Eldecalcitol Causes FGF23 Resistance for Pi Reabsorption and Improves Rachitic Bone Phenotypes in the Male Hyp Mouse

Abstract

X-linked hypophosphatemia (XLH), the most common form of inheritable rickets, is caused by inactivation of phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) and leads to fibroblast growth factor (FGF) 23-dependent renal inorganic phosphate (Pi) wasting. In the present study, we investigated whether maintaining Pi homeostasis with a potent vitamin D3 analog, eldecalcitol [1α,25-dihydroxy-2β-(3-hydroxypropyloxy) vitamin D3; ED71], could improve hypophosphatemic rickets in a murine model of XLH, the Hyp mouse. Vehicle, ED71, or 1,25-dihydroxyvitamin D was subcutaneously injected five times weekly in wild-type (WT) and Hyp mice for 4 weeks, from 4 to 8 weeks of age. Injection of ED71 into WT mice suppressed the synthesis of renal 1,25-dihydroxyvitamin D and promoted phosphaturic activity. In contrast, administration of ED71 to Hyp mice completely restored renal Pi transport and NaPi-2a protein levels, although the plasma-intact FGF23 levels were further increased. In addition, ED71 markedly increased the levels of the scaffold proteins, renal sodium-hydrogen exchanger regulatory factor 1, and ezrin in the Hyp mouse kidney. Treatment with ED71 increased the body weight and improved hypophosphatemia, the bone volume/total volume, bone mineral content, and growth plate structure in Hyp mice. Thus, ED71 causes FGF23 resistance for phosphate reabsorption and improves rachitic bone phenotypes in Hyp mice. In conclusion, ED71 has opposite effects on phosphate homeostasis in WT and Hyp mice. Analysis of Hyp mice treated with ED71 could result in an additional model for elucidating PHEX abnormalities.

Sclerostin Antibody Treatment Increases Bone Mass and Normalizes Circulating Phosphate Levels in Growing Hyp Mice

“…Despite an increase in bone mass, Scl‐Ab treatment did not improve femoral length or body weight in Hyp animals. However, other studies have found that calcitriol is capable of normalizing body weight and femur length in Hyp mice . Therefore, it is possible that combining calcitriol with Scl‐Ab treatment, as has been done in Scl‐Ab clinical trials for osteoporosis, could potentially improve growth in XLH.…”

“…However, other studies have found that calcitriol is capable of normalizing body weight and femur length in Hyp mice. (19,20) Therefore, it is possible that combining calcitriol with Scl-Ab treatment, as has been done in Scl-Ab clinical trials for osteoporosis, (8) could potentially improve growth in XLH. Additionally, burosumab, a monoclonal antibody to FGF23 protein, has been reported to increase bone length in Hyp mice (21) and may present another potential option for combinatory therapy with Scl-Ab.…”

Phosphate Transporter Regulator That Prevents Abnormal Hyperphosphatemia.

“…In fact, NaPi2c expression is suppressed in NHERF3-KO mice 33 . We previously reported differences in signals between the phosphaturic action of FGF23 and the inhibitory effect on vitamin D synthesis 34 . Therefore, it is considered that the effect of TRAP deficiency is limited to the control function of NaPi2a.…”

“…TRAP is expected to regulate the amount of NaPi2a in response to a Pi deficiency or excess and regulates the responsiveness of phosphaturic hormone. For example, vitamin D treatment in Hyp mice restores serum Pi levels by causing FGF23 resistance to NaPi2a/NHERF1 34,45 . Thus, TRAP, a 12/13/21 strongly correlated molecule with NaPi2a in the GCNs, is thought to be involved in the regulation of NaPi2a by phosphaturic hormones in the kidney and the prevention of hyperphosphatemia in response to a high dietary Pi load (Figure 11).…”

“…Mice were individually placed in the metabolic cages at 10:00 for quantitative urine and fecal collection for 24 h with free access to food and water. Fecal samples were ashed according to a modified protocol, as described previously 34,47,52,53 .…”