Serum MEPE-ASARM-peptides are elevated in X-linked rickets (HYP): implications for phosphaturia and rickets.
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 microM n=9; S.E.M.=0.51 and HYP-patients 15.74 microM, 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 muM, S.E.M.=0.57, n=3; and hyp-mice 23.4 microM, 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.
Bresler
Doron
D
United States Air Force (USAF) Lackland, San Antonio, Texas, USA.
Bruder
Jan
J
Mohnike
Klaus
K
Fraser
William D
WD
Rowe
Peter S N
PS
D000818:Animals; D016022:Case-Control Studies; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D016326:Extracellular Matrix Proteins / Q000032:analysis / Q000097:blood*; D005260:Female; D006023:Glycoproteins / Q000032:analysis / Q000097:blood*; D006801:Humans; D007015:Hypophosphatemia, Familial / Q000097:blood*; D007150:Immunohistochemistry / Q000379:methods; D007684:Kidney Tubules / Q000737:chemistry; D008297:Male; D051379:Mice; D010710:Phosphates / Q000652:urine; D010750:Phosphoproteins / Q000032:analysis / Q000097:blood*
D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; C486579:MEPE protein, human; D010710:Phosphates; D010750:Phosphoproteins