Roles of Phosphate in Skeleton.

Toshimi Michigami,Keiichi Ozono

doi:10.3389/fendo.2019.00180

Abstract

Phosphate is essential for skeletal mineralization, and its chronic deficiency leads to rickets and osteomalacia. Skeletal mineralization starts in matrix vesicles (MVs) derived from the plasma membrane of osteoblasts and chondrocytes. MVs contain high activity of tissue non-specific alkaline phosphatase (TNSALP), which hydrolyzes phosphoric esters such as pyrophosphates (PPi) to produce inorganic orthophosphates (Pi). Extracellular Pi in the skeleton is taken up by MVs through type III sodium/phosphate (Na+/Pi) cotransporters and forms hydroxyapatite. In addition to its roles in MV-mediated skeletal mineralization, accumulating evidence has revealed that extracellular Pi evokes signal transduction and regulates cellular function. Pi induces apoptosis of hypertrophic chondrocytes, which is a critical step for endochondral ossification. Extracellular Pi also regulates the expression of various genes including those related to proliferation, differentiation, and mineralization. In vitro cell studies have demonstrated that an elevation in extracellular Pi level leads to the activation of fibroblast growth factor receptor (FGFR), Raf/MEK (mitogen-activated protein kinase/ERK kinase)/ERK (extracellular signal-regulated kinase) pathway, where the type III Na+/Pi cotransporter PiT-1 may be involved. Responsiveness of skeletal cells to extracellular Pi suggests their ability to sense and adapt to an alteration in Pi availability in their environment. Involvement of FGFR in the Pi-evoked signal transduction is interesting because enhanced FGFR signaling in osteoblasts/osteocytes might be responsible for the overproduction of FGF23, a key molecule in phosphate homeostasis, in a mouse model for human X-linked hypophosphatemic rickets (XLH). Impaired Pi sensing may be a pathogenesis of XLH, which needs to be clarified in future.

Highlights

Phosphorus mediates almost all biological processes including composition of cell membrane, maintenance and inheritance of genetic materials as nucleic acids, energy metabolism, and regulation of proteins by phosphorylation/dephosphorylation, as well as skeletal mineralization in vertebrates [1]
In osteocytes partially restored the Fibroblast Growth Factor 23 (FGF23) overproduction and rescued the hypophosphatemia and mineralization defect in Hyp mice [58]. These findings indicate the possible involvement of activated fibroblast growth factor receptor (FGFR) signaling in the FGF23 overproduction in Hyp osteocytes
In HEK293 cells, knockdown of FGFR1 diminished the phosphorylation of ERK1/2 induced by an increased extracellular produce inorganic orthophosphates (Pi) [10]. These results suggest that FGFR plays a critical role in the transduction of the signaling evoked by an increased extracellular Pi

Summary

INTRODUCTION

Phosphorus mediates almost all biological processes including composition of cell membrane, maintenance and inheritance of genetic materials as nucleic acids, energy metabolism, and regulation of proteins by phosphorylation/dephosphorylation, as well as skeletal mineralization in vertebrates [1]. Hypophosphatemic rickets/osteomalacia related to an excessive action of FGF23 is caused by inactivating mutations in the phosphate-regulating gene with homologies to endopeptidases, on the X chromosome (PHEX), dentin matrix protein 1 (DMP1), ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), and family with sequence similarity 20 C (FAM20C) genes [48, 50,51,52,53,54,55]. A human disease called osteoglophonic dysplasia caused by activating mutations in FGFR1 is often associated with hypophosphatemia due to increased FGF23 levels [60], which suggests the regulation of FGF23 production by FGFR signaling. In a recent human study, plasma FGF23 levels were transiently elevated 4 weeks after high phosphorus intake but FIGURE 2 | Transduction of signal evoked by extracellular Pi. In various cell types including osteoblasts and chondrocytes, an increased extracellular Pi induces the activation of Raf/MEK/ERK pathway to regulate gene expression, and this process is mediated by Na+/Pi cotransporter and FGFR. Knockdown experiments have implicated that PiT-1 might mediate the Pi-induced signal transduction upstream of FGFR (Figure 2)

A Possible Relationship Between FGFR and Pi-Sensing

Findings

CONCLUSION