The research in this group is aimed at increasing our understanding of the molecular bone-renal mechanisms that maintain a healthy mineralized skeleton and dentition. Since this dynamic-process is disturbed dramatically in many tumor-acquired and inherited diseases we are also studying these diseases in the hope that our findings will help to improve clinical treatment. Recently, in collaboration with an international consortium (HYP-consortium) we successfully identified the primary gene defect in an inherited bone-renal disease, X-linked hypophosphatemic rickets (HYP). This disease is characterized by severe under-mineralization of the skeleton and marked changes in renal-phosphate handling and vitamin D metabolism. We named this novel gene PHEX (acronym: phosphate regulating gene with homologies to endopeptidases on the X-chromosome). This discovery has stimulated new research and provided new reagents aimed at unraveling the molecular pathways downstream of the primary PHEX gene-product defect. More recently, we were the first to characterize and clone a completely novel bone-matrix protein (MEPE) from patients with tumor-induced osteomalacia. Also, we have demonstrated biological activity of this new MEPE protein and confirmed a direct interaction with PHEX. Our research indicates that a small acidic, protease-resistant MEPE-peptide that we named ASARM-peptide, could potentially be the first 'biological bisphosphonate' described. This peptide occurs in MEPE and some related family proteins (SIBLINGs) and the acronym ASARM stands for acidic-serine-aspartate-rich-MEPE-associated motif. The biological and physicochemical properties of the ASARM-peptide are remarkably similar to etidronate, a bisphosphonate. The ASARM-peptide (like etidronate) inhibits mineralization in-vivo and in-vitro and impacts on renal phosphate handling.
The ASARM-Model (Rowe, PSN 2004, Rowe PSN et al 2004) is a scheme that proposes an interrelated role for MEPE, PHEX, FGF23 and matrix proteins in mineraliztion, renal phosphate handling, vitamin D metabolism, familial rickets and tumor induced osteomalacia. The figure below focuses on MEPE, PHEX and proteases and a more detailed animated scheme (MEPE, PHEX, FGF23, matrix proteins and ASARM-peptide) can be obtained by clicking the indicated links. Also a more detailed description is given in the following review Rowe, PSN 2004 (The wrickened-pathways of FGF23, MEPE and PHEX).
MEPE is elevated in X-linked rickets (HYP) and PHEX is the primary defect. Also, a number of key osteoblastic proteases are markedly elevated. PHEX interacts with MEPE via the carboxy MEPE-ASARM-motif and protects MEPE from proteolysis. Thus in Hyp, PHEX cannot sequester and/or protect MEPE from proteolysis and the increased protease levels results in the degradation of MEPE. The ASARM-motif/peptide is remarkably resistant to proteolysis and is thus elevated in Hyp and may be wholly or in part responsible for the defects in mineralization and renal phosphate handling. The motif is present in a number of related bone-dentin proteins (SIBLING family) that all map to chromosome 4q. These include MEPE, DMP-1, Osteopontin, Dentin sialophosphoprotein (DSPP) etc. Remarkably statherin, a salivary protein also maps to 4q and contains the ASARM-motif and this plays a major role in preventing the ectopic precipitation of calicum/phosphate supersaturated saliva, tooth mineralization dynamics and likely parotid gland phosphate transport.