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

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 Dmp1KO 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 Dmp1KO male mice and in 20-week-old WT, Fgf23cKO, Dmp1KO, and Dmp1KO/Fgf23cKO male and female mice. Results: As expected, at 12 and 20 weeks of age, Dmp1KO 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, Fgf23cKO mice showed a 40% reduction in FGF23 levels. In contrast with Dmp1KO male mice, FGF23 levels were further increased in Dmp1KO females (+18-fold vs. WT). However, this led only to a 15% reduction in serum Pi levels. Similar to Dmp1KO males, Dmp1KO 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 Dmp1KO 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