Disturbances of Wnt/ -catenin pathway and energy metabolism in early CKD: effect of phosphate binders

Oliveira, Rodrigo Bueno de; Graciolli, Fabiana G.; Reis, Luciene M. dos; Cancela, Ana; Cuppari, Lílian; Canziani, María Eugênia Fernandes; Carvalho, Aluízio Barbosa de; Jorgetti, Vanda; Moysés, Rosa Maria Affonso

doi:10.1093/ndt/gft234

Cited by 44 publications

(21 citation statements)

References 42 publications

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“…In animal models of early CKD caused by polycystic kidney disease and Alport's disease, normal or elevated modeling rates were observed as osteodystrophy was detected, despite findings of decreased nuclear b-catenin in osteocytes and elevated sclerostin levels. 15,55,56 Wnt and PTH are regulators of the skeletal stem cell niche, 18,57,58 and Wnt inhibition produces PTH-mediated adaptation, which maintained remodeling rates in CKD. Here, Dkk1 neutralization prevented the development of renal osteodystrophy.…”

Section: Discussionmentioning

confidence: 99%

“…Increased osteocyte expression of sclerostin was also shown along with decreased portmanteau of Wingless and Integration1 (Wnt) signaling. 14,15,18 Thus, the early CKD-MBD is characterized as increased levels of bone turnover inhibitory signals, elevated production of osteocytic proteins FGF23 and sclerostin, the onset of renal osteodystrophy, dedifferentiation in the vascular smooth muscle, and the stimulation of vascular calcification. 11,13,15,19 This new characterization of the early CKD-MBD when Ca, Pi, PTH, and calcitriol levels are normal raises the question of its pathogenesis.…”

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confidence: 99%

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CKD-Induced Wingless/Integration1 Inhibitors and Phosphorus Cause the CKD–Mineral and Bone Disorder

Fang¹,

Ginsberg

Seifert

et al. 2014

Journal of the American Society of Nephrology

149

176

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In chronic kidney disease, vascular calcification, renal osteodystrophy, and phosphate contribute substantially to cardiovascular risk and are components of CKD-mineral and bone disorder (CKD-MBD). The cause of this syndrome is unknown. Additionally, no therapy addresses cardiovascular risk in CKD. In its inception, CKD-MBD is characterized by osteodystrophy, vascular calcification, and stimulation of osteocyte secretion. We tested the hypothesis that increased production of circulating factors by diseased kidneys causes the CKD-MBD in diabetic mice subjected to renal injury to induce stage 2 CKD (CKD-2 mice). Compared with non-CKD diabetic controls, CKD-2 mice showed increased renal production of Wnt inhibitor family members and higher levels of circulating Dickkopf-1 (Dkk1), sclerostin, and secreted klotho. Neutralization of Dkk1 in CKD-2 mice by administration of a monoclonal antibody after renal injury stimulated bone formation rates, corrected the osteodystrophy, and prevented CKD-stimulated vascular calcification. Mechanistically, neutralization of Dkk1 suppressed aortic expression of the osteoblastic transcription factor Runx2, increased expression of vascular smooth muscle protein 22-a, and restored aortic expression of klotho. Neutralization of Dkk1 did not affect the elevated plasma levels of osteocytic fibroblast growth factor 23 but decreased the elevated levels of sclerostin. Phosphate binder therapy restored plasma fibroblast growth factor 23 levels but had no effect on vascular calcification or osteodystrophy. The combination of the Dkk1 antibody and phosphate binder therapy completely treated the CKD-MBD. These results show that circulating Wnt inhibitors are involved in the pathogenesis of CKD-MBD and that the combination of Dkk1 neutralization and phosphate binding may have therapeutic potential for this disorder. CKD is a pandemic affecting 26 million Americans in its early stages. 1 CKD is associated with high rates of cardiovascular mortality, making it much more likely that affected individuals will sustain cardiovascular morbidity, including death, than reach end stage kidney disease that requires RRT.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

CKD-Induced Wingless/Integration1 Inhibitors and Phosphorus Cause the CKD–Mineral and Bone Disorder

Fang¹,

Ginsberg

Seifert

et al. 2014

Journal of the American Society of Nephrology

149

176

View full text Add to dashboard Cite

show abstract

“…12 A disturbed phosphate metabolism may also be implicated in its increased expression. 34 In a CKD animal model of adynamic bone disease, high dietary phosphate intake was associated with a high osteocytic expression of SOST. 35 Moreover, a significant and independent positive association has been observed between serum phosphate, FGF23, and sclerostin concentrations in different cohort studies.…”

Section: Determinants and Correlates Of Circulating Sclerostinmentioning

confidence: 99%

Sclerostin and DKK1: new players in renal bone and vascular disease

Evenepoel

D’Haese

Brandenburg

2015

Kidney International

125

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For more than a decade, the Wnt-β-catenin pathway has been the focus of intense basic and clinical research in the bone field because of its importance in skeletal development and maintenance of bone mass. Wnt activation increases bone formation and decreases bone resorption. The Wnt-β-catenin signaling pathway is tightly regulated by several inhibitors, among which Dickkopf-related protein 1 (DKK1) and sclerostin have been most comprehensively studied. Mounting evidence indicates that a disturbed Wnt-β-catenin signaling is also implicated in the pathogenesis of the chronic kidney disease-associated bone and mineral disorder (CKD-MBD) and affects its various components. DKK1 and sclerostin, more specifically, may be involved in the intense cross-talk between the kidneys, vasculature, and bone. Studies exploring clinical correlates of circulating sclerostin and DKK1 levels so far yielded conflicting results. Biological variability and analytical issues account at least partly for this inconsistency. Antibodies neutralizing Wnt inhibitors may be an appealing strategy to prevent or treat CKD-MBD. Caution is however warranted as sclerostin not only opposes mineralization in the bone but possibly also in the vasculature. Additional studies are required to define determinants of Wnt inhibitors in CKD and to evaluate the efficacy and safety of recently introduced pharmaceuticals targeting these inhibitors.

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“…Indeed, in a cross-sectional study of 154 CKD pre-dialysis patients, higher sclerostin levels correlated with the absence of calcification in addition to increased age, male gender, lower bone-specific alkaline phosphatase, and renal function [44]. In a short 6-week, post hoc analysis of 40 normophosphatemic stage 3-4 CKD patients, sevelamer-HCl, but not calcium acetate, treatment was associated with a significant decrease in sclerostin levels [45]. However, this study did not correlate expression with vascular calcification or other cardiac complications.…”

Section: Association Of Sclerostin With Clinical Outcomesmentioning

confidence: 97%

Sclerostin and CKD-MBD

Schiavi

2015

Curr Osteoporos Rep

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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.

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Disturbances of Wnt/ -catenin pathway and energy metabolism in early CKD: effect of phosphate binders

Abstract: Early stages of CKD are associated with an impairment of the Wnt pathway, as reflected by elevated sclerostin, and a dysregulation of energy-regulating hormones. Many of these disturbances can be ameliorated by phosphate binder treatment, more with sevelamer-HCl than with calcium acetate.

Cited by 44 publications

References 42 publications

CKD-Induced Wingless/Integration1 Inhibitors and Phosphorus Cause the CKD–Mineral and Bone Disorder

CKD-Induced Wingless/Integration1 Inhibitors and Phosphorus Cause the CKD–Mineral and Bone Disorder

Sclerostin and DKK1: new players in renal bone and vascular disease

Sclerostin and CKD-MBD

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