A unified model for bone–renal mineral and energy metabolism

• FGF23 is an important regulator of vitamin D, phosphate and mineral metabolism.
• An osteocyte membrane complex of PHEX, DMP1, α5β3-integrin suppresses FGF23.
• SIBLING ASARM-peptides disrupts this complex and increases FGF23 (FAP pathway).
• Phosphorylation of ASARM and FGF23 by FAM20C-kinase also regulates this pathway.
• FAM20C-kinase and ATP provide a nexus to matrix vesicle mineralization the FAP pathway and energy metabolism.

The beginning of the millennium saw the discovery of a new bone-matrix protein, Matrix Extracellular PhosphoglycoprotEin (MEPE) and an associated C-terminal motif called ASARM. This motif and other distinguishing features occur in a group of proteins called SIBLINGs. These proteins include dentin matrix protein 1 (DMP1), osteopontin, dentin-sialophosphoprotein (DSPP), statherin, bone sialoprotein (BSP) and MEPE. MEPE, DMP1 and ASARM-motifs regulate expression of a phosphate regulating cytokine FGF23. Further, a trimeric interaction between phosphate regulating endopeptidase homolog X-linked (PHEX), DMP1, and α5β3-integrin that occurs on the plasma-membrane of the osteocyte mediates FGF23 regulation (FAP pathway). ASARM-peptides competitively inhibit the trimeric complex and increase FGF23. A second pathway involves specialized structures, matrix vesicles pathway (MVP). This review will discuss the FAP and MVP pathways and present a unified model for mineral and energy metabolism.