Serum MEPE-ASARM-peptides are elevated in X-linked rickets (HYP): implications for phosphaturia and rickets

• Published in: Journal of endocrinology Vol. 183; no. 3; pp. R1 - R9
• Main Authors: Bresler, Doron, Bruder, Jan, Mohnike, Klaus, Fraser, William D, Rowe, Peter S N
• Format: Journal Article
• Language: English
• Published: England BioScientifica 01.12.2004
• Subjects: Animals; Case-Control Studies; Enzyme-Linked Immunosorbent Assay - methods; Extracellular Matrix Proteins - analysis; Extracellular Matrix Proteins - blood; Female; Glycoproteins - analysis; Glycoproteins - blood; Humans; Hypophosphatemia, Familial - blood; Immunohistochemistry - methods; Kidney Tubules - chemistry; Male; Mice; Phosphates - urine; Phosphoproteins - analysis; Phosphoproteins - blood; Rapid Communications
• ISSN: 0022-0795; 1479-6805
• DOI: 10.1677/joe.1.05989

MEPE (Matrix Extracellular PhosphoglycoprotEin) expression is markedly elevated in X-linked-hypophosphatemic-rickets (HYP) and tumor-induced osteomalacia (TIO). In normal individuals, circulating serum-levels of MEPE are tightly correlated with serum-phosphorus, parathyroid hormone (PTH) and bone mineral density (BMD). Also, MEPE derived, C-terminal ASARM-peptides are candidate minhibins and/or phosphatonins. Our aims were to determine: 1. whether MEPE-ASARM-peptide(s) are abnormally elevated in HYP/hyp serum, and, 2. whether the ASARM-peptide(s) accumulate in hyp mice kidney renal-tubules. Using a specific competitive ELISA we measured a five fold increase (P=0.007) of serum ASARM-peptide(s) in human HYP patients (normal subjects 3.25 μM n=9; s.e.m.=0.51 and HYP-patients 15.74 μM, n=9; s.e.m.=3.32). A 6.23 fold increase (P=0.008) was measured in hyp male mice compared with their normal male siblings (normal-siblings, 3.73 μM, s.e.m.=0.57, n=3; and hyp-mice 23.4 μM, n=3, s.e.m.=4.01). Renal immuno-histological screening also revealed a dramatic increase of ASARM-peptides in regions anatomically consistent with the proximal convoluted tubules. This study demonstrates for the first time that markedly elevated serum levels of protease-resistant ASARM-peptide(s) occur in HYP/hyp and they accumulate in murine hyp kidneys. These peptides are thus likely responsible for the phosphaturia and defective mineralization in HYP/hyp and TIO.