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CKD-induced wingless/integration1 inhibitors and phosphorus cause the CKD-mineral and bone disorder.
J Am Soc Nephrol. 2014 Aug; 25(8):1760-73.JA

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-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-α, 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.

Authors+Show Affiliations

Departments of Pediatrics/Nephrology and.Medicine, Washington University, St. Louis, Missouri;Departments of Pediatrics/Nephrology and Department of Pediatric Nephrology, Southern Illinois School of Medicine, Springfield, Illinois;Departments of Pediatrics/Nephrology and.Departments of Pediatrics/Nephrology and.Pathology, and.Internal Medicine/Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina; and.Department of Medicine/Nephrology, University of Kentucky, Lexington, Kentucky.Department of Medicine/Nephrology, University of Kentucky, Lexington, Kentucky.Departments of Pediatrics/Nephrology and Medicine, Washington University, St. Louis, Missouri; hruska_k@kids.wustl.edu.

Pub Type(s)

Journal Article
Randomized Controlled Trial
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

24578135

Citation

Fang, Yifu, et al. "CKD-induced Wingless/integration1 Inhibitors and Phosphorus Cause the CKD-mineral and Bone Disorder." Journal of the American Society of Nephrology : JASN, vol. 25, no. 8, 2014, pp. 1760-73.
Fang Y, Ginsberg C, Seifert M, et al. CKD-induced wingless/integration1 inhibitors and phosphorus cause the CKD-mineral and bone disorder. J Am Soc Nephrol. 2014;25(8):1760-73.
Fang, Y., Ginsberg, C., Seifert, M., Agapova, O., Sugatani, T., Register, T. C., Freedman, B. I., Monier-Faugere, M. C., Malluche, H., & Hruska, K. A. (2014). CKD-induced wingless/integration1 inhibitors and phosphorus cause the CKD-mineral and bone disorder. Journal of the American Society of Nephrology : JASN, 25(8), 1760-73. https://doi.org/10.1681/ASN.2013080818
Fang Y, et al. CKD-induced Wingless/integration1 Inhibitors and Phosphorus Cause the CKD-mineral and Bone Disorder. J Am Soc Nephrol. 2014;25(8):1760-73. PubMed PMID: 24578135.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - CKD-induced wingless/integration1 inhibitors and phosphorus cause the CKD-mineral and bone disorder. AU - Fang,Yifu, AU - Ginsberg,Charles, AU - Seifert,Michael, AU - Agapova,Olga, AU - Sugatani,Toshifumi, AU - Register,Thomas C, AU - Freedman,Barry I, AU - Monier-Faugere,Marie-Claude, AU - Malluche,Hartmut, AU - Hruska,Keith A, Y1 - 2014/02/27/ PY - 2014/3/1/entrez PY - 2014/3/1/pubmed PY - 2014/12/15/medline SP - 1760 EP - 73 JF - Journal of the American Society of Nephrology : JASN JO - J Am Soc Nephrol VL - 25 IS - 8 N2 - 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-α, 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. SN - 1533-3450 UR - https://www.unboundmedicine.com/medline/citation/24578135/CKD_induced_wingless/integration1_inhibitors_and_phosphorus_cause_the_CKD_mineral_and_bone_disorder_ L2 - https://jasn.asnjournals.org/cgi/pmidlookup?view=long&pmid=24578135 DB - PRIME DP - Unbound Medicine ER -