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Although recognized as a major complication of chronic kidney disease (CKD), the pathophysiology of the CKD-related mineral and bone disorder (CKD-MBD) is not completely understood. Recently, the inhibition of Wnt/β-catenin pathway in osteocytes by sclerostin has been shown to play a role in CKD-MBD. The study by Carrilo-Lopez et al. confirms this inhibition in an experimental model of CKD. Moreover, they describe direct actions of FGF23-Klotho on osteoblasts, increasing the expression of DKK1, another Wnt/β-catenin pathway inhibitor., (Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Osteocytes respond to kidney damage by increasing production of secreted factors important to bone and mineral metabolism. These circulating proteins include the antianabolic factor, sclerostin, and the phosphaturic hormone, fibroblast growth factor 23 (FGF23). Elevated sclerostin levels correlate with increased FGF23, localized reduction in Wnt/β-catenin signaling in the skeleton and reduced osteoblast differentiation/activity. Decreased Wnt/β-catenin signaling occurs regardless of the overall changes in bone formation rates, suggesting that a reduction in the anabolic response may be a common feature of renal bone disorders but additional mechanisms may contribute to the diversity of osteodystrophy phenotypes. Recent preclinical studies support this hypothesis, as treatment with antisclerostin antibodies improved bone quality in the context of low but not high turnover renal osteodystrophy. Sclerostin also appears in the circulation suggesting additional roles outside the skeleton in normal and disease states. In patients with chronic kidney disease (CKD), serum levels are elevated several fold relative to healthy individuals. Emerging data suggest that these changes are associated with increased fracture rates but the relationship between sclerostin and cardiovascular disease is unclear. Additional epidemiologic studies that examine stage specific and patient sub-populations are needed to assess whether sclerostin elevations influence comorbidities associated with CKD., (© 2015 Wiley Periodicals, Inc.)

Declining kidney function is associated with sequential systemic changes in mineral homeostasis leading to pathologic alterations in the cardiovascular system and the skeleton. One of the earliest changes in response to renal injury is the increased osteocyte production of secreted factors including the anti-anabolic protein, sclerostin. Elevated sclerostin is associated with reduced Wnt/β-catenin signaling in bone and decreased osteoblast differentiation/activity. Agents that directly or indirectly inhibit β-catenin signaling have differential skeletal effects suggesting additional mechanisms contribute to the diversity of renal osteodystrophies. Similarly, Wnt/β-catenin activation in smooth muscle cells contributes to cardiovascular calcification yet emerging data suggests that this pathway may also be protective when elevated in neighboring tissues. The ongoing epidemiology studies examining the relationship between circulating sclerostin and cardiovascular disease, particularly those that investigate stage specific and/or patient sub-populations, will be useful in understanding the overall contributions of this pathway, its antagonist sclerostin, and the progression of CKD-MBD.