The emergence of phosphate as a specific signaling molecule in bone and other cell types in mammals

Abstract

Although considerable advances in our understanding of the mechanisms of phosphate homeostasis and skeleton mineralization have recently been made, little is known about the initial events involving the detection of changes in the phosphate serum concentrations and the subsequent downstream regulation cascade. Recent data has strengthened a long-established hypothesis that a phosphate-sensing mechanism may be present in various organs. Such a phosphate sensor would detect changes in serum or local phosphate concentration and would inform the body, the local environment, or the individual cell. This suggests that phosphate in itself could represent a signal regulating multiple factors necessary for diverse biological processes such as bone or vascular calcification. This review summarizes findings supporting the possibility that phosphate represents a signaling molecule, particularly in bone and cartilage, but also in other tissues. The involvement of various signaling pathways (ERK1/2), transcription factors (Fra-1, Runx2) and phosphate transporters (PiT1, PiT2) is discussed.

IGF-1 and Survival in ESRD

“…Because calcium and phosphate are key regulators of PTH, it is likely that calcium and phosphate may influence the IGF-1 system directly or indirectly through the PTH pathway. Thus, phosphate and calcium modulate the osteoblastic proliferation through IGF-1 in in vivo studies (29)(30)(31). The bone-forming effects of PTH require involvement of IGF-1, suggesting that IGF-1 plays a role as a potential mediator of the anabolic action of PTH (32).…”

Increased circulating levels of FGF23: an adaptive response in primary hyperparathyroidism?

“…Data on the effect of changes in phosphate intake on FGF23 concentrations are inconsistent, with different responses observed with short-term or long-term alterations in phosphate intake (16)(17)(18)(19)(20). It has also been shown that early and rapid changes in renal phosphate excretion occur following a high-phosphorus meal, independent of FGF23, PTH, secreted frizzledrelated protein (sFRP4), or 1,25(OH) 2 D, suggesting the presence of an intestinal 'phosphate sensor', although its exact biochemical nature is not known (21)(22)(23)(24)(25).…”

Phosphate (Pi)-regulated heterodimerization of the high-affinity sodium-dependent Pi transporters PiT1/Slc20a1 and PiT2/Slc20a2 underlies extracellular Pi sensing independently of Pi uptake

“…In addition to the widespread structural and metabolic functions of Pi, it has become increasingly apparent during the past 15 years that extracellular Pi can act as a signaling molecule directly altering gene expression and cell phenotype (6)(7)(8)(9). The abundance of Pi in the skeleton has led to early studies describing the effects of extracellular Pi in this organ.…”

“…The ability of organisms to detect changes in extracellular levels of other metabolites (such as Ca 2+ , glucose or amino-acids) has already been described (31)(32)(33), and emerging evidence suggests that similar events are at work to mediate the cellular effects of Pi (8,(34)(35)(36). Although the identity of the molecules involved in these mechanisms is still unknown in mammals, Pi sensing machineries have been characterized in prokaryotic and eukaryotic unicellular organisms (37).…”