title: Repression of osteocyte Wnt/β-catenin signaling is an early event in the progression of renal osteodystrophy.
abstract: Chronic kidney disease-mineral bone disorder (CKD-MBD) is defined by abnormalities in mineral and hormone metabolism, bone histomorphometric changes, and/or the presence of soft-tissue calcification. Emerging evidence suggests that features of CKD-MBD may occur early in disease progression and are associated with changes in osteocyte function. To identify early changes in bone, we utilized the jck mouse, a genetic model of polycystic kidney disease that exhibits progressive renal disease. At 6 weeks of age, jck mice have normal renal function and no evidence of bone disease but exhibit continual decline in renal function and death by 20 weeks of age, when approximately 40% to 60% of them have vascular calcification. Temporal changes in serum parameters were identified in jck relative to wild-type mice from 6 through 18 weeks of age and were subsequently shown to largely mirror serum changes commonly associated with clinical CKD-MBD. Bone histomorphometry revealed progressive changes associated with increased osteoclast activity and elevated bone formation relative to wild-type mice. To capture the early molecular and cellular events in the progression of CKD-MBD we examined cell-specific pathways associated with bone remodeling at the protein and/or gene expression level. Importantly, a steady increase in the number of cells expressing phosphor-Ser33/37-β-catenin was observed both in mouse and human bones. Overall repression of Wnt/β-catenin signaling within osteocytes occurred in conjunction with increased expression of Wnt antagonists (SOST and sFRP4) and genes associated with osteoclast activity, including receptor activator of NF-κB ligand (RANKL). The resulting increase in the RANKL/osteoprotegerin (OPG) ratio correlated with increased osteoclast activity. In late-stage disease, an apparent repression of genes associated with osteoblast function was observed. These data confirm that jck mice develop progressive biochemical changes in CKD-MBD and suggest that repression of the Wnt/β-catenin pathway is involved in the pathogenesis of renal osteodystrophy.
authors.affiliation: The Sanofi-Genzyme R&D Center, Genzyme, A Sanofi Company, Framingham, MA 01701, USA.
authors.forename: Yves
authors.initials: Y
authors.lastname: Sabbagh
authors.forename: Fabiana Giorgeti
authors.initials: FG
authors.lastname: Graciolli
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Brien
authors.forename: Wen
authors.initials: W
authors.lastname: Tang
authors.forename: Luciene Machado
authors.initials: LM
authors.lastname: dos Reis
authors.forename: Susan
authors.initials: S
authors.lastname: Ryan
authors.forename: Lucy
authors.initials: L
authors.lastname: Phillips
authors.forename: Joseph
authors.initials: J
authors.lastname: Boulanger
authors.forename: Wenping
authors.initials: W
authors.lastname: Song
authors.forename: Christina
authors.initials: C
authors.lastname: Bracken
authors.forename: Shiguang
authors.initials: S
authors.lastname: Liu
authors.forename: Steven
authors.initials: S
authors.lastname: Ledbetter
authors.forename: Paul
authors.initials: P
authors.lastname: Dechow
authors.forename: Maria Eugenia F
authors.initials: ME
authors.lastname: Canziani
authors.forename: Aluizio B
authors.initials: AB
authors.lastname: Carvalho
authors.forename: Vanda
authors.initials: V
authors.lastname: Jorgetti
authors.forename: Rosa M A
authors.initials: RM
authors.lastname: Moyses
authors.forename: Susan C
authors.initials: SC
authors.lastname: Schiavi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001706:Biopsy; D016723:Bone Remodeling; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D002113:Calcification, Physiologic; D018376:Cardiovascular Abnormalities / Q000097:blood / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D012080:Chronic Kidney Disease-Mineral and Bone Disorder / Q000097:blood / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007676:Kidney Failure, Chronic / Q000097:blood / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D000072379:NIMA-Related Kinases; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D010011:Osteocytes / Q000378:metabolism* / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D061205:Vascular Calcification; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C486030:Sost protein, mouse; D000072379:NIMA-Related Kinases; C499219:Nek8 protein, mouse; D017346:Protein Serine-Threonine Kinases