Extracellular phosphate sensing in mammals: what do we know?

in Journal of Molecular Endocrinology
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  • 1 INSERM, UMR 1229, RMeS, Regenerative Medicine and Skeleton, Université de Nantes, ONIRIS, Nantes, France
  • 2 Université de Nantes, UFR Odontologie, Nantes, France

Correspondence should be addressed to L Beck: laurent.beck@inserm.fr

The critical role of phosphate (Pi) in countless biological processes requires the ability to control its concentration both intracellularly and extracellularly. At the body level, this concentration is finely regulated by numerous hormones, primarily parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23). While this control of the body’s Pi homeostasis is now well documented, knowledge of the mechanisms that allow the cell and the body to detect extracellular Pi variations is much less known. These systems are well described in bacteria, yeasts and plants, but as will be discussed in this review, knowledge obtained from these organisms is not entirely relevant to the requirements of Pi biology in mammals. In this review, we present the latest findings on extracellular Pi sensing in mammals, and describe the mammalian Pi sensors identified to date, such as SLC20A1 (PIT1)/SLC20A2 (PIT2) heterodimers and the calcium-sensing receptor (CaSR). While there are many questions remaining to be resolved, a clarification of the Pi sensing mechanisms in mammals is critical to understanding the deregulation of Pi balance in certain life-threatening disease states, such as end-stage renal disease and associated vascular calcifications, and to proposing relevant therapeutic approaches.

Abstract

The critical role of phosphate (Pi) in countless biological processes requires the ability to control its concentration both intracellularly and extracellularly. At the body level, this concentration is finely regulated by numerous hormones, primarily parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23). While this control of the body’s Pi homeostasis is now well documented, knowledge of the mechanisms that allow the cell and the body to detect extracellular Pi variations is much less known. These systems are well described in bacteria, yeasts and plants, but as will be discussed in this review, knowledge obtained from these organisms is not entirely relevant to the requirements of Pi biology in mammals. In this review, we present the latest findings on extracellular Pi sensing in mammals, and describe the mammalian Pi sensors identified to date, such as SLC20A1 (PIT1)/SLC20A2 (PIT2) heterodimers and the calcium-sensing receptor (CaSR). While there are many questions remaining to be resolved, a clarification of the Pi sensing mechanisms in mammals is critical to understanding the deregulation of Pi balance in certain life-threatening disease states, such as end-stage renal disease and associated vascular calcifications, and to proposing relevant therapeutic approaches.

Introduction

Phosphorus is a vital component of the cell and organism, playing critical roles in many essential processes. It is a mandatory component of the lipid bilayer of cell membranes, nucleoproteins and nucleic acids, and is essential for bone mineralization (Rothfield & Finkelstein 1968, Hansen et al. 1976, Kornberg 1979). Moreover, phosphorus is central to the storage and liberation of metabolic energy, cellular signaling, enzyme activity, lipid metabolism, muscle and neurological functions and the delivery of oxygen to the peripheral tissues through the formation of 2,3-diphosphoglycerate (Krebs & Beavo 1979, Bessman & Carpenter 1985, Crook & Swaminathan 1996, Hubbard & Till 2000). Approximately 85% of total body phosphorus is found in bone, where it is mainly complexed with hydrogen, oxygen and calcium (Ca2+) to form apatite crystals that are deposited on the collagen matrix (Hansen et al. 1976). The remainder of phosphorus is found in soft tissue (14%) with only about 1% in extracellular fluids (Crook & Swaminathan 1996).

In the serum, approximately 85% of the phosphorus content is found as unbound inorganic phosphate (Pi) in the form of HPO42− and H2PO4 at a 4:1 ratio, at pH 7.4. The remainder (15%) of the phosphorus is bound to proteins or complexed to cations (mainly Ca2+, Mg2+ and Na+). Maintaining a stable concentration of unbound circulating Pi is of major importance for cellular metabolism, bone mineralization and cardiovascular functions. Accordingly, the regulation of serum Pi levels is a very ancient protective system preserved over the course of evolution that allows the retention of Pi in states of Pi deficiency, or conversely the excretion of Pi in order to avoid Pi toxicity. Serum Pi concentrations are maintained within a narrow range mainly due to the coordinated action of PTH, FGF23 and vitamin D. While significant progress has been made in understanding the regulation of Pi homeostasis over the last 25 years, the mechanism underlying the very first step of this regulation, that is, the way in which Pi informs the cell about its variations in extracellular concentration, is much less known. Information about the Pi sensing mechanism is fundamental to understanding why the humoral and paracrine factors that regulate Pi levels in physiological situations are unable to correct Pi imbalance in disease states.

In this short review, we will present the current knowledge on the possible mechanisms underlying the ability of a mammalian cell to detect variations of extracellular Pi levels leading to its homeostatic regulation throughout the organism.

Sensing extracellular vs intracellular phosphate levels

Because Pi is present almost everywhere in the body and in the cell, in many different chemical forms, in bound and unbound states, the mere definition of ‘Pi sensing’ is a challenging task. As mentioned previously, systemic Pi sensing at the body level involves the detection of variations in the extracellular Pi concentration by specific cells, which will then respond to these variations by secreting appropriate hormones to maintain the homeostasis of Pi in the whole body. When defined as such, this type of Pi sensing has sometimes been termed ‘endocrine sensing’ (Chande & Bergwitz 2018), and is the main subject of this review.

However, it is important to keep in mind that in addition to circulating in extracellular fluids, Pi also enters cells where it is used as a basic element to make phospholipids and nucleic acids, or is used as a metabolic fuel to generate ATP and as an indispensable molecule in phosphorylation reactions. Considering this fundamental role, the intracellular concentration of the free available Pi must also be tightly controlled, involving a specific mechanism for the detection of intracellular concentration of Pi. This latter type of detection has been referred as to ‘cellular’ or ‘metabolic’ Pi sensing (Chande & Bergwitz 2018, Kritmetapak & Kumar 2019). The Pi sensing classification as either ‘endocrine sensing’ or ‘cellular/metabolic sensing’ has emerged for reasons of simplicity, and refers to the compartments in which Pi concentrations are homeostatically regulated: mainly the circulating fluids or the cellular compartment. However, paradoxically, this distinction can make the identification of the molecules involved in the Pi sensing mechanisms more complex. For instance, ‘endocrine’ Pi sensing, referring to circulating fluids, may include cell-based mechanisms such as Pi entry in the renal or intestinal cell, which will then trigger ‘metabolic’ Pi sensing in the respective cells. Therefore, when trying to identify and characterize an ‘endocrine’ Pi sensor molecule, should it be outside or inside the cell? Similarly, the ‘metabolic’ sensing of Pi may be influenced by many external hormonal stimuli, including hormones regulated by extracellular Pi. Therefore, in order to better encompass the mechanisms involved in Pi sensing and to better identify putative sensors, it is therefore perhaps more accurate to refer to the terms ‘extracellular’ or ‘intracellular’ sensing of Pi. This semantic distinction may seem trivial, but it is, in fact, essential to the understanding of sensing mechanisms and the identification of involved molecules. For instance, an extracellular Pi sensor may be essential to mineralising cells when the local concentration of calcium and Pi in the close vicinity of the cell will trigger cell-independent physical- or chemical-based mechanisms resulting in hydroxyapatite crystal formation (Weiner & Addadi 2011, Kerschnitzki et al. 2016). In this example, the sensing of Pi is not a matter of endocrine or metabolic sensing, but rather detecting local extracellular Pi variations. However, while the compartmentalization of Pi sensing as ‘extracellular’ or ‘intracellular’ involves different mechanisms and molecules, functional and molecular cross-talks between these two types of sensing are more than likely to exist.

Intracellular Pi sensing is much less known than extracellular Pi sensing, but recent studies have reported that the intracellular concentration of inositol polyphosphates (IP), particularly IP7, changes upon intracellular Pi availability (Wild et al. 2016), shedding light on possible intracellular Pi sensing mechanisms. In the latter study, IP7 was shown to bind the SPX (Syg1/Pho81/Xpr1) domain of the retrovirus receptor XPR1 (Battini et al. 1999) that was later characterized as a Pi exporter in mammalian cells (Giovannini et al. 2013). More recently, Wilson and colleagues identified the inositol hexakisphosphate kinases 1 and 2 (IP6K1 and 2) as being essential to the generation of IP7 upon intracellular Pi level changes, illustrating the central role of these enzymes in intracellular Pi sensing (Wilson et al. 2019). In fact, the role of IP6K1 and -2 is fully compatible with a true intracellular Pi sensor, as they are able to bind Pi and trigger the adaptive response leading to the normalisation of the intracellular Pi concentration by activating its export out of the cell through XPR1 transport activity (Fig. 1A). Finally, it is interesting to observe that in yeasts and plants, SPX domains present in membrane proteins can mediate intracellular signal transmission from variations of extracellular Pi concentration (Hürlimann et al. 2009, Ghillebert et al. 2011). This illustrates that the boundary between extracellular Pi sensing and intracellular Pi sensing may very well be thinner than we think.

Figure 1
Figure 1

Schematic view of putative Pi sensors and Pi sensing pathways in a composite mammalian cell. Knowledge of Pi sensing in mammals comes from a wide variety of cell types in the body, and the mechanisms described may not occur in all cell types. This view is to better identify which molecule can participate in Pi sensing, independently of the physiological endpoint. Sensing of extracellular Pi (Pi e) must not be confused with sensing of intracellular Pi (Pi i). In the latter case (A), the intracellular concentration of inositol polyphosphate 7 (IP7), changes upon intracellular Pi availability (Wild et al. 2016), upon action of inositol hexakisphosphate kinases 1 and 2 (IP6K1 and 2). Binding of IP7 on the SPX domain of XPR1 triggers Pi efflux from the cell, regulating intracellular Pi concentration (Wilson et al. 2019). (B) PiT1 and PiT2 are forming membrane-bound heterodimers allowing for extracellular Pi binding, triggering the ERK1/2 MAPK pathway and FGF23 secretion in vivo (Bon et al. 2017, 2018). However, the use of a MEK inhibitor did not block Pi-dependent PiT-mediated secretion of FGF23 indicating that other signaling pathways are involved. (C) Upon stimulation by extracellular Pi, FGFR1c has been implicated in FGF23 regulation, a phenomenon that involved the expression of Galnt3 activated through ERK1/2 pathway, leading to the protective O-glycosylation of FGF23. (?) The possibility that FGFR1 and PiT2 functionally interact together to control FGF23 secretion in vivo remains to be investigated. (D) The CaSR was recently illustrated as a Pi sensor whereby extracellular Pi binds to arginine residue 62 of CaSR in a non-competitive manner resulting in the activation of CaSR and increased PTH secretion. (E) While PiT1/PiT2 heterodimers and CaSR can be viewed as true extracellular Pi sensors able to detect changes in extracellular Pi levels by binding Pi at their external surface and trigger secondary intracellular events, a molecule that binds Pi does not necessarily represent a Pi sensor. For instance, Pi transporters present at the plasma membrane will bind and transport Pi into the cellular space, and therefore change the intracellular Pi concentration, activating intracellular Pi sensors such as IP6K1/2 (A).

Citation: Journal of Molecular Endocrinology 65, 3; 10.1530/JME-20-0121

Physiological and pathophysiological adaptations to changes in extracellular Pi

The main source of Pi comes from food which, following digestion, leads to the intestinal absorption of the anion involving two pathways: a passive paracellular pathway and an active transcellular transport pathway (Marks 2019). The paracellular Pi permeability allows a higher Pi absorption from the proximal small intestine lumen, where pH is lower and Pi concentrations are higher (Walling 1977, Knopfel et al. 2019). Passive paracellular Pi transport is dependent on the electrochemical gradient of Pi across the intestinal epithelium and is thought to occur through tight junction complexes comprising mainly occludins and claudins expressed along the gastrointestinal tract. While these proteins provide a regulated selective paracellular permeability for different ions, it is still unknown whether they truly bear this role for Pi (Amasheh et al. 2011, Knopfel et al. 2019). The transcellular transport mechanism of intestinal Pi absorption depends on secondary active Pi transport predominantly through the activity of Npt2b/Slc34a2 transporters (Marks 2019). While Npt2b, expressed on the apical membrane of enterocytes, accounts for 90% of Na+-dependent Pi transport into the intestinal cell (Sabbagh et al. 2009), the mechanisms accounting for the efflux at the basolateral membrane of the enterocytes are still unknown. Npt2b expression is directly upregulated by 1,25(OH)2D and indirectly by PTH through its action on vitamin D (Segawa et al. 2004). Interestingly, an earlier study has demonstrated that Pi increases the expression of Npt2b even in the absence of the vitamin D receptor in vivo, suggesting that the regulation by Pi is independent of 1,25(OH)2D (Segawa et al. 2004).

Following intestinal Pi absorption, Pi serum levels will rise, and Pi balance at the organismal level will be obtained mainly through the highly regulated renal excretion of Pi. The primary mechanism responsible for adjusting Pi serum levels is through Npt2a-mediated renal tubular Pi reabsorption (Beck et al. 1998), and to a lesser extent through Npt2c transporters (Segawa et al. 2009), at least in rodents. While renal Pi homeostasis is tightly regulated by many factors (including acid–base homeostasis, potassium status, and a number of hormones including calcitonin, dopamine, estrogen, glucocorticoids, growth hormone, insulin, insulin-like growth factor 1, EGF, and thyroid hormone (Bergwitz & Jüppner 2010, Levi et al. 2019)), the major factors that regulate renal Pi excretion are 1,25(OH)2D, PTH and FGF23 (Bergwitz & Jüppner 2010). To signal and exert its effects on Pi homeostasis and vitamin D metabolism, FGF23 requires αKlotho as an obligatory co-receptor that forms a ternary complex with FGFRs and the C-terminus of FGF23 (Kuro-O et al. 1997, Kurosu et al. 2006, Urakawa et al. 2006). This allows FGF23 to bind with high affinity to FGFR1c and FGFR3c, and activate ERK signaling (Kurosu et al. 2006, Urakawa et al. 2006). While studies have shown that in the heart, FGF23 binds to FGFR4 in the absence of αKlotho to induce left ventricular hypertrophy (Faul et al. 2011, Grabner et al. 2017), no αKlotho-independent action of FGF23 has yet been documented on Pi homeostasis regulation. Accordingly, Erben’s group has demonstrated that Klotho’s actions on mineral metabolism occur through its role as a co-receptor of FGFRs and that its actions are FGF23-dependent (Andrukhova et al. 2017, Erben 2018). Of primary importance, the secretion of 1,25(OH)2D, PTH, FGF23 and αKlotho is regulated by Pi levels (Ferrari et al. 2005, Fukumoto & Martin 2009, Bergwitz & Jüppner 2010, Jacquillet & Unwin 2019) representing the primary signal that determines the regulating cascade leading to an appropriate organismal Pi balance. Pi has also been shown to regulate directly the expression of Npt2a by modulating TFE3 transcription factor binding to a Pi-response element present in the promoter of the Npt2a gene (Kido et al. 1999), although it is still unknown whether this Pi effect on TFE3 has a significant physiological implication.

Homeostatic changes mainly involving vitamin D, PTH and FGF23 to adapt to chronic alterations in serum Pi levels require several hours to several days (Ferrari et al. 2005, Ito et al. 2007, Bergwitz & Jüppner 2010, Kritmetapak & Kumar 2019). In contrast, an early study suggested the presence of an intestine–kidney axis that would rapidly respond to changes in luminal intestinal Pi concentration by increasing renal Pi excretion within minutes (Berndt et al. 2007). This study was based on previous observations in humans showing a rapid increase in renal Pi excretion within 1 h following a high-Pi diet, without changes in PTH, FGF23 or 1,25(OH)2D serum levels, suggesting the presence of an intestinal Pi sensor (Nishida et al. 2006). In their paper, Berndt and colleagues showed that administration of Pi into the duodenum of WT or parathyroidectomized rats was associated with a rapid increase in the fractional excretion of Pi within 10 min, without hormonal changes (Berndt et al. 2007). When homogenates of the duodenal mucosa were infused into rats, a corresponding rapid increase in urinary fractional excretion of Pi was illustrated, strongly suggesting the presence of intestinal factors that signal to the kidney to control Pi excretion. This essential mechanism would allow for a rapid crosstalk between intestine and kidneys; however, the exact molecular identity of the intestinal Pi factor is still unknown. Importantly, when similar experiments were carried out in humans, no strong evidence for an intestinal-specific control of renal Pi excretion was shown, probably pointing out that this mechanism is species-dependent (Scanni et al. 2014). Moreover, a recent study in rats suggested that the intravenous or intragastric loading of Pi modulated renal excretion of Pi by a PTH-dependent mechanism (Thomas et al. 2017), reigniting the controversy over the existence of a short-term pathway and requiring the identification of the putative intestinal phosphatonin to definitively prove the existence of a PTH-independent, intestine-to-kidney short term pathway.

Precise knowledge of the mechanisms underlying the long-term and the putative short-term regulations of Pi homeostasis is crucial to propose an appropriate clinical response in relevant disease states. A persistent hyperphosphatemia has very serious deleterious pathological consequences, among which an increased risk of cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients is a striking example (Clinkenbeard et al. 2019). These patients have a notorious propensity to develop vascular calcifications (VC) (Witteman et al. 1986, 1990, Heine et al. 2013), which are a strong predictor of elevated cardiovascular mortality (Blacher et al. 2001, Schlieper et al. 2008). During renal failure, hyperphosphatemia triggers calcification of the medial layer of the arterial wall, but also exacerbates intimal atherosclerosis plaque calcification, which is already present in virtually all CKD patients. Since both types of calcification significantly affect cardiovascular mortality in CKD (London et al. 2003), it is crucial to understand the effects of Pi on each. Particularly, the mode of action of Pi that leads to calcification is still a matter of debate. Pi may simply act by precipitating on preexisting crystals, or through its signaling function in promoting the transdifferentiation of vascular smooth muscle cells (VSMC) into osteochondrocyte-like cells (Jono et al. 2000, Sage et al. 2011, Mokas et al. 2016, Hortells et al. 2017).

How relevant is the detection of Pi in lower organisms to mammals?

In order to identify Pi sensors in mammalian cells mediating Pi signaling function, an interesting approach has been to study the systems implemented in lower organisms and compare them with the need of more evolved cells and organisms. Excellent review articles on Pi sensing including a description of non-mammalian systems have been written recently, and we encourage readers to refer to them for more details on the detection of Pi in lower organisms (Conrad et al. 2014, Qi et al. 2016, Chande & Bergwitz 2018, Michigami et al. 2018, Kritmetapak & Kumar 2019). What is most striking when studying bacteria, yeast or even plant Pi sensing mechanisms, is that the requirement for Pi is very different than for mammalian cells. Bacteria, yeasts and plants are highly dependent upon their environment when it comes to Pi availability. The quantities of Pi in the soil or in the external environment are very low, in the micromolar range, whereas Pi is in the millimolar range in mammals. Accordingly, plants and unicellular organisms express Pi transporters and Pi sensing molecules that are adapted to low Pi availability. The ‘normal’ situation is actually a Pi deprivation for which uptake and sensing of Pi are constantly stimulated by default. It is only when Pi is in higher quantities that the system is turned off. In mammals, there is the reverse situation, since they can move to seek their nutrient needs. The ‘normal’ situation in mammals is actually to face too much Pi, especially in the modern era, where bioavailable free Pi is extensively used as an additive in industrialized processed food (Ritz et al. 2012, Vorland et al. 2017). Accordingly, the sensing of extracellular Pi in mammals has evolved to set up endocrine regulatory loops aimed at excreting Pi out of the body in order to avoid Pi toxicity. Another difference between lower organisms and mammals is the actual mechanism of Pi transport through the plasma membrane. In lower organisms, the molecules involved in Pi uptake are coupling the entry of Pi to the efflux of protons, whereas Pi entry in mammals is coupled to sodium uptake. A notable exception is the Pho89 transporter in yeast, which allows co-transport of phosphate and sodium ions within the cell. It is interesting to note that this transporter belongs to the large inorganic phosphate transporter (PiT) family (Transporter Classification Database 2.A.20), which includes the mammalian orthologs (SLC20A1/PiT1 and SLC20A2/PiT2, see subsequent paragraph), and the bacterial PitA and PitB transporters. Unfortunately, yeast studies so far have not been able to attribute a major role to Pho89 in the sensing of Pi (Qi et al. 2016), which could be related to its low affinity for Pi and particular transport properties in relation to the extracellular environment of yeast. Accordingly, a large majority of the Pit family of transporters do not transport sodium, but rather H+, including the bacterial PitA and PitB transporters, illustrating that their machinery of Pi transport and most probably Pi sensing is based upon different chemistry, stoichiometry, affinity and purpose. These differences in transport and environmental properties may explain why no mammalian Pi sensor has been identified from direct sequence comparison searches using unicellular organisms or plant Pi sensors sequences, or that if sequence homology can be evidenced, the transporters may play different roles in their respective cellular environment.

Identified Pi sensors in mammals

In mammals, several proteins have been recently identified as putative Pi sensors that can play a role in informing the organism of a change in extracellular Pi levels. Our recent work in Pi signaling has led us to identify the PiT1-PiT2 heterodimer complex as an essential membrane component to mediate Pi-dependent ERK1/2 signaling (Bon et al. 2017), which later led to the identification of PiT2 as being a key molecule to mediate FGF23 secretion upon Pi challenge (Bon et al. 2018) (Fig. 1B and text subsequently). PiT1 (Slc20a1) and PiT2 (Slc20a2) are high-affinity Na+-dependent Pi transporters (Kavanaugh et al. 1994, Miller & Miller 1994) that were originally identified as retrovirus receptors (O’Hara et al. 1990, Miller et al. 1994, van Zeijl et al. 1994). Unlike other high-affinity Na+-Pi co-transporters described in mammals that belong to the Slc34 family (Wagner et al. 2013), PiT proteins are widely expressed, including in key organs involved in Pi homeostasis regulation (Forster et al. 2013). However, despite this significant observation, their contribution to Pi homeostasis through their Pi transport capability has not been demonstrated.

Considering their role in Pi signaling (Bon et al. 2017), we explored the possibility that the involvement of PiTs in Pi homeostasis may rather derive from their Pi sensing capabilities. To test this hypothesis, we took advantage of the PiT2 KO mouse model and illustrated that the lack of PiT2 in vivo fully blunted the secretion of FGF23 in response to variations in dietary Pi loads, without changes in PTH or vitamin D levels (Bon et al. 2018). To further confirm these results, we reproduced this effect by stimulating ex vivo bone shaft cultures from WT and PiT2 KO mice and confirmed that PiT2 disruption blunted the Pi-dependent regulation of FGF23 secretion independently of PTH and vitamin D (Bon et al. 2018). These experiments were the first to report a complete absence of FGF23 secretion in response to Pi both in vivo and ex vivo. Of important note, we were not able to reproduce these data in osteoblasts and osteocytes in culture, either from established cell lines or primary cultures, despite the fact that this is an approach often used to study the Pi-dependent secretion of FGF23 (Michigami et al. 2018, Bon et al. 2019, Takashi & Fukumoto 2020). This most likely indicates that the natural 3D environment of osteocytes offered by ex vivo cultures of intact bone shafts may be crucial for responding to Pi level variations (Bon et al. 2018).

A recent interesting study has shown that high extracellular Pi levels resulted in phosphorylation of the FGF receptor FGFR1c in the absence of canonical ligands (Takashi et al. 2019). High Pi appeared to trigger the phosphorylation the FGFR substrate 2α (FRS2α), leading to activation of the MEK/ERK pathway and subsequent mechanisms that induces the expression of the polypeptide N-acetylgalactosaminyltransferase 3 (Galnt3) gene. O-glycosylation of FGF23 by the GALNT3 gene product prevented its proteolytic cleavage, leading to an increase in the serum levels of FGF23 in mice fed a high-phosphorus diet (Fig. 1C). Intriguingly, while FGFR1 is central to this mechanism, it is not known how it is activated by extracellular Pi since FGFRs do not bind Pi (Takashi & Fukumoto 2020). It is possible that the ‘sensing’ of extracellular Pi reported in this publication relates to the ability of Pi to enter the cell and phosphorylate FGFR1. If this is the case, FGFR1 may actually represent an intracellular Pi sensor playing a role in the secretion of FGF23. In contrast, the Pi sensing function of PiT2 most likely derives from extracellular Pi binding at the plasma membrane and subsequent activation of MAPK, rather than from Pi uptake (Bon et al. 2017). The possibility that FGFR1 and PiT2 functionally interact together to control FGF23 secretion in vivo remains to be investigated (Fig. 1B and C).

In addition to the control of FGF23 secretion by Pi through PiT2 and FGFR1-mediated sensing, a recent study has identified the calcium-sensing receptor (CaSR) as a Pi sensor controlling PTH secretion. While it has been known for a long time that Pi elicits a concentration-dependent stimulation of PTH (Almaden et al. 1996, Slatopolsky et al. 1996), the molecular mechanism mediating this effect is still uncertain. Ten years ago, the CaSR was identified in a genome-wide association study as a genetic determinant of serum Pi concentration (Kestenbaum et al. 2010). More recently, the crystal structure of the receptor revealed multiple binding sites for P043- ions in the extracellular domain of CaSR, suggesting that the binding of Pi may modify the conformation of CaSR, which therefore could modify the binding properties of Ca2+ to the receptor and have indirect consequences on the regulation of Pi homeostasis through Pi sensing (Geng et al. 2016). Based on these results, Centeno et al. identified arginine residue 62 (R62) as a Pi binding site in CaSR (Centeno et al. 2019). Binding of Pi to R62 significantly inhibited CaSR activity in a non-competitive manner resulting in increased PTH secretion, whereas mutation of this residue abolished Pi-induced inhibition of CaSR. Pathophysiologic Pi concentrations elicited a rapid and reversible increase in PTH secretion from human and WT murine parathyroid glands, but not in CaSR knockout glands. These results indicated that CaSR represents a Pi sensor in the parathyroid gland, explaining the stimulatory effect of Pi on PTH secretion (Fig. 1D) (Centeno et al. 2019).

Open questions regarding receptors, ligands and involved mechanisms of sensing

The cellular mechanisms that allow the detection of extracellular Pi are only beginning to be understood. A true sensor able to detect changes in extracellular Pi levels is expected to bind Pi at the external surface and trigger secondary intracellular events that will inform the cell of the extracellular Pi changes, leading to relevant cellular responses. A Pi sensor that detects changes in extracellular Pi concentrations would necessarily be expressed at the plasma membrane. Both CaSR and PiT2 meet this definition by triggering the intracellular ERK1/2 MAPK pathway in response to external Pi binding without Pi entry in the cell. As such they are true Pi sensor, respectively triggering PTH and FGF23 secretion upon Pi binding. What is less known is the precise link between the initial fast response of Pi binding (within seconds to minutes), for example, ERK phosphorylation, and the terminal slower cellular response (within minutes to hours), for example, hormonal secretion. Nevertheless, a main difference between CaSR/PiT2- and FGFR1c-mediated sensing is that, in the FGFR1c situation, the initial events of Pi sensing are still to be discovered, particularly how can this receptor inform the cell about extracellular Pi variations without binding extracellular Pi.

Importantly, while a true Pi sensor is expected to bind Pi, a molecule that binds Pi does not necessarily represent a Pi sensor. For instance, a Pi transporter expressed at the plasma membrane that will bind extracellular Pi and transport this anion into the cellular space will participate in changing the intracellular Pi concentration. As the intracellular Pi changes, an adaptive intracellular response will be triggered involving intracellular Pi sensors such as IP6K1/2 (Wild et al. 2016, Wilson et al. 2019), as discussed in the first paragraph of this review. As such, although the plasma membrane transporter activity is part of the sensing pathway, this is not actually the molecule that acts as a sensor. An interesting example of an important molecule participating in the extracellular Pi sensing is the Na+-Pi cotransporter Npt2b (Slc34a2) (Hilfiker et al. 1998, Feild et al. 1999). The intestinal deletion of Npt2b in mice leads to a decrease in Fgf23 serum levels (Sabbagh et al. 2009) and the involvement of Npt2b in an intestine-kidney axis regulating Pi levels (Berndt et al. 2007, Kumar 2009) and Pi sensing (Sabbagh & Schiavi 2014) was suggested. However, there is yet no study illustrating a role of Npt2b in specifically triggering downstream intracellular pathways independently of its Pi transport activity, nor regulation of its expression by Pi (Tenenhouse et al. 2001). So far, its possible involvement in Pi sensing pathway is more likely related to its transport activity, which indirectly modifies the intracellular concentrations of Pi that are detected by an intracellular Pi sensor triggering the relevant cellular response (Fig. 1E).

Another question relates to the functional interaction between identified Pi sensors and their roles in different tissues. Considering that both CaSR and PiT2 modulate the ERK pathway, could this mean that their Pi sensing capability are functionally interchangeable? More precisely, can CaSR trigger a FGF23 secretion and PiT2, a PTH secretion, depending on the tissue in which they are expressed? While this issue has yet to be studied in detail, we earlier showed that Pi stimulation of ERK pathway and MGP/OPN expression in MC3T3 osteoblastic cells were unchanged in the presence of either a CaSR agonist (gadolinium) or the G-protein inhibitor pertussis toxin, suggesting that the Pi signaling effect seen in these cells was not dependent upon CaSR (Khoshniat et al. 2011), but rather on PiT1/PiT2 expression (Bon et al. 2017). This results is somewhat consistent with the fact that Pi binding to PiT2 leads to ERK activation (Bon et al. 2017), whereas Pi binding to CaSR leads to ERK inactivation (Centeno et al. 2019). It also remains to be determined whether the roles of CaSR and PiT2 on PTH and FGF23 secretion are identical when expressed in different tissues. For instance, what is the contribution of the CaSR to PTH secretion following Pi stimulation in the intestine? Or, what is the physiological role of PiT2 as a Pi sensor in tissues not expressing FGF23?

Notwithstanding these many remaining issues, knowledge about the molecular nature of putative Pi sensors has largely progressed over the last few years. Conversely, knowledge about the precise nature of the involved ligands is still unclear and controversial. In in vitro signaling experiments aimed at testing the effect of extracellular Pi on downstream signaling pathways, Pi is traditionally added in the form of Na2HPO4 and NaH2PO42− in a 4:1 ratio (pH 7.4), where Na+ may be replaced by potassium. In these conditions, the PO4 anions are supposed to be the ligand triggering the cellular response. However, both in these experiments and in the in vivo situation, calcium is present in the fluids at a significant concentration, questioning its role in modulating Pi sensing. We and others have illustrated that both in vivo and in vitro, the presence of calcium modifies the Pi sensing response (Khoshniat et al. 2008, Quinn et al. 2013). We earlier showed in vitro that calcium was required for Pi to stimulate ERK1/2 phosphorylation and MGP/OPN genes expression and suggested that this effect could originate from extracellular-related effects of calcium-Pi precipitates (CaP particles) (Khoshniat et al. 2008). More recently, Quinn and colleagues illustrated the fundamental role of calcium in vivo in the Pi-dependent secretion of FGF23 (Quinn et al. 2013). Based on these findings, a recent study proposes that calciprotein particles, which are nanoparticles of calcium-Pi precipitates bound to the serum protein fetuin-A, are the true signal controlling FGF23 secretion, rather than PO4 anion alone (Akiyama et al. 2020). This study illustrates that deciphering ‘Pi sensing’, and whether it also depends on calcium or not, is not trivial. While PiT2 has clearly been shown to be involved in Pi-dependent FGF23 secretion both in vivo in mice and ex vivo in cultured bone shafts in controlled conditions (Bon et al. 2018), it is not known whether PiT2 can bind calciprotein particles. To date, the only structural study that provides strong arguments for a direct binding of PO4 anions to a Pi sensor was conducted on the crystal structure model of CaSR (Geng et al. 2016, Centeno et al. 2019). These experiments provided evidence that PO4 anions directly bind to the CaSR whereby PO4 acts as a non-competitive antagonist of CaSR efficacy, and were conducted in the presence of various calcimimetic molecules to lower Ca2+ concentration and reduce the risk of Ca×P association, most likely excluding a role for Ca2+ in the present Pi sensing mechanism (Centeno et al. 2019). Similar experiments are clearly required to elucidate the true nature of the ligand responsible for Pi sensing through PiT2 or other putative sensors triggering FGF23 secretion in response to modifications of extracellular Pi (alone or in combination with Ca modifications).

Conclusion

Understanding the Pi sensing mechanisms at the organismal level in mammals is not an easy task, and the very definition of sensing itself can be controversial. In this review, we have highlighted some aspects that are important for understanding the mechanisms that govern the detection of changes in extracellular Pi concentrations. In particular, we have made the reader aware of the complex links that may exist between intracellular and extracellular detection of Pi; the possible existence of short- and long-term detection mechanisms; the importance of calcium in the cellular response to Pi; the endocrine and non-endocrine parameters that influence Pi sensing; the identity of mammalian Pi sensors, both proven and hypothesized; and the fundamental importance of better understanding this field in order to generate appropriate clinical approaches to treat patients with Pi -related diseases.

Declaration of interest

The authors declare to have no financial or other potential conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

This work was supported by grants from Institut National de la Santé et de la Recherche Médicale (INSERM), Région des Pays de la Loire (’Senseo’ and ‘Adipos’ grants), and Société Française de Rhumatologie (SFR) (PITOA and PITAMO).

References

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    Schematic view of putative Pi sensors and Pi sensing pathways in a composite mammalian cell. Knowledge of Pi sensing in mammals comes from a wide variety of cell types in the body, and the mechanisms described may not occur in all cell types. This view is to better identify which molecule can participate in Pi sensing, independently of the physiological endpoint. Sensing of extracellular Pi (Pi e) must not be confused with sensing of intracellular Pi (Pi i). In the latter case (A), the intracellular concentration of inositol polyphosphate 7 (IP7), changes upon intracellular Pi availability (Wild et al. 2016), upon action of inositol hexakisphosphate kinases 1 and 2 (IP6K1 and 2). Binding of IP7 on the SPX domain of XPR1 triggers Pi efflux from the cell, regulating intracellular Pi concentration (Wilson et al. 2019). (B) PiT1 and PiT2 are forming membrane-bound heterodimers allowing for extracellular Pi binding, triggering the ERK1/2 MAPK pathway and FGF23 secretion in vivo (Bon et al. 2017, 2018). However, the use of a MEK inhibitor did not block Pi-dependent PiT-mediated secretion of FGF23 indicating that other signaling pathways are involved. (C) Upon stimulation by extracellular Pi, FGFR1c has been implicated in FGF23 regulation, a phenomenon that involved the expression of Galnt3 activated through ERK1/2 pathway, leading to the protective O-glycosylation of FGF23. (?) The possibility that FGFR1 and PiT2 functionally interact together to control FGF23 secretion in vivo remains to be investigated. (D) The CaSR was recently illustrated as a Pi sensor whereby extracellular Pi binds to arginine residue 62 of CaSR in a non-competitive manner resulting in the activation of CaSR and increased PTH secretion. (E) While PiT1/PiT2 heterodimers and CaSR can be viewed as true extracellular Pi sensors able to detect changes in extracellular Pi levels by binding Pi at their external surface and trigger secondary intracellular events, a molecule that binds Pi does not necessarily represent a Pi sensor. For instance, Pi transporters present at the plasma membrane will bind and transport Pi into the cellular space, and therefore change the intracellular Pi concentration, activating intracellular Pi sensors such as IP6K1/2 (A).

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