X-linked hypophosphatemic rickets (HYP) is associated with severe defects in renal phosphate handling, vitamin D metabolism and mineralization. Understanding the pathophysiology of bone-mineral/renal loss disorders is prerequisite to effective treatment of HYP, periodontal disease, tumor induced osteomalacia, renal-stones, osteoporosis, ectopic-calcifications and renal dysfunction. We have substantive preliminary data that supports the hypothesis that mineralization in teeth and bone is regulated by a protein-protein interaction between MEPE (a matrix extracellular phosphoglycoprotein markedly elevated in HYP) and PHEX (a Zn-metalloendopeptidase defective in HYP). The MEPE-PHEX protein-protein interaction protects MEPE from proteolytic cleavage by proteases markedly elevated in HYP (notably cathepsin B). Osteoblast and odontoblast secreted-MEPE in the absence of PHEX is proteolytically cleaved, releasing a phosphorylated, acidic-aspartate-serine-rich, COOH-terminal MEPE-fragment (ASARM-peptide). The ASARM-peptide (2 kDa) is remarkably resistant to a vast array of proteases resulting in increased levels in Hyp. The ASARM-peptide inhibits mineralization and is a negative modulator of normal mineralization and elevated ASARM-peptide is wholly or in part responsible for the mineralization defects in HYP. This proposal will specifically focus on the role of MEPE and ASARM-peptides in mineralization in disease and health.
Our specific aims will be: 1. Structural characterization and quantification of MEPE ASARM-peptide(s) in-vitro and in-vivo in normal and Hyp-mouse osteoblasts and HYP patient-serum. 2. Determination of MEPE ASARM-peptide effects on mineralization in-vitro and in-vivo (rats). The ASARM-motif is present in a number of tooth-bone matrix and salivary proteins (MEPE, dentin-matrix-protein-1, osteopontin, statherin, dentin-sialo-phosphoprotein, etc.) that all map to chromosome 4q21. Thus, the elucidation of its role in mineralization is of prime importance for understanding tooth and bone development. Importantly, the part the motif plays in the multiple functions of MEPE will have relevance to the treatment and understanding of periodontal disease, oncogenic hypophosphatemic osteomalacia (OHO), HYP, osteoporosis and disorders of mineralization in teeth, bone, renal-stones and arteries.
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| Rowe, Peter S N; Garrett, Ian R; Schwarz, Patricia M et al. (2005) Surface plasmon resonance (SPR) confirms that MEPE binds to PHEX via the MEPE-ASARM motif: a model for impaired mineralization in X-linked rickets (HYP). Bone 36:33-46 |
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