Cell Transitions Contribute to Glucocorticoid-Induced Bone Loss

Abstract

Glucocorticoid-induced bone loss is a toxic effect of long-term therapy with glucocorticoids resulting in a significant increase in the risk of fracture. Here, we find that glucocorticoids reciprocally convert osteoblast-lineage cells into endothelial-like cells. This is confirmed by lineage tracing showing the induction of endothelial markers in osteoblast-lineage cells following glucocorticoid treatment. Functional studies show that osteoblast-lineage cells isolated from glucocorticoid-treated mice lose their capacity for bone formation but simultaneously improve vascular repair. We find that the glucocorticoid receptor directly targets Foxc2 and Osterix, and the modulations of Foxc2 and Osterix drive the transition of osteoblast-lineage cells to endothelial-like cells. Together, the results suggest that glucocorticoids suppress osteogenic capacity and cause bone loss at least in part through previously unrecognized osteoblast–endothelial transitions.

Aurora Kinase A Regulates Cell Transitions in Glucocorticoid-Induced Bone Loss

“…Either unpaired 2-tailed Student's t test or one-way ANOVA with Tukey's multiplecomparisons test was used to analyze for statistical significance. We used pwr R package to calculate the size of the effect and the statistical power as previously described [23]. The number of animals in each group was sufficient to reach more than 80% power to identify differences in the results.…”

“…In a recent study, it was shown that a shift of osteoblast lineage cells toward endothelial differentiation was induced by glucocorticoids and that this unwanted cell transition caused osteoblast lineage cells to lose osteogenic capacity, thereby contributing to glucocorticoidinduced bone loss [23]. The study also showed that glucocorticoids suppress Osterix expression but activate Foxc2 in osteoblast lineage cells to switch the cell fate and functional capacity, contributing to osteoporosis [23]. Here, we unveil a new interaction between the glucocorticoid receptor and aurora A in controlling the plasticity of osteoblasts.…”

“…Then, the muscle was cleaned. The cleaned femurs were fixed in 4% (wt/vol) paraformaldehyde (PFA) for 24 h. Then, 50% alcohol was used to replace PFA, and the femurs were ready for Micro-CT imaging, which was performed at the Crump Imaging Center at UCLA as described [23].…”

“…After the cell transplantation experiments, the study uncovered that glucocorticoid-treated osteoblasts lose their osteogenic capacity in ectopic bone formation but improve their vascular repair capacity. Mechanistically, the study showed that the coupled alterations in Foxc2 and Osterix are responsible for the shift of osteoblast lineage cells into endothelial differentiation [23].…”

“…Endothelial cells are known to transform into osteoblast-like cells in several medical conditions [20][21][22]. In a previous study, it was found that glucocorticoid converted osteoblast lineage cells into endothelial-like cells to cause osteoporosis [23]. Using a glucocorticoid-induced mouse model and osteoblast lineage tracing, the study showed that endothelial markers emerge in the osteoblast lineage cells of glucocorticoidinduced bone loss.…”