The role of DMP1 in FGF23-induced hypophosphatemia

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PROJECT SUMMARY Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone produced by bone. Hypophosphatemic rickets disorders, such as X-linked hypophosphatemia (XLH) and autosomal recessive hypophosphatemic rickets (ARHR), are associated with FGF23 excess, impaired skeletal growth and osteomalacia leading to debilitating bone pain and fractures. New therapy consisting in FGF23 antibody injections to increase serum phosphate (Pi) levels in XLH improves bone growth and mineralization. However, further studies are needed to determine if this strategy is efficacious in the long term and in other diseases associated with FGF23 excess, including ARHR. XLH and ARHR type I are respectively caused by inactivating mutations of Pi regulating gene with homologies to endopeptidase X-linked (PHEX) and dentin matrix protein (DMP1) that work in concert to regulate FGF23 production. In preliminary data for this project, we show that (1) FGF23 excess and hypophosphatemia contribute to the bone defects in mice with ARHR, (2) excess FGF23 and parathryroid hormone are not solely responsible for renal Pi wasting, (3) DMP1 directly stimulates Pi reabsorption in the kidney, (4) PHEX and DMP1 are expressed in renal tubular cells where Pi reabsorption occurs, and (5) loss of kidney PHEX induces phosphaturia and bone loss despite increased DMP1 and low FGF23 levels. The goal of this project is to investigate the pathogenesis of hypophosphatemia induced by DMP1 deficiency. In Aim 1, we will define the contribution of FGF23 excess and hypophosphatemia to impaired bone mineralization in mice with ARHR. We will use normal and high dietary Pi administration, and genetic deletion of Fgf23 in wild- type (WT) and Dmp1KO to assess modifications of bone and mineral metabolism in mice and cultured primary osteoblasts over time. In Aim 2, we will establish the role of DMP1 in stimulating Pi reabsorption by antagonizing FGF23-FGFR1 signaling in the kidney. We will use normal and high dietary Pi administration, and genetic overexpression of Fgf23 or deletion of Fgfr1, in WT mice and in animals with genetic overexpression of Dmp1 (Dmp1TG). We will assess bone and mineral metabolism, Pi intake and excretion, kidney function and FGFR1 activation in the kidney, in presence of elevated FGF23 and DMP1 levels. Finally, in Aim 3, we will investigate the contribution of kidney DMP1 deficiency to the pathophysiology of ARHR and XLH by performing kidney transplants between Dmp1TG and Dmp1KO and between WT, Hyp and Dmp1TG donor and recipient mice. We will establish whether kidney-expressed DMP1 is required to fully correct hypophosphatemia in mice with ARHR, and if loss of kidney PHEX function is sufficient to induce hyperphosphaturia and bone loss despite elevated DMP1 and low FGF23 levels. This will demonstrate a key functional interaction between PHEX and DMP1 in the kidney. These innovative aims are supported by a productive collaborative team at Northwestern University that will further develop our understanding of DMP1, FGF23 and Pi function, and ultimately help to develop novel therapies to improve outcomes in diseases associated with altered Pi balance.