The chicken or the egg: PHEX, FGF23 and SIBLINGs unscrambled

The eggshell is an ancient innovation that helped the vertebrates' transition from the oceans and gain dominion over the land. Coincident with this conquest, several new eggshell and noncollagenous bone‐matrix proteins (NCPs) emerged. The protein ovocleidin‐116 is one of these proteins with an ancestry stretching back to the Triassic. Ovocleidin‐116 is an avian homolog of Matrix Extracellular Phosphoglycoprotein (MEPE) and belongs to a group of proteins called Small Integrin‐Binding Ligand Interacting Glycoproteins (SIBLINGs). The genes for these NCPs are all clustered on chromosome 5q in mice and chromosome 4q in humans. A unifying feature of the SIBLING proteins is an Acidic Serine Aspartate‐Rich MEPE (ASARM)‐associated motif. The ASARM motif and the released ASARM peptide play roles in mineralization, bone turnover, mechanotransduction, phosphate regulation and energy metabolism. ASARM peptides and motifs are physiological substrates for phosphate‐regulating gene with homologies to endopeptidases on the X chromosome (PHEX), a Zn metalloendopeptidase. Defects in PHEX are responsible for X‐linked hypophosphatemic rickets. PHEX interacts with another ASARM motif containing SIBLING