title: CKD-induced wingless/integration1 inhibitors and phosphorus cause the CKD-mineral and bone disorder.
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.affiliation: Departments of Pediatrics/Nephrology and.
authors.forename: Yifu
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Medicine, Washington University, St. Louis, Missouri;
authors.forename: Charles
authors.initials: C
authors.lastname: Ginsberg
authors.affiliation: Departments of Pediatrics/Nephrology and Department of Pediatric Nephrology, Southern Illinois School of Medicine, Springfield, Illinois;
authors.forename: Michael
authors.initials: M
authors.lastname: Seifert
authors.affiliation: Departments of Pediatrics/Nephrology and.
authors.forename: Olga
authors.initials: O
authors.lastname: Agapova
authors.affiliation: Departments of Pediatrics/Nephrology and.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Sugatani
authors.affiliation: Pathology, and.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Register
authors.affiliation: Internal Medicine/Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina; and.
authors.forename: Barry I
authors.initials: BI
authors.lastname: Freedman
authors.affiliation: Department of Medicine/Nephrology, University of Kentucky, Lexington, Kentucky.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Monier-Faugere
authors.affiliation: Department of Medicine/Nephrology, University of Kentucky, Lexington, Kentucky.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Malluche
authors.affiliation: Departments of Pediatrics/Nephrology and Medicine, Washington University, St. Louis, Missouri; hruska_k@kids.wustl.edu.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Hruska
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000818:Animals; D001851:Bone Diseases, Metabolic / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004311:Double-Blind Method; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005966:Glucuronidase / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D000090265:Klotho Proteins; D007811:Lanthanum / Q000627:therapeutic use; D008297:Male; D008810:Mice, Inbred C57BL; D010710:Phosphates / Q000378:metabolism*; D016226:Phosphorus, Dietary; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D051155:Wnt1 Protein / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; C501127:Dkk1 protein, mouse; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D010710:Phosphates; D016226:Phosphorus, Dietary; C486030:Sost protein, mouse; C483887:Sostdc1 protein, mouse; D051155:Wnt1 Protein; C119467:lanthanum carbonate; D005346:Fibroblast Growth Factors; D007811:Lanthanum; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase; D000090265:Klotho Proteins