechanism on how GC differentially affects bone precursor cells to become mature osteoblasts during osteogenesis remains elusive. In this study, the dose and temporal regulation of Dex on MSC differentiation into osteoblasts were investigated. We found that continuous Dex treatment led to a net reduction of the maturation potential of differentiating osteoblasts. This phenomenon correlated with a decrease in glucocorticoid receptor (GR) expression, hastened degradation, and impaired sub cellular localization. Similarly, Histone Deacetylase 6 (HDAC6) expression was found to be regulated by Dex, co-localized with GR and this GR-HDAC6 complex occupied the promoter region of the osteoblast late marker osteocalcin (OCN). Combinatorial inhibition of HDAC6 and GR enhanced OCN expression. Together, the cross-talk between the Dex effector molecule GR and the inhibitory molecule HDAC6 provided mechanistic explanation of the bimodal effect of Dex during osteogenic differentiation of MSCs. These findings may provide new directions of research to combat glucocorticoid-induced osteoporosis.

Osteochondral Tissue Chip Derived From iPSCs: Modeling OA Pathologies and Testing Drugs

“…On one hand, Dex increased the expression of RUNX2 and its transcriptional targets, ALP and OSX. On the other hand, Dex significantly downregulated the expression of late osteogenic markers, COL1A1, OPN, OCN, and BSP2 (Subramaniam et al, 1992;Langenbach and Handschel, 2013;Rimando et al, 2016). Therefore, we hypothesized that extended Dex treatment is likely to inhibit osteogenesis.…”

“…To optimize osteogenesis, we tested the supplementation of 1α, 25-dihydroxyvitamin D3 (VitD3) (Lou et al, 2017) and an osteogenic protein BMP7 (Luu et al, 2007). We also examined if the withdrawal of dexamethasone (Dex) at a later stage could enhance osteogenesis (Subramaniam et al, 1992;Rimando et al, 2016). As shown in Figure 2A, five different osteogenic medium compositions were compared: Group 1 (Gr 1), MM (negative control); Gr 2, OM; Gr 3, OM + 10 nM VitD3; Gr 4, OM + 10 nM VitD3 + 100 ng/ml BMP-7; Gr 5, OM + 10 nM VitD3 + 100 ng/ml BMP-7, with Dex treatment only during the first 14 days.…”

Hazards of Short- and Long-term Administration of Glucocorticoids on the Periodontium in Rats: A Histological and Electron Microscopic Study

“…35 Our results could be also explained by the fact that dexamethasone could down regulate the osteogenic markers, such as alkaline phosphatase, osteocalcin, and Runt-related transcription factor 2 (Runx2). 36 Dexamethasone motivates the expression of histone deacetylase 6 (HDAC6) that binds to glucocorticoid receptor and may prevent the osteocalcin expression. 37 Other researchers concluded that dexamethasone could reduce the expression of insulin like growth factors I and II because these growth factors increase osteoblast differentiation, type I collagen synthesis, and bone formation.…”

Calcium Phosphate/Clay Nanotube Bone Cement with Enhanced Mechanical Properties and Sustained Drug Release

“…Inability of Group 3 and 4 scaffolds to induce differentiation may be attributed to very high concentrations of DEX released. The optimum concentration of DEX needed to induce the osteogenic differentiation is 10-7 [49][50][51]. In the CPC discs doped with DEX, DEX may have been eluted in excess and thus had an inhibitory effect.…”