Glucocorticoid signalling exerts distinct lineage-permissive and dose-dependent disruptive actions during human osteoblast differentiation

At physiological levels glucocorticoid (GC) signalling within the osteoblast lineage has been proposed to be required for skeletal homeostasis, whereas supraphysiological activation supresses bone formation and causes bone loss. While these observations suggest that GC exert dose- and context-dependent effects, the molecular mechanisms underlying these opposing actions remain unresolved. Here we systematically dissected the receptor-, lineage-, and concentration-dependent effects of GC signalling on human bone marrow stromal cell (BMSC) differentiation using integrated transcriptional, epigenomic, and functional analyses. Our findings suggest that GC opposing effects are not simply due to a GR dose-response but instead reflect distinct context- and concentration-dependent modes of action. During early BMSC differentiation, the cellular context induced GR-dependent licensing of lineage-specific gene and enhancer programs. The adverse effects of high-dose GC developed over time and could not be predicted from the early transcriptional response. We found that high-dose GC caused osteoblast maturation arrest, accompanied with a cellular stress response sustained by myeloid zinc finger 1 (MZF1) also identified as an endogenous inhibitor of osteoblast differentiation.