Kidney Week

Abstract: PO0533

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

Session Information

• Bone and Mineral Metabolism: Causes and Consequences
  November 04, 2021 | Location: On-Demand, Virtual Only
  Abstract Time: 10:00 AM - 12:00 PM

Category: Bone and Mineral Metabolism

• 401 Bone and Mineral Metabolism: Basic

Authors

• Wang, Xueyan, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Xueyan Wang, MS

• Spindler, Jadeah Jeannine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Jadeah Jeannine Spindler,

• Courbon, Guillaume, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Guillaume Courbon,

• Martinez-Calle, Marta, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Marta Martinez-Calle,

• Chang, Wenhan, University of California San Francisco Department of Medicine, San Francisco, California, United States

Wenhan Chang,

• Feng, Jian, Texas A&M University, Dallas, Texas, United States

Jian Feng,

• David, Valentin, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Valentin David,

• Martin, Aline, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Aline Martin,

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 (Dmp1^KO) mice. We studied the bone and mineral phenotype of WT, Fgf23^cKO, Dmp1^KO and Dmp1^KO/Fgf23^cKO mice at 12 and 20 weeks of age.

Results

Fgf23^cKO 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 Dmp1^KO 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 Dmp1^KO mice partially corrected FGF23 levels (-80%), PTH levels (-50%), and ameliorated the bone phenotype (+50% in femur length and bone mineral density) (vs. Dmp1^KO). 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 Dmp1^KO/Fgf23^cKO mice which showed recurrent hypophosphatemia despite nearly normal FGF23 levels. In contrast, phosphaturia persisted in Dmp1^KO/Fgf23^cKO mice at 12 and 20 weeks (vs. Dmp1^KO), suggesting that lowering FGF23 and PTH is insufficient to prevent phosphaturia in Dmp1^KO mice.

Conclusion

These data suggest that in DMP1^KO 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