CKD-induced wingless/integration1 inhibitors and phosphorus cause the CKD-mineral and bone disorder

Yifu Fang, Charles Ginsberg, Michael Seifert, Olga Agapova, Toshifumi Sugatani, Thomas C. Register, Barry I. Freedman, Marie Claude Monier-Faugere, Hartmut Malluche, Keith A. Hruska

Research output: Contribution to journalArticlepeer-review

100 Scopus citations

Abstract

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-2mice by administration of amonoclonal 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 smoothmuscleprotein 22-a, and restoredaortic expressionof 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 andphosphate binder therapy completely treated theCKD-MBD.These results showthat circulating Wnt inhibitors are involved in the pathogenesis of CKD-MBDand that the combination ofDkk1 neutralization and phosphate binding may have therapeutic potential for this disorder.

Original languageEnglish
Pages (from-to)1760-1773
Number of pages14
JournalJournal of the American Society of Nephrology
Volume25
Issue number8
DOIs
StatePublished - Aug 1 2014

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