Basigin links altered skeletal stem cell lineage dynamics with glucocorticoid-induced bone loss and impaired angiogenesis

Thomas H. Ambrosi (), David Morales, Kun Chen, Ethan J. Hunt, Kelly C. Weldon, Amber N. Maifeld, Fatima I. M. Chavez, Yuting Wang, Liming Zhao, Luke Wang, Matthew P. Murphy, Amin Cressman, Erika E. Wheeler, Augustine M. Saiz, J. Kent Leach, Fernando A. Fierro, Charles K. F. Chan and Nancy E. Lane ()
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Thomas H. Ambrosi: University of California at Davis Medical School
David Morales: University of California at Davis Medical School
Kun Chen: University of California at Davis Medical School
Ethan J. Hunt: University of California at Davis Medical School
Kelly C. Weldon: University of California at Davis Medical School
Amber N. Maifeld: University of California at Davis Medical School
Fatima I. M. Chavez: University of California at Davis Medical School
Yuting Wang: University of California at Davis Medical School
Liming Zhao: Stanford University School of Medicine
Luke Wang: University of California at Davis Medical School
Matthew P. Murphy: Stanford University School of Medicine
Amin Cressman: University of California Davis
Erika E. Wheeler: University of California at Davis Medical School
Augustine M. Saiz: University of California at Davis Medical School
J. Kent Leach: University of California at Davis Medical School
Fernando A. Fierro: University of California Davis
Charles K. F. Chan: Stanford University School of Medicine
Nancy E. Lane: University of California Davis

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-62881-w

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