Sclerostin deficiency modifies the development of CKD-MBD in mice.

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 11weeks. 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 genotype-independent 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.

• Authors: Nadine Kaesler, Anja Verhulst, Annelies De Maré, Annika Deck, Geert J Behets, Ayshe Hyusein, Pieter Evenepoel, Jürgen Floege, Nikolaus Marx, Anne Babler, Ina Kramer, Michaela Kneissel, Rafael Kramann, Daniel Weis, Patrick C D'Haese, Vincent M Brandenburg
• Journal: Bone (Bone) Vol. 107 Pg. 115-123 (02 2018) ISSN: 1873-2763 [Electronic] United States
• PMID: 29175269 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• Adaptor Proteins, Signal Transducing
• Glycoproteins
• Intercellular Signaling Peptides and Proteins
• Sost protein, mouse

Topics

• Adaptor Proteins, Signal Transducing
• Animals
• Chronic Kidney Disease-Mineral and Bone Disorder (metabolism, pathology)
• Female
• Glycoproteins (deficiency)
• Intercellular Signaling Peptides and Proteins
• Mice
• Mice, Inbred C57BL
• Mice, Knockout