Irradiation-induced senescence of bone marrow mesenchymal stem cells aggravates osteogenic differentiation dysfunction via paracrine signaling.

The role of cellular senescence induced by radiation in bone loss has attracted much attention. As one of the common complications of anti-cancer radiotherapy, irradiation-induced bone deterioration is common and clinically significant, but the pathological mechanism has not been elucidated. This study was performed to explore the cellular senescence and senescence-associated secretory phenotype (SASP) induction of bone marrow-derived mesenchymal stem cells (BMSCs) by irradiation and its role in osteogenic differentiation dysfunction. It was observed that irradiated BMSCs lost typical fibroblast-like morphology, exhibited suppressed viability and differentiation potential accompanied with senescence phenotypes, including an increase in senescence-associated beta-galactosidase (SA-beta-gal) staining-positive cells and up-regulated senescence related genes p53/p21, while none changes happened to p16. Additionally, DNA damage foci gamma-H2AX, G0/G1 of cell cycle arrest, cellular and mitochondrial reactive oxygen species (ROS) increased in an irradiation dose-dependent manner. Meanwhile, the JAK1/STAT3 pathway was activated and accompanied by an increase in SASP secretion, such as IL-6, IL-8 and MMP9, while 0.8muM JAK1 inhibitor (JAKi) treatment could effectively inhibited the JAK pathway and SASP production. Furthermore, conditioned medium (CM) from irradiation-induced senescent (IRIS) BMSCs exhibited a markedly reduced ability in osteogenic differentiation and marker gene expression of osteoblasts, while CM with JAKi intervention may effectively improve this deterioration effects. In conclusion, irradiation could provoke BMSCs senescence and their SASP secretion, further aggravate osteogenic differentiation dysfunction via paracrine signaling, while SASP targeting may be a possible intervention strategy for alleviating irradiation-induced bone loss.