Only minor differences in renal osteodystrophy features between wild-type and sclerostin knockout mice with chronic kidney disease

Abstract

Renal osteodystrophy affects the majority of patients with advanced chronic kidney disease (CKD) and is characterized by progressive bone loss. This study evaluated the effects of sclerostin knockout on bone in a murine model of severe, surgically induced CKD in both sclerostin knockout and wild-type mice. Mice of both genotypes with normal kidney function served as controls. Tibiae were analyzed using micro-computed tomography, and lumbar vertebrae were analyzed by histomorphometry. Results were tested for statistical significance by 2-way ANOVA to investigate whether bone of the knockout mice reacted differently to CKD compared with bone of wild-type mice. In the tibiae, there was no difference after creation of CKD between wild-type and knockout animals for cortical thickness or cross-sectional moment of inertia. Increases in cortical porosity induced by CKD differed significantly between genotypes in the tibial metaphysis but not in the diaphysis. In the trabecular compartment, no difference in reaction to CKD between genotypes was found for bone volume, trabecular number, trabecular thickness, and trabecular separation. In the lumbar vertebrae, significant differences in response to CKD between wild-type and knockout mice were seen for both bone volume and trabecular thickness. Osteoblast parameters did not differ significantly, whereas osteoclast numbers significantly increased in the wild-type but significantly decreased in knockout mice with CKD. No differences in response to CKD between genotypes were found for bone formation rate or mineral apposition rate. Thus, complete absence of sclerostin has only minor effects on CKD-induced bone loss in mice.

Klotho expression in long bones regulates FGF23 production during renal failure

“…Uremic mice in the current study, as well as in previous studies (50)(51)(52)(53), showed elevated rather than diminished serum 1,25(OH) 2 D 3 levels that are commonly observed in patients with CKD. While increased FGF23 leads to decreased 1,25(OH) 2 D 3 production and secondary hyperparathyroidism in early to moderate CKD (23,54), it fails to exert its physiologic effects in end-stage renal disease.…”

Klotho expression in osteocytes regulates bone metabolism and controls bone formation

“…A common experimental model for renal failure is 5/6 nephrectomy, and high-phosphate feeding is frequently used to promote secondary hyperparathyroidism and high-turnover renal osteodystrophy. 24,[40][41][42][43] As expected, nephrectomized mice exhibited elevated PTH levels, which were accompanied by increased bone formation and bone resorption parameters. Despite the induction of high-turnover renal osteodystrophy, bone volume paradoxically increased.…”

“…The increases in bone volume and serum calcium and 1,25(OH) 2 levels in nephrectomized mice were unexpected but have been observed by other investigators. 24,[40][41][42] One possible reason for the varying metabolic changes observed in nephrectomized mice may be the preserved sensitivity of the remnant kidney to elevated PTH, which could lead to increased 1,25(OH) 2 production and consequent increased bone mass. Our findings, together with previous reports, confirm the difference in mineral and bone metabolism between the nephrectomized mouse model and human CKD.…”

Association of Serum Sclerostin with Bone Sclerostin in Chronic Kidney Disease is Lost in Glucocorticoid Treated Patients

“…Silencing of the SOST gene or treatment with a sclerostin antibody in mice has rendered conflicting results concerning the association of serum sclerostin with bone turnover [34][35][36]. Possible explanations are differences in experimental methods, sclerostin assays, type of bone, and species specific differences in regulation of bone turnover.…”