Chronic kidney disease bone and mineral disorder (CKD–MBD) in apolipoprotein E-deficient mice with chronic renal failure

Abstract

Background Chronic kidney disease (CKD) is associated with disorders of mineral and bone metabolism (MBD) which include renal osteodystrophy and vascular calcifications. This is of clinical concern because the high risk of cardiovascular (CVD) complications observed in uremic patients may be linked with bone disease. In this context, our aim was to characterize the bone lesions in CKD–apolipoprotein E-deficient mice (apoE −/−) and analyze their relationships with the vascular calcifications which these animals develop rapidly in this model. With ApoE being also involved in bone metabolism, we compared the effects of CRF on the bone of apoE −/− mice to those observed in wild type mice (WT) of the same genetic background, C57/BL6. Methods After CRF creation or sham surgery, 10 week-old female apoE −/− and WT mice were randomized to 4 groups ( n = 10–14/group) and fed with standard diet. Eight weeks later, animals were euthanized. Serum, aorta and femur were sampled. Femurs were imaged with 3-dimensional microtomography (µCT) and processed for bone histomorphometry (BHM). Additional quantitative histology was performed on atherosclerotic and calcified lesions in the aortas of apoE −/− mice. Results First, apoE −/− mice exhibited higher cortical (10%) and trabecular (31%) bone mass than WT. CRF led to a further increase in trabecular BV/TV in WT and in apoE −/− mice (10.2% and 77.2%, respectively). We observed a similar increase in osteoid surface and osteoblastic parameters in CRF mice of both genotypes while resorption parameters were less augmented by CRF in apoE −/− mice. Finally, based on either BHM or µCT we found positive correlations between the extent of atheroclerotic lesions and bone volume parameters, and between the size of plaque calcification and osteoclast parameters in apoE −/− mice. Conclusion ApoE deficiency is associated with an increase in bone mass and volumetric mineral density in 20 week-old female mice. Bone mass is further increased, whereas bone mineral density is decreased, in response to CRF in association with histological features of osteitis fibrosa. Finally, our findings of correlations between changes in bone and aortic lesions in apoE −/− mice, are compatible with the hypothesis of a link between bone and vascular disease and require further study.