Document Type

Poster

Publication Date

4-30-2020

Institution/Department

Maine Medical Center, Medical Education, Maine Medical Center Research Institute

MeSH Headings

Cancellous Bone, Bone Marrow, Whole-Body Irradiation, Antibodies, Adipose Tissue

Abstract

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.

Comments

2020 Costas T. Lambrew Research Retreat

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