About the Article
Article Files
[This article belongs to Volume - 69, Issue - 8]
Published on : 2024-08-10 12:18:53
Article Code: AMJ-10-08-2024-12295
Title : Cellular Senescence in the Bone Marrow Niche Drives Osteoclast Mediated Bone Resorption in Glucocorticoid-Induced Osteoporosis Through SASP-Derived RANKL
Author(s) : Dr. Robert Chen, Dr. Fatima Osei
Abstract :
Glucocorticoid-induced osteoporosis (GIOP) is the most common secondary cause of bone loss, yet the cellular
senescence contribution remains undefined. We demonstrate that therapeutic-dose dexamethasone induces
p16INK4a-positive senescence in bone marrow mesenchymal stromal cells (BMSCs) and osteoblasts within 14 days
in murine models. The senescence-associated secretory phenotype (SASP) from these cells exhibited 8-fold elevated
soluble RANKL levels compared to non-senescent controls. Senolytic treatment with fisetin or genetic clearance of
p16-positive cells abrogated osteoclastogenesis and preserved trabecular bone mineral density despite continued
glucocorticoid exposure. Mechanistically, SASP-derived IL-6 amplified RANKL expression through JAK/STAT signaling
in pre-osteoclasts. Targeting the senescence-skeletal axis offers a disease-modifying strategy distinct from anti
resorptive bisphosphonates.