Glucocorticoid-induced alterations of skeletal stem cell-based processes

Glucocorticoid (GC) induced osteoporosis (GIOP) and osteonecrosis remain a significant health issue with few approved therapies that can treat the bone loss and dysfunction of skeletal vasculature. Therefore, we aimed to investigate the cellular and molecular processes by which GCs affect osteogenesis and angiogenesis, as well as how treatment with parathyroid hormone (hPTH 1-34) modifies these effects in a mouse model of GIOP. GC treatment reduced bone mass through decreased bone formation by skeletal stem cells (SSCs) while also increasing osteoclast mediated resorption. Concomitantly, endothelial cells were increased in numbers but displayed distorted phenotypical features. However, hPTH treatment prevented GC induced changes in osteogenesis and angiogenesis. Transplantation studies of SSCs combined with molecular analysis by single cell RNA-sequencing and functional testing of primary human cells tied GC-induced skeletal changes to altered stem and progenitor cell differentiation dynamics. This in turn perpetuated reduced osteogenesis and vascular malformation through direct SSC-endothelial crosstalk mediated at least in part by Basigin. In accordance, the conditional heterozygous deletion of Basigin in the skeletal lineage as well as antibody-mediated blockade of Basigin during GC treatment prevented detrimental bone loss. Intriguingly, aging also increases skeletal Basigin levels. When administered to 2-year-old mice, anti-Basigin therapy reinstated bone remodeling to significantly improve bone mass independent of sex. These findings, while helping to explain the cellular and molecular basis of GC induced bone loss, provide new therapeutic vantage points for GIOP and potentially other conditions associated with bone loss.