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Intracellular Calcium Overload Promotes NFATc1-ATF3 Activation and Induces the Senescence-Associated Phenotype in Irradiated Osteocytes
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Intracellular Calcium Overload Promotes NFATc1-ATF3 Activation and Induces the Senescence-Associated Phenotype in Irradiated Osteocytes
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Journal Article
Intracellular Calcium Overload Promotes NFATc1-ATF3 Activation and Induces the Senescence-Associated Phenotype in Irradiated Osteocytes
2026
Overview
Although calcium overload dysregulation has been implicated in cellular senescence, its role in ionizing radiation (IR)-induced osteocyte senescence, a key pathogenic mechanism underlying radiotherapy-associated bone injury, remains poorly explored. This study investigated whether IR-induced osteocyte senescence is mediated through the Ca
-NFATc1-ATF3 pathway. Exposure to 2 Gy X-rays impaired osteocyte homeostasis, manifesting as reduced viability and proliferation, G2/M phase arrest, and dendritic retraction. IR also induced persistent DNA damage response and senescence-associated phenotypes, including increased γ-H2AX foci, SA-β-gal activity, condensed punctate DAPI-dense nuclear foci, p16/p21 expression, and pro-inflammatory SASP profile. Intracellular Ca
levels surged within 6 h post-irradiation and remained elevated for at least 72 h in a dose-dependent manner. Pharmacological Ca
modulation with BAPTA-AM or verapamil attenuated IR-induced intracellular Ca
accumulation, G2/M arrest, SA-β-gal positivity, p21/p53 upregulation, and SASP secretion. Conditioned medium from irradiated osteocytes inhibited BMSC-mediated osteogenesis and enhanced BMM-driven osteoclastogenesis, whereas Ca
modulation partially mitigated these paracrine effects. Mechanistically, IR promoted NFATc1 nuclear translocation and ATF3 upregulation. Collectively, these findings support an important role for pathological intracellular Ca
elevation in IR-induced osteocyte senescence and suggest that the Ca
-NFATc1-ATF3 axis may represent a potential therapeutic target for mitigating radiation-associated disruption of bone homeostasis.
Publisher
MDPI AG,Multidisciplinary Digital Publishing Institute (MDPI)
