Matrix Extracellular Phosphoglycoprotein (MEPE) belongs to a group of
proteins called Short Integrin Binding Ligand Interacting Glycoproteins (SIBLINGs).
These proteins are all localized to a defined region on chromosome 5q in mice and
chromosome 4q in humans. A unifying feature of SIBLING proteins is an Acidic Serine
Aspartate Rich MEPE associated motif (ASARM). The ASARM-motif and SIBLINGs
appeared 300 million years ago with terrestrial vertebrates coincident with the new
environmental challenge of gravity. Recent research has shown that the ASARM-motif
and the released ASARM-peptide also play regulatory roles in mineralization (bone and
teeth), phosphate regulation, vascularization, soft tissue calcification,
osteoclastogenesis, mechanotransduction and fat energy metabolism. The MEPE
ASARM-motif and peptide are physiological substrates for PHEX, a Zn
metalloendopeptidase. Defects in PHEX are responsible for X-linked
hypophosphatemic rickets (HYP). There is evidence that PHEX interacts with another
ASARM-motif containing SIBLING protein, Dentin Matrix Protein-1 (DMP1). DMP1
mutations cause bone-renal defects that are identical with the defects caused by loss of
PHEX function. This results in autosomal recessive hypophosphatemic rickets (ARHR).
In both HYP and ARHR increased FGF23 expression occurs and activating mutations
in FGF23 cause autosomal dominant hypophosphatemic rickets (ADHR). ASARMpeptide
administration in vitro and in vivo also induces increased FGF23 expression.
Recent work indicates a competitive displacement of a PHEX DMP1 interaction by
ASARM-peptide and thus increased FGF23 expression.
Keywords: Matrix extracellular phosphoglycoprotein, SIBLINGs, chromosome
5q, ASARM-motif, PHEX, X-linked hypophosphatemic rickets, FGF23.
