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Abstract: TH-OR34

Direct Effects of FGF23 on Osteoblasts Contribute to Bone Defects in Dmp1KO Mice Independently of Phosphate

Session Information

Category: Bone and Mineral Metabolism

  • 501 Bone and Mineral Metabolism: Basic

Authors

  • Kentrup, Dominik, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Courbon, Guillaume, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Tsai, Hao-Hsuan, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Wang, Xueyan, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Von Drasek, John Charles, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Spindler, Jadeah Jeannine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Hivert, Lauriane, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • David, Valentin, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Martin, Aline, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
Background

Fibroblast growth factor 23 (FGF23) is a phosphate (Pi)-regulating hormone produced in bone. Hereditary hypophosphatemic disorders are associated with FGF23 excess that leads to hypophosphatemia, impaired skeletal growth, rickets and osteomalacia. The blockade of FGF23 signaling to correct serum Pi levels has become a superior therapeutic strategy to Pi supplementation in X-linked hypophosphatemia, but remains untested in autosomal recessive hypophosphatemic rickets (ARHR). In this study, we compared the effects of reducing circulating FGF23 levels using osteocyte-specific deletion of Fgf23 (Fgf23cKO) to the effects of dietary Pi supplementation in the Dmp1 knockout (Dmp1KO) mouse model of ARHR.

Methods

We deleted Fgf23 specifically in osteocytes (Fgf23cKO) using a Dmp1-cre recombinase, in wild-type (WT) and Dmp1KO mice. In addition, we fed WT and Dmp1KO mice a diet containing either 0.5% (NP) or 2% Pi (HP). In parallel, we cultured primary osteoblasts isolated from WT, Fgf23cKO, Dmp1KO and Dmp1KO/Fgf23cKO mice to understand the direct impact of FGF23 and DMP1 on osteoblast differentiation and activity.

Results

Compared with WT mice and concurrent with successful Fgf23 deletion, Fgf23cKO mice showed reduced serum FGF23 levels and increased serum Pi levels, whereas Dmp1KO mice displayed highly increased serum FGF23 levels, hypophosphatemia, impaired growth, rickets and osteomalacia. In contrast, Dmp1KO/Fgf23cKO mice showed a near complete correction of FGF23 excess, which fully restored serum Pi levels, but only partially corrected the bone phenotype. Compared to NP diet, HP diet increased circulating FGF23 levels, PTH levels, and phosphaturia in WT mice. HP-Dmp1KO mice remained hypophosphatemic and showed exacerbated FGF23 production, hyperparathyroidism, and phosphaturia, resulting in a worsened bone phenotype. In vitro, we found that FGF23 directly impairs osteoblast differentiation and that DMP1 deficiency contributes to impaired mineralization independently of FGF23 or Pi levels.

Conclusion

To conclude, our data suggest that the direct effects of FGF23 and DMP1 on osteoblasts need to be considered to effectively correct ARHR-associated mineral and bone disorders, independently of hypophosphatemia.

Funding

  • NIDDK Support