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.