Disrupted bone microenvironment and immune recovery following total body irradiation in a murine model

Irradiation is an effective therapy for eliminating cancer cells and serves as a critical preparative regimen for hematopoietic stem cell transplantation (HSCT). However, irradiation affects healthy tissue, disrupting bone tissue and bone marrow homeostasis, which leads to skeletal and immune dysfunction. To investigate these effects, we used a female murine model to explore the mechanisms underlying the skeletal damage caused by total body irradiation. Experiments were carried out over a 12-week period of total body irradiation and HSCT, supplemented by an acute study involving only total body irradiation and osteoclastogenesis. Irradiation resulted in a depletion of bone marrow immune cells, followed by an increase in bone marrow cellularity 12 weeks after irradiation and HSCT compared to naive controls, indicating late-stage local immune induction. Cortical and trabecular bone loss appeared 2 weeks post-irradiation and HSCT and persisted throughout the study. This bone damage was accompanied by a sustained increase in apoptotic cells in the bone marrow within 6 h post-irradiation and persisted for up to 12 weeks after irradiation and HSCT. This was coupled with elevated local expression of the pro-apoptotic Bax gene and an increase in TGF-β1, a gene associated with the clearance of apoptotic cells. In vitro studies demonstrated that macrophages and pre-osteoclasts, but not fully differentiated osteoclasts, efficiently cleared apoptotic cells, resulting in increased levels of TGF-β1 in the culture supernatant. While the clearance of apoptotic cells and associated TGF-β1 signaling were evident, their direct role in skeletal outcomes remains unclear. These findings suggest that persistent apoptotic cells contribute to impaired bone remodeling, potentially affecting osteoclast function and the bone microenvironment. Additional research is needed to investigate whether targeting apoptotic cell clearance can mitigate bone damage and promote skeletal recovery following irradiation.