Repression of osteocyte Wnt/β-catenin signaling is an early event in the progression of renal osteodystrophy


Yves Sabbagh, Fabiana Giorgeti Graciolli, Stephen O'Brien, Wen Tang, Luciene Machado dos Reis, Susan Ryan, Lucy Phillips, Joseph Boulanger, Wenping Song, Christina Bracken, Shiguang Liu, Steven Ledbetter, Paul Dechow, Maria Eugenia F Canziani, Aluizio B Carvalho, Vanda Jorgetti, Rosa MA Moyses, Susan C Schiavi


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 40-60% 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 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 RANKL. The resulting increase in the RANKL/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.

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