ASARM peptides: PHEX-dependent and -independent regulation of serum phosphate.

Abstract

Increased acidic serine aspartate-rich MEPE-associated motif (ASARM) peptides cause mineralization defects in X-linked hypophosphatemic rickets mice (HYP) and "directly" inhibit renal phosphate uptake in vitro. However, ASARM peptides also bind to phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) and are a physiological substrate for this bone-expressed, phosphate-regulating enzyme. We therefore tested the hypothesis that circulating ASARM peptides also "indirectly" contribute to a bone-renal PHEX-dependent hypophosphatemia in normal mice. Male mice (n = 5; 12 wk) were fed for 8 wk with a normal phosphorus and vitamin D(3) diet (1% P(i) diet) or a reduced phosphorus and vitamin D(3) diet (0.1% P(i) diet). For the final 4 wk, transplantation of mini-osmotic pumps supplied a continuous infusion of either ASARM peptide (5 mg·day(-1)·kg(-1)) or vehicle. HYP, autosomal recessive hypophosphatemic rickets (ARHR), and normal mice (no pumps or ASARM infusion; 0.4% P(i) diet) were used in a separate experiment designed to measure and compare circulating ASARM peptides in disease and health. ASARM treatment decreased serum phosphate concentration and renal phosphate cotransporter (NPT2A) mRNA with the 1% P(i) diet. This was accompanied by a twofold increase in serum ASARM and 1,25-dihydroxy vitamin D(3) [1,25 (OH)(2)D(3)] levels without changes in parathyroid hormone. For both diets, ASARM-treated mice showed significant increases in serum fibroblast growth factor 23 (FGF23; +50%) and reduced serum osteocalcin (-30%) and osteopontin (-25%). Circulating ASARM peptides showed a significant inverse correlation with serum P(i) and a significant positive correlation with fractional excretion of phosphate. We conclude that constitutive overexpression of ASARM peptides plays a "component" PHEX-independent part in the HYP and ARHR hypophosphatemia. In contrast, with wild-type mice, ASARM peptides likely play a bone PHEX-dependent role in renal phosphate regulation and FGF23 expression. They may also coordinate FGF23 expression by competitively modulating PHEX/DMP1 interactions and thus bone-renal mineral regulation.

• Authors: Valentin David, Aline Martin, Anne-Marie Hedge, Marc K Drezner, Peter S N Rowe
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 300 Issue 3 Pg. F783-91 (Mar 2011) ISSN: 1522-1466 [Electronic] United States
• PMID: 21177780 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Dmp1 protein, mouse
• Extracellular Matrix Proteins
• Fgf23 protein, mouse
• Glycoproteins
• Mepe protein, mouse
• Peptides
• Phosphates
• Phosphoproteins
• Slc34a1 protein, mouse
• Sodium-Phosphate Cotransporter Proteins, Type IIa
• Aspartic Acid
• Serine
• Fibroblast Growth Factors
• Fibroblast Growth Factor-23
• PHEX Phosphate Regulating Neutral Endopeptidase
• Phex protein, mouse

Topics

• Amino Acid Sequence
• Animals
• Aspartic Acid
• Extracellular Matrix Proteins (metabolism, physiology)
• Fibroblast Growth Factor-23
• Fibroblast Growth Factors (metabolism)
• Glycoproteins (physiology)
• Hypophosphatemia (metabolism)
• Kidney (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Models, Animal
• Molecular Sequence Data
• PHEX Phosphate Regulating Neutral Endopeptidase (physiology)
• Peptides (physiology)
• Phosphates (blood)
• Phosphoproteins (physiology)
• Serine
• Sodium-Phosphate Cotransporter Proteins, Type IIa (metabolism)