Aging & Gerontology

Abstract

Glucocorticoid (GC)-induced osteoporosis is the most common secondary cause of osteoporosis, resulting in fractures and significant morbidity. The mechanisms behind GC-induced bone deterioration are not fully understood. We have identified that cellular senescence plays distinct roles in GC-induced bone impairment in mice during childhood and adulthood. In growing young mice, GC treatment induces senescence in vascular endothelial cells in the metaphysis of long bone. Inhibition of endothelial cell senescence improves GC-impaired bone angiogenesis along with osteogenesis. We have also found that angiogenin-ribosomal RNA transcription signaling is a key mechanism that protects bone vascular cells from cellular senescence. In adult mice, bone-marrow adipocytes (BMAds) rapidly undergo cellular senescence upon GC treatment. These senescent BMAds acquire a SASP, which spreads senescence in bone and bone marrow. Mechanistically, GCs increase the synthesis of oxylipins, such as 15d-PGJ2, to active PPARγ. PPARγ stimulates the expression of key senescence genes and also promotes oxylipin synthesis in BMAds, forming a positive feedback loop. Transplanting senescent BMAds into the bone marrow of healthy mice is sufficient to induce bone-loss phenotypes. However, transplanting BMAds with a p16INK4a deletion does not have such effects. Thus, GC treatment induces a lipid metabolic circuit that robustly triggers the senescence of BMAd lineage cells that, in turn, act as the mediators of GC-induced bone deterioration in adult mice. Taken together, our findings suggest that the primary cell types undergoing cellular senescence in response to GC treatment are age- and location-dependent. The underlying molecular mechanisms of cellular senescence also differ accordingly.

Biography

Mei Wan, Ph.D. is a Frank J. Frassica Professor at the Johns Hopkins University School of Medicine.  She studies the contribution of fundamental aging processes, particularly cellular senescence, to the development of skeletal disorders. The impact of Dr. Wan’s research is evident in her extensive publication record, which includes papers in Cell Metabolism, Nature Communications, Cell Stem Cell, Journal Clinical Investigation, eLife, PNAS, Bone Research, etc. Dr. Wan has served on the editorial boards of two leading skeletal-related journals, Bone Research and the Journal of Bone and Mineral Research. Since 2021, she serves on the Reviewing Editor Board of eLife.