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Sclerostin deficiency modifies the development of CKD-MBD in mice

Kaesler, Nadine and Verhulst, Anja and De Maré, Annelies and Deck, Annika and Behets, Geert J. and Hyusein, Ayshe and Evenepoel, Pieter and Floege, Jürgen and Marx, Nikolaus and Babler, Anne and Kramer, Ina and Kneissel, Michaela and Kramann, Rafael and Weis, Daniel and D`Haese, Patrick C. and Brandenburg, Vincent M. (2017) Sclerostin deficiency modifies the development of CKD-MBD in mice. Bone. ISSN 1873-2763; 8756-3282

Abstract

Sclerostin is a soluble antagonist of canonical Wnt signaling and a strong inhibitor of bone
formation. We present experimental data on the role of sclerostin in chronic kidney disease -
bone mineral disorder (CKD-MBD).
Methods: We performed 5/6 nephrectomies in 36-week-old sclerostin-deficient (SOST-/-) B6-
mice and in C57BL/6J wildtype (WT) mice. Animals received a high phosphate diet for 11
weeks. The bones were analyzed by high-resolution micro-computed tomography (μCT) and
quantitative bone histomorphometry. Aortic tissue was analyzed regarding the extent of
vascular calcification.
Results: All nephrectomized mice had severe renal failure, and parathyroid hormone was
highly increased compared to corresponding sham animals. All SOST-/- animals revealed the
expected high bone mass phenotype. Overall, the bone compartment in WT and SOST-/- mice
responded similarly to nephrectomy. In uremic WT animals, μCT data at both the distal femur
and lumbar spine revealed significantly increased trabecular volume compared to non-uremic
WTs. In SOST-/- mice, the differences between trabecular bone volume were less pronounced
when comparing uremic with sham animals. Cortical thickness and cortical bone density at
the distal femur decreased significantly and comparably in both genotypes after 5/6
nephrectomy compared to sham animals (cortical bone density -18% and cortical thickness -
32%). Overall, 5/6 nephrectomy and concomitant hyperparathyroidism led to a genotypeindependent
loss of cortical bone volume and density. Overt vascular calcification was not
detectable in either of the genotypes.
Conclusion: Renal osteodystrophy changes were more pronounced in WT mice than in
SOST-/- mice. The high bone mass phenotype of sclerostin deficiency was detectable also in
the setting of chronic renal failure with severe secondary hyperparathyroidism.

Item Type: Article
Date Deposited: 13 Dec 2017 00:45
Last Modified: 13 Dec 2017 00:45
URI: https://oak.novartis.com/id/eprint/34490

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