Kidney Week

Abstract: TH-OR057

Fibroblast Growth Factor 23 (FGF-23) Induces Left Ventricular Hypertrophy in Mice with Autosomal Recessive Hypophosphatemia

Session Information

• New Developments in Bones, Stones, and Mineral Metabolism
  November 06, 2025 | Location: Room 370A, Convention Center
  Abstract Time: 04:50 PM - 05:00 PM

Category: Bone and Mineral Metabolism

• 501 Bone and Mineral Metabolism: Basic

Authors

• Kentrup, Dominik, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Dominik Kentrup, PhD

• Tsai, Hao-Hsuan, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Hao-Hsuan Tsai

• 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

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

Valentin David, MS, PhD

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

Aline Martin, MS, PhD

Background

Fibroblast growth factor 23 (FGF23) is a phosphate (Pi)-regulating hormone mainly produced by osteocytes. Elevated levels of FGF23 induce left ventricular hypertrophy (LVH) in humans and animals with chronic kidney disease (CKD). X-linked hypophosphatemia (XLH) and autosomal recessive hypophosphatemic rickets (ARHR) are rare hereditary diseases caused respectively by loss-of-function mutations in Pi-regulating endopeptidase X-linked (Phex) and dentin matrix protein 1 (Dmp1) that result in FGF23 excess and overlapping characteristics without a decline in kidney function. Studies showed that FGF23 excess contributes to LVH in humans and animals with XLH, but it has not been studied in ARHR.

Methods

To study the role of FGF23 on the development of LVH in male and female mice with ARHR, we deleted Fgf23 specifically in osteocytes of wild-type (WT) and Dmp1^KO mice using a Dmp1-cre recombinase, and we assessed circulating markers of mineral metabolism as well as heart morphology and function in 12-week-old WT and Dmp1^KO male mice and in 20-week-old WT, Fgf23^cKO, Dmp1^KO, and Dmp1^KO/Fgf23^cKO male and female mice.

Results

As expected, at 12 and 20 weeks of age, Dmp1^KO male mice showed similar increases in FGF23 levels (+14-fold vs. WT) that resulted in hypophosphatemia (-35% serum Pi vs. WT). However, only 20 but not 12-week-old males developed LVH. Twenty-week-old WT females showed nearly twice as much FGF23 in the circulation compared to WT males. As expected, Fgf23^cKO mice showed a 40% reduction in FGF23 levels. In contrast with Dmp1^KO male mice, FGF23 levels were further increased in Dmp1^KO females (+18-fold vs. WT). However, this led only to a 15% reduction in serum Pi levels. Similar to Dmp1^KO males, Dmp1^KO females developed LVH, albeit less severe. The osteocyte-specific deletion of Fgf23 reduced circulating FGF23 excess by 80% and prevented the development of LVH in male and female Dmp1^KO mice.

Conclusion

To conclude, our results show that hypophosphatemic mice with ARHR develop FGF23-induced cardiac hypertrophy notably in absence of hyperphosphatemia, in mice with normal kidney function. We further show that females with ARHR show greater FGF23 excess than males, and a milder LVH for the degree of FGF23 excess. In aggregate, our study suggests that patients with ARHR might benefit from FGF23-lowering therapies.

Funding

• NIDDK Support

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.20257pgtyzpy