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Abstract: PO0533

Recurrence of Hypophosphatemia Despite FGF-23 Reduction in Dmp1 Knockout Mice

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Wang, Xueyan, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Spindler, Jadeah Jeannine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Courbon, Guillaume, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Martinez-Calle, Marta, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Chang, Wenhan, University of California San Francisco Department of Medicine, San Francisco, California, United States
  • Feng, Jian, Texas A&M University, Dallas, Texas, 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 phosphaturic hormone produced by bone. Hypophosphatemic rickets diseases, such as X-linked hypophosphatemia (XLH) and autosomal recessive hypophosphatemic rickets (ARHR), are associated with FGF23 excess, impaired skeletal growth and osteomalacia. Treatment with FGF23 blocking antibody has shown great promise to improve serum phosphate (Pi) levels and bone mineralization in XLH. Further studies need to determine if blocking FGF23 is efficacious in the long term and in other diseases associated with FGF23 excess, including ARHR.

Methods

We deleted Fgf23 in osteocytes using a Dmp1-cre in wild-type (WT) and Dmp1 knockout (Dmp1KO) mice. We studied the bone and mineral phenotype of WT, Fgf23cKO, Dmp1KO and Dmp1KO/Fgf23cKO mice at 12 and 20 weeks of age.

Results

Fgf23cKO mice showed a 40% reduction in serum intact FGF23 levels and a 25% increase in Pi levels (vs. WT), confirming successful deletion. As expected, DMP1 deficiency in Dmp1KO mice induced significant elevations in serum FGF23 levels (+15-fold) and PTH levels (+5-fold), phosphaturia, hypophosphatemia, rickets and osteomalacia (vs. WT). At 12 and 20 weeks, osteocyte specific deletion of Fgf23 in Dmp1KO mice partially corrected FGF23 levels (-80%), PTH levels (-50%), and ameliorated the bone phenotype (+50% in femur length and bone mineral density) (vs. Dmp1KO). Partial reduction of FGF23 levels was sufficient to fully correct serum Pi levels in 12 week-old (NS vs. WT), but not in 20 week-old Dmp1KO/Fgf23cKO mice which showed recurrent hypophosphatemia despite nearly normal FGF23 levels. In contrast, phosphaturia persisted in Dmp1KO/Fgf23cKO mice at 12 and 20 weeks (vs. Dmp1KO), suggesting that lowering FGF23 and PTH is insufficient to prevent phosphaturia in Dmp1KO mice.

Conclusion

These data suggest that in DMP1KO mice, hypophosphatemia is only partially responsible for the bone defects and that blocking FGF23 might not be sufficient to prevent hypophosphatemia in the long term.

Funding

  • NIDDK Support