Sclerostin antibody increases trabecular bone and bone mechanical properties by increasing osteoblast activity damaged by whole-body irradiation in mice

Samantha Costa; Heather Fairfield; Mariah Farrell; Connor S Murphy; Ashley Soucy; Calvin Vary; Gill Holdsworth; Michaela R Reagan

doi:10.1016/j.bone.2021.115918

Sclerostin antibody increases trabecular bone and bone mechanical properties by increasing osteoblast activity damaged by whole-body irradiation in mice

Bone. 2021 Jun:147:115918. doi: 10.1016/j.bone.2021.115918. Epub 2021 Mar 16.

Authors

Samantha Costa¹, Heather Fairfield¹, Mariah Farrell¹, Connor S Murphy¹, Ashley Soucy², Calvin Vary¹, Gill Holdsworth³, Michaela R Reagan⁴

Affiliations

¹ Maine Medical Center Research Institute, Scarborough, ME, USA; University of Maine Graduate School of Biomedical Science and Engineering, Orono, ME, USA; Tufts University School of Medicine, Boston, MA, USA.
² Maine Medical Center Research Institute, Scarborough, ME, USA; University of Maine Graduate School of Biomedical Science and Engineering, Orono, ME, USA.
³ UCB Pharma, Slough, UK.
⁴ Maine Medical Center Research Institute, Scarborough, ME, USA; University of Maine Graduate School of Biomedical Science and Engineering, Orono, ME, USA; Tufts University School of Medicine, Boston, MA, USA. Electronic address: Mreagan@mmc.org.

Abstract

Irradiation therapy causes bone deterioration and increased risk for skeletal-related events. Irradiation interferes with trabecular architecture through increased osteoclastic activity, decreased osteoblastic activity, and increased adipocyte expansion in the bone marrow (BM), which further compounds bone-related disease. Neutralizing antibodies to sclerostin (Scl-Ab) increase bone mass and strength by increasing bone formation and reducing bone resorption. We hypothesized that treatment with Scl-Ab would attenuate the adverse effects of irradiation by increasing bone volume and decreasing BM adipose tissue (BMAT), resulting in better quality bone. In this study, 12-week-old female C57BL/6J mice were exposed to 6 Gy whole-body irradiation or were non-irradiated, then administered Scl-Ab (25 mg/kg) or vehicle weekly for 5 weeks. Femoral μCT analysis confirmed that the overall effect of IR significantly decreased trabecular bone volume/total volume (Tb.BV/TV) (2-way ANOVA, p < 0.0001) with a -43.8% loss in Tb.BV/TV in the IR control group. Scl-Ab independently increased Tb.BV/TV by 3.07-fold in non-irradiated and 3.6-fold in irradiated mice (2-way ANOVA, p < 0.0001). Irradiation did not affect cortical parameters, although Scl-Ab increased cortical thickness and area significantly in both irradiated and non-irradiated mice (2-way ANOVA, p < 0.0001). Femoral mechanical testing confirmed Scl-Ab significantly increased bending rigidity and ultimate moment independently of irradiation (2-way ANOVA, p < 0.0001). Static and dynamic histomorphometry of the femoral metaphysis revealed osteoblast vigor, not number, was significantly increased in the irradiated mice treated with Scl-Ab. Systemic alterations were assessed through serum lipidomic analysis, which showed that Scl-Ab normalized lipid profiles in the irradiated group. This data supports the theory of sclerostin as a novel contributor to the regulation of osteoblast activity after irradiation. Overall, our data support the hypothesis that Scl-Ab ameliorates the deleterious effects of whole-body irradiation on bone and adipose tissue in a mouse model. Our findings suggest that future research into localized and systemic therapies after irradiation exposure is warranted.

Keywords: Adipocytes; Bone marrow adipose; Irradiation; Irradiation-induced bone damage; Sclerostin antibody; Sost.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bone and Bones
Cancellous Bone*
Female
Mice
Mice, Inbred C57BL
Osteoblasts
Osteogenesis
Whole-Body Irradiation*

Abstract

Publication types

MeSH terms

Grants and funding