Osteogenesis is controlled by osteoblast/osteoclast functional balance in close association with phosphate (Pi) homeostasis regulated by complicated systems operating across the parathyroid gland, intestine, bone and kidney [3, 4]. Parathyroid hormone (PTH), 1,25-vitamin D3 and calcium-sensing receptors constitute the classic pathway of Pi/calcium homeostasis, which is essential for bone differentiation and remodeling. In addition, two important key mediators have been identified through clinical observation and subsequent molecular approaches, fibroblast growth factor-23 (FGF23) and a phosphate-regulating gene product with homology to endopeptidases linked to the X chromosome (PHEX). Gain-of-function mutations of FGF23 lead to autosomal dominant hypophosphatemia/osteomalacia , while its loss-of-function mutations are causative of recessive familial tumoral calcinosis with hyperphosphatemia [6, 7]. FGF23, secreted mainly from osteoblasts/osteocytes [8, 9], is a potent inhibitor of renal Pi reabsorption, leading to phosphate wasting. This phosphaturic hormone binds to renal FGF23 receptor (FGF23r)/Klotho heterodimeric molecules much more tightly than to FGF23r alone, thereby exerting marked inhibitory actions against renal Pi reabsorption [10, 11].
PHEX, another potent mediator of phosphate homeostasis, has been identified from analyses of human X-linked hypophosphatemic rickets (XLH)  and Hyp mutant models [13, 14]. Loss-of-function mutations of PHEX/Phex lead to skeletal abnormalities and hypophosphatemia, and are genetically fully dominant . Aberrant PHEX/Phex expression also results in abnormalities in cartilages [16, 17] and teeth . Phex belongs to the M13-type plasma membrane-integrated metalloendopeptidase family, and is expressed exclusively in cells of the osteoblast/osteocyte lineage [19, 20]. Accumulating evidence indicates that the Phex substrates are protease-resistant acidic serine-aspartate-rich motif peptides (ASARM peptides) generated from small integrin-binding ligand, N-linked glycoproteins (SIBLING proteins) by cathepsin actions [21–29]. Phex interacts with and degrades ASARM peptides of SIBLINGs, such as matrix extracellular phosphoglycoprotein (MEPE), osteopontin and dentin matrix protein 1. Although the SIBLINGs are not highly homologous in structure , their ASARM peptides bind, in a phosphorylation-dependent manner, to matrix Ca × PO4 to inhibit mineralization. Both SIBLINGs and ASARM peptides are increased in Hyp and human XLH and strongly inhibit renal Pi reabsorption [23, 31]. Finally, transgenic mice overexpressing MEPE in bone mimic the Hyp model, displaying growth and mineralization defects with altered bone-renal vascularization .
To date, six Phex mutant models, Hyp (a 3'-deletion of the Phex gene) [13, 14], Gy (partial deletion of both spermine synthase and Phex) [13, 33], Phex(Ska1) (skipping of exon 8) , Hyp-J2 (deletion of exon 15) , Hyp-Duk (deletion of exons 13 and 14) , and Phex(pug) (glycosylation defects due to Phe-to-Ser substitution at a.a. 80 of Phex)  have been reported, while over 260 human disease-associated PHEX mutations have been identified [37–41] http://http:/www.phexdb.mcgill.ca. We have now established a dwarfism-like strain of short-tailed mouse, Kbus/Idr, carrying a novel intragenic deletion of the Phex gene.