Abstract
Glucocorticoid (GC) induced osteoporosis (GIOP) and osteonecrosis remain a significant health issue with few approved therapies. Here, we investigate the cellular and molecular processes by which GCs affect osteogenesis and angiogenesis. We find that GC treatment reduces bone mass through decreased bone formation by skeletal stem cells (SSCs). Concomitantly, endothelial cells increase in number but display distorted phenotypical features. Transplantation studies of SSCs combined with molecular analysis by single cell RNA-sequencing and functional testing of primary human cells tie GC-induced skeletal changes to altered stem cell differentiation dynamics. This in turn perpetuates reduced osteogenesis and vascular malformation through direct SSC-endothelial crosstalk mediated at least in part by Basigin. The genetic deletion of Basigin in the skeletal lineage as well as antibody-mediated blockade of Basigin during GC treatment prevents bone loss. Intriguingly, when administered to 2-year-old mice, anti-Basigin therapy reinstates bone remodeling to significantly improve bone mass. These findings provide therapeutic vantage points for GIOP and potentially other conditions associated with bone loss.