MEPE has the properties of an osteoblastic phosphatonin and minhibin

P. S.N. Rowe, Y. Kumagai, G. Gutierrez, I. R. Garrett, R. Blacher, D. Rosen, J. Cundy, S. Navvab, D. Chen, M. K. Drezner, L. D. Quarles, G. R. Mundy

Research output: Contribution to journalArticlepeer-review

238 Scopus citations

Abstract

Matrix extracellular phosphoglycoprotein (MEPE) is expressed exclusively in osteoblasts, osteocytes and odontoblasts with markedly elevated expression found in X-linked hypophosphatemic rickets (Hyp) osteoblasts and in oncogenic hypophosphatemic osteomalacia (OHO) tumors. Because these syndromes are associated with abnormalities in mineralization and renal phosphate excretion, we examined the effects of insect-expressed full-length human-MEPE (Hu-MEPE) on serum and urinary phosphate in vivo, 33PO4 uptake in renal proximal tubule cultures and mineralization of osteoblast cultures. Dose-dependent hypophosphatemia and hyperphosphaturia occurred in mice following intraperitoneal (IP) administration of Hu-MEPE (up to 400 μg kg-1 31 h-1), similar to mice given the phosphaturic hormone PTH (80 μg kg-1 31 h-1). Also the fractional excretion of phosphate (FEP) was stimulated by MEPE [65.0% (P < 0.001)] and PTH groups [53.3% (P < 0.001)] relative to the vehicle group [28.7% (SEM 3.97)]. In addition, Hu-MEPE significantly inhibited 33PO 4 uptake in primary human proximal tubule renal cells (RPTEC) and a human renal cell line (Hu-CL8) in vitro (Vmax 53.4% inhibition; Km 27.4 ng/ml, and Vmax 9.1% inhibition; Km 23.8 ng/ml, respectively). Moreover, Hu-MEPE dose dependently (50-800 ng/ml) inhibited BMP2-mediated mineralization of a murine osteoblast cell line (2T3) in vitro. Inhibition of mineralization was localized to a small (2 kDa) cathepsin B released carboxy-terminal MEPE peptide (protease-resistant) containing the acidic serine-aspartate-rich motif (ASARM peptide). We conclude that MEPE promotes renal phosphate excretion and modulates mineralization.

Original languageEnglish (US)
Pages (from-to)303-319
Number of pages17
JournalBone
Volume34
Issue number2
DOIs
StatePublished - Feb 2004
Externally publishedYes

Keywords

  • MEPE
  • Mineralization
  • Renal phosphate excretion

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Histology

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