Understanding The Pathophysiology of X-linked Hypophosphatemia

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2024-12-01

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McGill University

Abstract

X-linked hypophosphatemia (XLH) is a hereditary disorder that causes rickets and osteomalacia. In the 1970s, a mouse model with a natural mutation termed "Hyp" was discovered that faithfully mimicked the skeletal phenotypes of the XLH patients. A loss-of-function mutation in the phosphate-regulating endopeptidase X-linked gene (PHEX) results in the increased production of the phosphaturic hormone Fibroblast Growth Factor 23 (FGF23). FGF23 lowers serum phosphate levels by suppressing proximal tubular phosphate reabsorption and intestinal phosphate absorption. Conventional treatment for XLH comprises phosphate and vitamin D supplements, which improve the circulating serum phosphate levels and correct osteomalacia only partially. Recently developed antibody-based treatment inhibiting FGF23 signaling results in a markedly improved outcomes, but not all the XLH-associated anomalies are corrected fully. In this study, we used a genetic approach to demonstrate that PHEX deficiency may contribute to the XLH-associated skeletal pathophysiology via multiple mechanisms. We showed that while a high phosphorus diet only partially corrected the bone mineralization defects in Hyp mice, it corrected almost all the mineralization defects in a transgenic mouse line overexpressing FGF23. Moreover, our data from a double Knockout mouse Enpp1;Hyp suggest that PHEX mutation may induce additional regulators of bone mineralization. Identification of novel pathways contributing to XLH pathophysiology may lead to the future development of new therapeutic strategies that can be used in combination with the existing therapies.

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XLH, FGF23, Hyp

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