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Canonical Wnt signaling activity contributes to physiological and adaptive bone mineralization and is an essential player in bone remodeling. Sclerostin is a prototypic soluble canonical Wnt signaling pathway inhibitor that is produced in osteocytes and blocks osteoblast differentiation and function. Therefore, sclerostin is a potent inhibitor of bone formation and mineralization. Accordingly, rodent sclerostin-deficiency models exhibit a strong bone phenotype. Moreover, blocking sclerostin represents a promising treatment perspective against osteoporosis. Beyond the bone field novel data definitely associate Wnt signaling in general and sclerostin in particular with ectopic extraosseous mineralization processes, as is evident in cardiovascular calcification or calciphylaxis. Uremia is characterized by parallel occurrence of disordered bone mineralization and accelerated cardiovascular calcification (chronic kidney disease mineral and bone disorder, CKD-MBD), linking skeletal and cardiovascular diseasethe so-called bone-vascular calcification paradox. In consequence, sclerostin may qualify as an emerging player in CKD-MBD. We present a stepwise review approach regarding the rapidly evolving field sclerostin participation in CKD-MBD. Starting from data originating in the classical bone field we look separately at three major areas of CKD-MBD: disturbed mineral metabolism, renal osteodystrophy, and uremic cardiovascular disease. Our review is intended to help the nephrologist revise the potential importance of sclerostin in CKD by focusing on how sclerostin research is gradually evolving from the classical osteoporosis niche into the area of CKD-MBD. In particular, we integrate the limited amount of available data in the context of pediatric nephrology.

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 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. Abbreviations α-SMA, alpha smooth muscle actin; AjAR, adjusted apposition rate; B.Ar, bone area; BFR, bone formation rate; cbfa1, core binding factor 1; CKD-MBD, chronic kidney disease and mineral bone disorder; EPm, eroded perimeter; Ntx, nephrectomy; O.Ar, osteoid area; Ob, osteoblast perimeter; Oc, osteoclast perimeter; O.Wi, osteoid width; PTH, parathyroid hormone; s.c., subcutaneous; VSMCs, vascular smooth muscle cells; WT, wildype

Sclerostin is an endocrine regulator in chronic kidney disease - mineral and bone disorder (CKD-MBD). Validation of assay comparability and pre-analytical handling is mandatory for establishment of sclerostin as a biomarker.Blood samples (serum, EDTA, heparin and citrate plasma) were obtained from 12 hemodialysis (HD) patients after the long dialysis interval. Passing-Bablok regression analysis and Bland-Altman difference plots were used to evaluate the agreement between sclerostin levels measured with two commercially available ELISAs from TECOmedical and Biomedica.Independent of the sample type, the agreement of the two assays was poor with a strong proportional but no systematic bias. Compared to the TECOmedical assay, the Biomedica test yielded almost 2-fold higher sclerostin values throughout all sample types. Spike recovery and linear dilution studies revealed a higher accuracy of the TECOmedical assay (97% and 96%) compared to the Biomedica assay (118% and 78%). Sclerostin levels were stable within 4 hours after sample collection, in particular when analyzed in plasma. In contrast to the Biomedica assay, the TECOmedical showed a systematic but no proportional bias between serum and plasma samples with higher values for plasma samples. Among the 3 different plasma samples no systematic error could be documented.Careful consideration of the pre-analytical handling and comparative assay validation are necessary to facilitate a more differentiated interpretation of studies reporting circulating sclerostin levels. The presence of a proportional bias demonstrates that in HD patients the two ELISAs for measuring sclerostin should not be used interchangeably. Furthermore, caution is necessary when comparing sclerostin results obtained from different blood sample types.