Kidney Week

Abstract: FR-PO263

Increased FGF23 Production in CKD Is Associated with Altered Osteocyte Development and Bone Mineralization

Session Information

• Mineral Disease: Vitamin D, PTH, FGF23
  November 03, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Mineral Disease

• 1202 Mineral Disease: Vitamin D, PTH, FGF-23

Authors

• Dussold, Corey, Northwestern University, Chicago, Illinois, United States

Corey Dussold,

• Neuburg, Samantha, Northwestern University, Chicago, Illinois, United States

Samantha Neuburg,

• Liu, Ying, Texas A&M-Baylor College of Dentistry, Dallas, Texas, United States

Ying Liu,

• Feng, Jian, Texas A&M-Baylor College of Dentistry, Dallas, Texas, United States

Jian Feng,

• Wang, Xueyan, Northwestern University, Chicago, Illinois, United States

Xueyan Wang,

• David, Valentin, Northwestern University, Chicago, Illinois, United States

Valentin David,

• Wolf, Myles S., Duke University, Durham, North Carolina, United States

Myles S. Wolf,

• Martin, Aline, Northwestern University, Chicago, Illinois, United States

Aline Martin,

Background

Fibroblast growth factor (FGF)-23 is a hormone produced by osteocytes that regulates phosphate (Pi) homeostasis. Chronic kidney disease mineral and bone disease (CKD-MBD) leads to alterations of mineral and bone metabolism, including elevation of circulating FGF23 levels that is associated with increased risk of cardiovascular mortality. The mechanism of increased FGF23 in CKD is poorly understood and the impact of CKD on osteocyte development and maturation has not been described. We tested the hypothesis that CKD induces changes in osteocyte morphology that result in altered osteocyte network, bone mineralization and mineral metabolism.

Methods

Using 3D-microtomography, acid-etched scanning electron microscopy, whole bone FITC staining and Imaris modelisation, we studied the bone and osteocyte phenotype of 9 week-old Col4a3^KO mice with advanced CKD and wild-type (WT) littermates. We assessed in vitro matrix mineralization by alizarin red S (ARS) staining and osteoblast differentiation by alkaline phosphatase (ALP) staining of WT and Col4a3^KO isolated primary osteoblasts (BMSCs). In parallel, we measured serum FGF23 and Pi levels, assessed renal function and measured FGF23 mRNA expression in vitro and in vivo.

Results

Renal function was dramatically impaired in Col4a3^KO mice (BUN: 100±12 vs 18±1 mg/dL) and we observed a 15-fold increase in bone FGF23 mRNA expression, a 70-fold increase in serum FGF23 and a 50% increase in serum Pi levels (p<0.05 vs. WT for each). Col4a3^KO mice displayed a 5% decrease in bone mineral density and a rounder, less polarized osteocyte morphology (osteocyte roundness index: 0.43±0.17 vs. 0.34±0.12) (p<0.05 vs. WT for each). The osteocyte network showed an 80% reduction in number and length of the dendritic processes (p<0.05 vs. WT). In vitro, Col4a3^KO BMSCs maintained intrinsic abnormalities in activity and mineralization (-40% ALP activity and ARS; p<0.05 vs. WT).

Conclusion

Our data show that impaired osteocyte morphology and function is associated with defective bone mineralization and FGF23 overproduction in CKD. Whether altered osteocyte morphology is a cause of FGF23 overproduction and whether rescue of the bone mineralization and osteocyte morphology defects could prevent FGF23 elevation in CKD requires further investigation.

Funding

• NIDDK Support