Osteocyte necroptosis drives cortical bone resorption via osteocytic osteolysis in glucocorticoid-induced osteoporosis

Abstract

Glucocorticoid-induced osteoporosis (GIOP) is characterized by progressive cortical bone fragility accompanied by osteocyte lacunar enlargement and peri-lacunar osteolysis. However, whether these microstructural alterations arise from a specific cell death program remains unclear. Here, we demonstrate that glucocorticoids activate STIM1-ORAI1-dependent store-operated calcium entry (SOCE) in osteocytes, thereby promoting NFATc1 nuclear translocation. Activated NFATc1 induces mitophagy arrest, accumulation of dysfunctional mitochondria, and a burst of mitochondrial reactive oxygen species (mtROS), which subsequently triggers RIPK1/RIPK3/MLKL-mediated necroptosis. In a murine GIOP model, pharmacological inhibition of SOCE and NFATc1 knockdown each abrogated osteocyte necroptosis, alleviated cortical osteolysis, and preserved bone mechanical properties. Osteocyte-specific deletion of MLKL phenocopied these protective effects, further confirming necroptosis as the terminal effector of this process. Collectively, these findings identify the SOCE–NFATc1–mitophagy–mtROS axis as a critical signaling pathway linking calcium dysregulation to oxidative injury in osteocytes. Targeting this pathway disrupts the redox vulnerability underlying glucocorticoid-induced cortical bone loss and provides a therapeutic strategy for preserving skeletal integrity during long-term glucocorticoid therapy.