Sclerostin Antibody Does Not Promote Atheroprogression, Plaque Mineralization, or Inflammation in Ovariectomized Apolipoprotein E–Deficient Mice

Objective—Overexpression or administration of sclerostin has been reported to have atheroprotective and anti-inflammatory effects in apolipoprotein E knockout (ApoE KO) mice infused with angiotensin II; however, effects of sclerostin inhibition on these processes are not known. This study examined the effects of sclerostin inhibition with a sclerostin antibody on transcriptional changes in the aortic arch, associated morphological changes in aortic atherosclerotic plaques, and circulating markers of inflammation in ApoE KO ovariectomized (OVX) mice fed a high-fat diet. Approach and Results—Sclerostin antibody or vehicle was administered by subcutaneous injection once weekly for 3, 8, or 16 weeks to ApoE KO-OVX and wild-type-OVX mice fed a high-fat diet. As a comparator, alendronate or saline was administered twice weekly for 16 weeks to ApoE KO-OVX mice fed a high-fat diet. Sclerostin antibody had no effect on aortic total or mineralized plaque volume, determined by microcomputed tomography. Sclerostin antibody had no meaningful effects on plaque histopathology or systemic markers of inflammation or endothelial/platelet activation. Transcriptional analysis of the aortic arch revealed significant gene expression and signaling pathway changes in ApoE KO mice compared with wild-type, consistent with the genotype and atheroprogression, that were not affected by sclerostin antibody treatment. Alendronate treatment did not alter plaque volume or histopathology. Conclusions—This study shows that inhibition of sclerostin by sclerostin antibody does not promote atheroprogression or affect systemic markers of inflammation in the high-fat diet ApoE KO-OVX mouse model and does not alter the expression of genes/pathways implicated in atherosclerosis. The objective of this substudy was to evaluate transcriptional changes in the aorta in response to sclerostin antibody (Scl-Ab) treatment in high fat diet-fed ovariectomized (OVX) wild-type (WT) and Apolipoprotein E (ApoE) knockout mice. The test (Scl-Ab) and reference (vehicle) items were administered to OVX female mice by subcutaneous injection (interscapular region) once weekly. The aortic arch was harvested from the satellite animals after 3, 8 and 16 weeks of treatment, RNA extracted, and the transcriptional profile assessed using RNA-seq in three batches for timely evaluation. Differential gene expression in response to sclerostin antibody treatment was examined in wild-type and ApoE knockout mice.