Maine Medical Center, Medical Education, Maine Medical Center Research Institute
Cancellous Bone, Bone Marrow, Whole-Body Irradiation, Antibodies, Adipose Tissue
Irradiation therapy continues to be an accepted medical treatment for many cancers, yet patients are at increased risk for bone deterioration and other skeletal-related events. Irradiation (IR) negatively affects trabecular architecture through increased osteoclast activity and decreased osteoblast activity. Additionally, IR induces increased bone marrow (BM) adipocyte expansion, which may compound IR-induced bone disease. Antibodies to sclerostin (Scl-Ab) increase bone mass and strength by increasing bone formation and reducing bone resorption. We hypothesized Scl-Ab treatment would reverse the adverse effects of IR by increasing bone volume and decreasing BM adipose tissue (BMAT), resulting in improved bone quality. In this study, 12-week-old female C57BL/6J mice were exposed to 6 Gy whole-body IR or were non-irradiated (Non-IR), then administered Scl-Ab (25 mg/kg) or vehicle weekly for 5 weeks. Tibial µCT analysis confirmed IR decreased trabecular bone volume per total volume (Tb.BV/TV) by 43.1% (p=0.0246). Scl-Ab increased Tb.BV/TV by 2.45 fold (p<0.0001) in IR and 2.22 fold (p=0.0415) in Non-IR-mice compared to vehicle. Cortical parameters were unaffected by IR while Scl-Ab increased cortical thickness and area significantly in both IR (Femur: 1.26 and 1.38 fold; Tibia: 1.28 and 1.25 fold, respectively) and Non-IR-mice (Femur: 1.30 and 1.35 fold; Tibia 1.21 and 1.19 fold, respectively). Femoral mechanical testing confirmed Scl-Ab significantly increased bending rigidity and ultimate moment by 1.34 and 1.53 fold, respectively in IR and by 1.33 and 1.56 fold, respectively in Non-IR-mice. Static and dynamic histomorphometry of the femoral metaphysis revealed IR did not significantly affect the number of osteoblasts or osteoclasts, but rather the overall efficacy of these cells. Scl-Ab were able to improve bone parameters by increasing osteoblast function (e.g. bone formation rate/bone surface, mineral apposition rate, and mineralizing surface/bone surface). In regards to BM adiposity, adipocyte volume/TV in the femoral metaphysis and whole tibia was increased following IR; Scl-Ab diminished this effect in the femoral metaphysis (p=0.0182) and distal tibia (p=0.002). Overall, our data support the hypothesis that Scl-Ab ameliorate the deleterious effects of IR on trabecular bone and BMAT in a mouse irradiation model. This suggests further research into the cellular effects of irradiation and alternative methods to modulate the bone marrow microenvironment are warranted.
Costa, Samantha; Fairfield, Heather; Farrell, Mariah; Murphy, Connor; Soucy, Ashley; Holdsworth, Gill; and Reagan, Michaela R., "Sclerostin antibody normalizes decreased trabecular bone and increased bone marrow adipose tissue caused by whole-body irradiation in mice" (2020). Costas T. Lambrew Research Retreat 2020. 24.