Parabiosis suggests a humoral factor is involved in X-linked hypophosphatemia in mice

Abstract

Reduced renal tubular reabsorption of phosphate of unknown etiology is characteristic of X-linked hypophosphatemia in both humans and mice. To test whether a humoral abnormality is involved in the renal effect, parabiosis was performed between Hyp and normal mice at 4 weeks of age. The normal mice joined to Hyp mice showed a progressive diminution of plasma phosphate over the next 3 weeks to approach the level of the Hyp mice. These normal mice had a greater renal phosphate excretion index (urine P/plasma P/urine creatinine) than normal-normal pairs, thus suggesting a reduced renal tubular reabsorption of phosphate. At the same time the expected rises in plasma calcium and plasma 1,25-dihydroxyvitamin D did not occur. There was a significant reduction in their femoral mineral content but not in their femoral length or body growth relative to normal-normal pairs. This change in renal handling of phosphate was specific since the urinary losses of potassium and magnesium were not significantly changed. Separation of normal-Hyp pairs 3 or 6 weeks after parabiosis caused the normal mice to achieve normal plasma phosphate levels within 24 h. At 48 h and 7 days after separation these normal mice had plasma phosphate levels higher than normal mice separated from normal-normal pairs. In summary, the data suggest the presence of a phosphaturic factor in the Hyp mice that can cross a parabiotic union into normal mice and induce many of the symptoms of X-linked hypophosphatemia.

Proteolytic processing of osteopontin by PHEX and accumulation of osteopontin fragments in Hyp mouse bone, the murine model of X-linked hypophosphatemia

“…(44) Thus, it has been proposed that the accumulation of a secreted, circulating substrate of PHEX, present in the absence of this enzyme, contributes to the XLH/Hyp phenotype. (81)(82)(83)(84)(85)(86) In addition to this systemic, phosphaturic change initiated by the loss of PHEX activity, it is also reasonable to consider that more local, direct changes in the extracellular matrix of bone might occur that could affect mineralization. Indeed, previous in vivo studies have shown partial correction of the osteomalacic phenotype when Phex/PHEX is overexpressed in osteoblasts, (83,84) and local, microenvironmental effects of PHEX within the extracellular matrix have been explicitly proposed.…”

The skeleton as an endocrine organ

“…29 Further examination of the physiological defect in patients with XLH and in experimental mouse models revealed impaired proximal renal tubular reabsorp tion of phosphate caused by reduced expression of sodium-phosphate co-transporters, further suggesting a missing phosphate-regulating hormone. [30][31][32] In the mid-1990s, positional cloning determined that a single gene, PHEX, was responsible for most cases of XLH. 33 Surprisingly, PHEX did not encode the phosphate-regulating hormone that had been anticipated, but instead encoded a protein with homology to endopeptidases: phosphate-regulating neutral endo peptidase.…”

The PTH-Vitamin D-FGF23 axis

“…Using a rodent model of X-linked hypophosphatemic rickets (XLH, the hyp mouse), Meyers et al demonstrated that the renal phosphate wasting factor was transferrable to normal mice by parabiosis [2]. Thus, it was evident that it was a circulating hormone that was responsible for XLH.…”