Chronic kidney disease bone and mineral disorder (CKD-MBD) in apolipoprotein E-deficient mice with chronic renal failure.
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 (microCT) 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 microCT we found positive correlations between the extent of atherosclerotic lesions and bone volume parameters, and between the size of plaque calcification and osteoclast parameters in apoE(-/-) mice.


CONCLUSIONS
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.
Nikolov
Igor G
IG
Inserm ERI-12, University of Picardie, Amiens, France. nikolov_igor@yahoo.com
Joki
Nobuhiko
N
Nguyen-Khoa
Thao
T
Ivanovski
Ognen
O
Phan
Olivier
O
Lacour
Bernard
B
Drüeke
Tilman B
TB
Massy
Ziad A
ZA
Dos Reis
Luciene Machado
LM
Jorgetti
Vanda
V
Lafage-Proust
Marie-Hélène
MH
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000378:metabolism; D001808:Blood Vessels / Q000473:pathology; D001835:Body Weight; D001847:Bone Diseases / Q000097:blood / Q000150:complications* / Q000000981:diagnostic imaging / Q000503:physiopathology; D016723:Bone Remodeling / Q000502:physiology; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000473:pathology* / Q000503:physiopathology; D002113:Calcification, Physiologic / Q000502:physiology; D005260:Female; D007676:Kidney Failure, Chronic / Q000097:blood / Q000150:complications* / Q000000981:diagnostic imaging / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008903:Minerals / Q000378:metabolism*; D009929:Organ Size; D055114:X-Ray Microtomography
D001057:Apolipoproteins E; D008903:Minerals