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

Abstract

Irradiation is an effective therapy for killing cancer cells and a critical preparative regimen for hematopoietic stem cell transplantation (HSCT). However, irradiation causes side effects on healthy tissue, disrupting bone tissue and bone marrow homeostasis and leading to skeletal and immune dysfunction. To investigate these effects, we utilized a female murine model to examine the mechanisms underlying skeletal damage caused by total body irradiation. Experiments were conducted over a 12-week period of total body irradiation and HSCT, complemented by an acute study involving only total body irradiation. Irradiation led to a transient depletion of bone marrow immune cells, followed by a late increased bone marrow cellularity 12 weeks after irradiation and HSCT compared to naive, indicative of late-stage local immune induction. Cortical and trabecular bone damage emerged two weeks post-irradiation and HSCT and persisted throughout the study. This bone damage was accompanied by a sustained increase in bone marrow adiposity. Accumulation of apoptotic cells was observed in the bone marrow within six hours post-irradiation and persisted up to 12 weeks post-irradiation and HSCT. Accompanied by elevated local expression of the pro-apoptotic BAX gene and a gene elevated with the clearance of apoptotic cells, TGF-{beta}1. In vitro studies revealed that macrophages and pre-osteoclasts, but not fully differentiated osteoclasts, efficiently cleared apoptotic cells with an elevation of TGF-{beta}1 in culture supernatant. While the clearance of apoptotic cells and associated TGF-{beta}1 signaling were evident, their direct role in skeletal outcomes remains unclear. These findings suggest that persistent apoptotic cells contribute to impaired bone remodeling, possibly influencing osteoclast function and the bone microenvironment. Further research is warranted to explore whether targeting apoptotic cell clearance could reduce bone damage and support skeletal recovery following irradiation.