Asarm peptides: PHEX-dependent and -independent regulation of serum phosphate

Valentin David, Aline Martin, Anne Marie Hedge, Marc K. Drezner, Peter S N Rowe

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

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 D3 diet (1% Pi diet) or a reduced phosphorus and vitamin D3 diet (0.1% Pi 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% Pi 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% Pi diet. This was accompanied by a twofold increase in serum ASARM and 1,25-dihydroxy vitamin D3 [1,25 (OH)2D3] 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 osteo-pontin (- 25%). Circulating ASARM peptides showed a significant inverse correlation with serum Pi 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.

Original languageEnglish (US)
Pages (from-to)F783-F791
JournalAmerican Journal of Physiology - Renal Physiology
Volume300
Issue number3
DOIs
StatePublished - Mar 1 2011

Keywords

  • 1
  • 25 dihydroxy vitamin D3
  • Dentin matrix protein-1
  • Fibroblast growth factor 23
  • Matrix extracellular phosphoglycoprotein
  • Mineralization
  • Osteomalacia
  • SIBLING proteins
  • X-linked hypophosphatemic rickets

ASJC Scopus subject areas

  • Physiology
  • Urology

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