Abstract: FR-PO423
Sclerostin and Wnt Signaling in Pediatric Renal Osteodystrophy
Session Information
- Pediatric Nephrology - I
November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Pediatric Nephrology
- 1800 Pediatric Nephrology
Authors
- Albrecht, Lauren V., University of California Irvine School of Biological Sciences, Irvine, California, United States
- Laster, Marciana, University of California Los Angeles David Geffen School of Medicine, Los Angeles, California, United States
Background
Renal osteodystrophy (ROD) is a complex disorder of bone and mineral metabolism that impacts pediatric CKD patients. Adverse clinical consequences of ROD include bone loss, increased fractures, and cardiovascular events, which often persist into adulthood. Current therapies and biomarkers of disease are limited by a lack of molecular insight into the mechanisms of disease at the cellular level. An emerging player in CKD progression is the osteocyte and its secreted factors. Sclerostin is secreted from osteocytes and leads to decreased bone formation through the inhibition of the Wnt signaling pathway. Whether sclerostin is misregulated in pediatric ROD and contributes to bone loss through the inhibition of the Wnt signaling pathway remains to be defined. Understanding the molecular underpinnings of ROD and the impact of relative signaling pathways could help to develop new targeted therapies or biomarkers.
Methods
Cross-sectional analysis of ROD pediatric CKD patients were used to evaluate bone sclerostin expression by immunofluorescence analyses. Bone biopsies were evaluated from patients before and after dialysis treatments. Sclerostin expression was evaluated with antibodies towards phosphorylated b-catenin and an unphosphorylated (active) b-catenin, marking Wnt inhibition or activity, respectively.
Results
We report that pediatric ROD patients demonstrated elevated levels of serum sclerostin was elevated in both early and late CKD. The increased levels of sclerostin in circulation were associated with histomorphometric parameters of bone turnover and mineralization. High resolution microscopy immunofluorescence revealed that the levels of sclerostin expression in bone corresponded to relative levels of circulating sclerostin. Further, sclerostin expression in bone was colocalized with a classic marker of Wnt inhibition with a phosphorylated β-catenin antibody. Patients with lower circulating sclerostin levels osteocytes had increased levels of an unphosphorylated β-catenin antibody, which indicates Wnt signaling activity.
Conclusion
We report that sclerostin expression in bone regulates the canonical Wnt pathway, which results in elevated serum sclerostin and regulation of Wnt signaling by sclerostin. These new insights into the pathogenesis of CKD-MBD raise the possibility that sclerostin should be investigated as a potential biomarker and/or therapeutic target in pediatric ROD.
Funding
- NIDDK Support