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Keywords:

  • CALCITONIN;
  • CALCITONIN RECEPTOR;
  • BONE TURNOVER;
  • CALCIUM HOMEOSTASIS

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. CTRs and Intracellular Signaling
  5. The Physiological Role of Calcitonin
  6. Conclusion
  7. Disclosures
  8. Acknowledgements
  9. References
  10. Supporting Information

Calcitonin, a potent hypocalcemic hormone produced by the C-cells of the thyroid, was first discovered by Harold Copp in 1962. The physiological significance of calcitonin has been questioned, but recent studies using genetically modified mouse models have uncovered additional actions of calcitonin acting through its receptor (CTR) that are of particular significance to the regulation of bone and calcium homeostasis. Mice in which the CTR is deleted in osteoclasts are more susceptible to induced hypercalcemia and exogenous calcitonin is able to lower serum calcium in younger animals. These data are consistent with the hypothesis that calcitonin can regulate serum calcium by inhibiting the efflux of calcium from bone, and that this action is most important when bone turnover is high. Calcitonin has also been implicated in protecting the skeleton from excessive loss of bone mineral during times of high calcium demand, such as lactation. This action may be linked to an intriguing and as yet unexplained observation that calcitonin inhibits bone formation, because deletion of the CTR leads to increased bone formation. We propose several mechanisms by which calcitonin could protect the skeleton by regulating bone turnover, acting within the bone and/or centrally. A new more holistic notion of the physiological role of calcitonin in bone and calcium homeostasis is required and we have highlighted some important knowledge gaps so that future calcitonin research will help to achieve such an understanding. © 2013 American Society for Bone and Mineral Research.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. CTRs and Intracellular Signaling
  5. The Physiological Role of Calcitonin
  6. Conclusion
  7. Disclosures
  8. Acknowledgements
  9. References
  10. Supporting Information

Calcitonin is a potent hypocalcemic hormone, thought until recently to act predominantly on bone to inhibit osteoclastic bone resorption. There is also evidence for an action in the kidney to decrease tubular reabsorption of calcium, and in the brain and hypothalamus, where a number of actions have been reported. Despite these documented effects, the physiological role of calcitonin has long been debated, with some suggesting that calcitonin is a vestigial hormone. The basis for this view is the absence of any obvious bone or calcium pathophysiology in patients with low levels of calcitonin following thyroidectomy, or conversely, in patients with elevated levels of calcitonin, such as those with medullary thyroid carcinoma. Recently, there have been significant advances using genetically modified mouse models to explore physiological roles for calcitonin acting via its receptor, the calcitonin receptor (CTR). Data from these studies allows the proposition that calcitonin has important and related roles in (1) protecting the skeleton by regulating bone turnover and (2) maintaining calcium homeostasis. In this Perspective we focus on the recent evidence supporting these putative physiological roles for calcitonin acting via the CTR.

CTRs and Intracellular Signaling

  1. Top of page
  2. Abstract
  3. Introduction
  4. CTRs and Intracellular Signaling
  5. The Physiological Role of Calcitonin
  6. Conclusion
  7. Disclosures
  8. Acknowledgements
  9. References
  10. Supporting Information

Calcitonin signals intracellularly by binding to its receptor, the CTR, on the plasma membrane of effector cells. The CTR has been extensively characterized previously and has been the subject of several reviews.1–3 It belongs to the class II (family B) subclass of G protein-coupled receptors (GPCRs), which include the receptors for other peptide hormones such as secretin, parathyroid hormone (PTH) and PTH-related peptide (PTHrP), glucagon, glucagon-like peptide 1, vasoactive intestinal polypeptide, pituitary adenylate cyclase-activating peptide and gastric inhibitory peptide. The CTR exists in several isoforms, which have distinct ligand binding and intracellular signaling profiles,2, 4, 5 although the physiological significance of these isoforms is not understood. It has also been established that CTR coreceptor molecules, receptor activity modifying proteins (RAMPs), can associate with the CTR and other receptors of its class to change ligand recognition and signaling.6 For example, depending on the RAMP protein, the CTR can act as a calcitonin or amylin receptor. Like other GPCRs which can form homodimers or heterodimers, the CTR can also form dimers, and probably greater aggregates, which may have consequences for their cellular localization and function.7 Calcitonin binding to the CTR activates multiple G-protein–mediated signaling pathways, leading, in a tissue-dependent manner to activation of the cyclic adenosine monophosphate (cAMP)/protein kinase A pathway8, 9 or protein kinase C pathways.10 In addition, CTR-mediated activation of the mitogen-activated protein kinase (MAPK) pathway has been described, with a role for both Gq and Gi/o proteins.11, 12 There is also evidence that calcitonin can influence cell attachment, particularly of osteoclasts, by modulating components of focal adhesions and the cytoskeleton.13 The presence of CTR isoforms, the contribution to calcitonin binding and binding specificity of RAMP coreceptors, and the multiple intracellular signaling pathways activated by calcitonin, all add considerable complexity to the mechanism of action of this molecule, which needs to be considered at the level of specific responding cells rather than in a generic sense. This complexity has been covered in greater detail in several recent reviews.14, 15

The Physiological Role of Calcitonin

  1. Top of page
  2. Abstract
  3. Introduction
  4. CTRs and Intracellular Signaling
  5. The Physiological Role of Calcitonin
  6. Conclusion
  7. Disclosures
  8. Acknowledgements
  9. References
  10. Supporting Information

Calcitonin actions on osteoclasts and the kidney

The best understood action of calcitonin, and that for which there is the most comprehensive data, is its action to inhibit osteoclast activity and therefore to inhibit bone resorption. This inhibitory action has been shown in vivo,16 in organ culture of bone,17 and in isolated osteoclasts in vitro.10, 18, 19 As reviewed by Del Fattore and colleagues,20 calcitonin treatment of osteoclasts rapidly (within minutes) induces loss of their ruffled border and cell immobility, followed by cell retraction and arrest of bone resorption. These actions are perhaps mediated by calcitonin-induced changes in osteoclast adhesion, because calcitonin affects integrin engagement, the actin cytoskeleton and a number of components of the cell adhesion apparatus.11 Although calcitonin does not affect osteoclast apoptosis or the expression of a wide variety of transcription factors and genes important for osteoclast differentiation and activity,9 it has been reported to alter ion transporter distribution, impair enzyme activity,21 and inhibit the osteoclastogenic effects of receptor activator of NF-κB ligand (RANKL).22

Calcitonin has also been shown to affect the renal handling of calcium in humans by promoting renal excretion of calcium, presumably via its actions to decrease the tubular reabsorption of calcium.1, 23, 24 In addition, calcitonin may regulate serum calcium by increasing the renal conversion of 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) with direct stimulation of the transcription of the 1α-hydroxylase gene in the proximal tubule of the kidney.1, 25, 26 In fact, calcitonin, and not PTH, appears to be a major regulator of 1α-hydroxylase and serum levels of 1,25(OH)2D3 in the normocalcemic state.26, 27 These actions of calcitonin to regulate the renal synthesis of 1,25(OH)2D3 appear not to be mediated via the CTR, because CTRs have not been identified in the proximal tubule of the kidney.26, 28 CTRs are, however, located in the thick ascending limb and the early portion of the distal convoluted tubule of the kidney, where they activate adenylate cyclase.29

Calcitonin, the CTR, and bone formation

Despite the well documented antiresorptive actions of calcitonin on osteoclasts, Hoff and colleagues30 made the surprising discovery that global deletion of the gene encoding calcitonin and its splice variant, calcitonin gene related peptide (CGRP) in mice (CT/CGRPKOs), led to increased trabecular bone as a result of increased bone formation at 1 and 3 months of age, whereas bone resorption and calcium homeostasis were unaffected. These intriguing data were the first to suggest a putative action of calcitonin to inhibit bone formation. The initial characterization of the CT/CGRPKOs by Hoff and colleagues30 was performed on mice of a mixed genetic background. Because bone mineral density (BMD) differs markedly between different inbred strains, data arising from the characterization of genetically modified mice of a mixed background may be difficult to interpret. Further studies by Huebner and colleagues31, 32 confirmed the high bone mass phenotype of the CT/CGRPKO mice on a homogeneous C57BL/6 background at up to 18 months of age. Of significant interest, however, was the observation that in addition to the increased bone formation, CT/CGRPKO mice also exhibited a fourfold increase in bone resorption, which was not evident until 12 months of age. This increased bone turnover in 12-month-old CT/CGRPKOs resulted in increased cortical porosity. The trabecular bone mass was maintained as a result of increased bone formation, in the absence of any changes in several key hormones involved in bone remodeling.32 Although the pharmacological action of calcitonin to inhibit bone resorption is well established, this study in CT/CGRPKO mice at 12 months of age provided the first evidence for a physiological role of calcitonin to inhibit bone resorption in vivo.

The studies performed in the CT/CGRPKO mice yielded important data in relation to the physiological actions of calcitonin and its related peptide in regulating bone turnover. CGRP has been shown to have inhibitory actions on osteoclasts33 and stimulatory effects on osteoblast proliferation,34 in addition to potent vasodilatory effects in the cerebral and peripheral vasculature.35 Therefore, in order to investigate whether the increased bone formation and age-dependent increase in bone resorption observed in the CT/CGRPKOs was a result of the loss of calcitonin or CGRP, Schinke and colleagues36 characterized the bone phenotype of a mouse model unable to express α-CGRP, whereas calcitonin production is unaffected. Mice lacking α-CGRP exhibited a mild, age-dependent osteopenia due to decreased bone formation, whereas bone resorption and serum levels of PTH, calcium, and phosphate were unaffected. Conversely, overexpression of human CGRP specifically in osteoblasts under the control of the rat osteocalcin promoter in mice, results in increased trabecular bone volume attributable to increased bone formation.37 Together, these data demonstrate that the increased bone formation and resorption observed in the CT/CGRPKOs at 12 months of age can be attributed to the inhibitory actions of calcitonin, rather than α-CGRP.

To address the issue of whether the inhibitory actions of calcitonin on bone formation are mediated via the CTR or by another member of the calcitonin-like receptor family, Dacquin and colleagues38 characterized the bone phenotype of a haploinsufficient mouse model of the CTR. Deletion of one copy of the CTR in these mice led to a 50% reduction in CTR mRNA expression. Haploinsufficient CTR mice at 8 weeks of age exhibited increased vertebral trabecular bone volume as a result of increased bone formation rate, whereas bone resorption was unaffected.38 Further investigation into the role of the CTR in bone formation in these mice was limited by the fact that homozygous deletion of the CTR resulted in embryonic lethality,38 indicating for the first time that the CTR is essential for embryonic development. The haploinsufficient mice were also of mixed genetic background. These data, therefore, prompted us to generate a global-CTRKO mouse model on a homogenous C57BL/6 background using the Cre/loxP system, by breeding floxed CTR mice39 with cytomegalovirus–cyclic recombinase (CMV-Cre) mice.40 The deletion of the CTR in global-CTRKO mice was estimated to be greater than 94% but less than 100%, with a small amount of CTR expression remaining (<6%), which was consistent with a requirement of the CTR for embryonic viability. This level of CTR deletion in the global-CTRKO mice was sufficient to abolish the inhibitory actions of calcitonin on osteoclasts.39 Consistent with previous findings in haploinsufficient CTR mice, male global-CTRKO mice exhibited an increase in bone formation at 12 and 24 weeks of age, but in contrast to the haploinsufficient CTR mice, this did not result in a significant increase in trabecular bone volume. The differences in the magnitude of the increased bone formation observed between these global-CTRKO mice and the haploinsufficient CTR mice are difficult to explain, but are most likely attributable to one or more of the following: differences in genetic background, the region of the CTR targeted for deletion, and the technology used to introduce the genetic modification, in addition to potential environmental and experimental differences arising from the mice being generated and characterized in different laboratories. Nonetheless, the data from these two different CTR-deficient mouse models identifies a potential role for the CTR to regulate bone formation. To date, the question relating to whether the age-dependent inhibitory actions of CT observed in the CT/CGRPKO mice are mediated via the CTR remains unanswered because the haploinsufficient and global-CTRKO mice have not yet been characterized at 12 months of age.

The mechanism by which calcitonin, acting via the CTR, may exert an inhibitory effect on bone formation remains to be determined; however, insight has been provided by recent studies. Evidence obtained from mice, in which the CTR was specifically deleted in osteoclasts,41 generated by breeding floxed CTR mice39 with cathepsin K (Ctsk)-cre mice,42 suggests that the inhibitory effects of calcitonin on bone formation are not mediated via the CTR expressed by osteoclasts, because bone formation was not increased in these mice. In fact, osteoclast-CTRKO mice exhibited transient decreases in bone formation during growth, when bone mineral accretion was highest, which normalized to control levels by adulthood.41

An intriguing possible mechanism for the effect of calcitonin on bone formation is by regulating the production of sclerostin, an osteocyte-derived negative regulator of bone formation.43 Previous reports have identified CTR expression in osteocyte-like MLO-Y4 cells44, 45 and that calcitonin can protect these cells from various apoptotic stimuli.44 More recently, Gooi and colleagues46 reported that osteocytes embedded within the bone matrix, or freshly isolated from bone, express abundant CTR, the expression of which cannot be detected after a short period of culture of the isolated cells. The authors showed that administration of salmon calcitonin (sCT) to young female rats blunted their response to anabolic PTH treatment. The anabolic action of PTH is likely to be mediated by osteocytes, because expression of a constitutively active PTH receptor specifically in osteocytes increases bone mass and remodeling to similar levels to that observed following treatment with exogenous PTH.47 The blunting of the anabolic response to PTH following sCT treatment in the rat model was associated with an upregulation of sclerostin production in the bone and an increased number of sclerostin-positive osteocytes.46 Overexpression of the SOST gene in mice leads to low bone mass and decreased bone strength as a result of reduced bone formation.43 Sclerostin also decreases osteoblastic mineralization43, 48 by increasing the expression of matrix extracellular phosphoglycoprotein (MEPE) and MEPE–acidic serine aspartate-rich MEPE-associated (ASARM)48 and can induce osteocyte expression of RANKL, thereby increasing osteocyte support for osteoclast formation and activity.49 On the basis of these data, we propose that calcitonin can act in bone to regulate bone turnover, by inhibiting bone formation via stimulation of the production of sclerostin by osteocytes and also by directly inhibiting osteoclastic resorption. Proof of the notion that calcitonin and PTH can co-regulate osteocyte activity, in order to regulate bone mass, obviously requires more targeted research, but the idea is attractive because all biological processes, including bone turnover, need to proceed at an optimum rate. The consequences of increased rates of bone remodeling in older age, with a net loss of bone, have been well described.50 It may be relevant that postmenopausal women receiving calcitonin in the QUEST study showed significant preservation of trabecular bone microarchitecture compared with placebo, as determined by MRI.51 As discussed below, the more catabolic action of PTHrP to release calcium during lactation52 could also be regulated by calcitonin to protect bone mass, although there is no evidence for this to date.

It has been proposed that another potential mechanism, by which calcitonin exerts an inhibitory effect on bone formation, is via actions in the brain.31, 53 The premise for this hypothesis has been provided by the recent discovery of other neural regulators of bone, including leptin and neuropeptide Y, whose actions originate from the hypothalamus and are mediated via efferent neural pathways to regulate bone turnover.54, 55 Evidence supporting this hypothesis is the high level of CTR expression and calcitonin binding within the arcuate nucleus of the hypothalamus,56–58 together with the observations that calcitonin and CGRP act via the central nervous system (CNS) to inhibit appetite and gastric acid secretion, to modulate hormone secretion, to exert analgesic effects, and to control the secretion of prolactin.59–62 It remains to be tested whether calcitonin acting in the hypothalamus can influence bone metabolism.

Calcitonin and calcium homeostasis

The second major action of calcitonin is to maintain calcium homeostasis. The first evidence for calcitonin providing protection against hypercalcemia was obtained in the 1960 s. Thyroidectomized patients with negligible levels of serum calcitonin were challenged with an intravenous calcium load. Serum calcium levels remained elevated for a prolonged period in thyroidectomized patients compared to control patients with normal circulating levels of calcitonin.63, 64 This ability of calcitonin to reduce serum calcium levels is dependent on the rate of bone turnover. In states of high bone turnover, such as in childhood or in patients with malignancy-induced hypercalcemia, exogenous calcitonin rapidly decreases serum calcium. In contrast, little effect is observed in adults with normal, but comparatively lower rates of bone turnover.65, 66 Figure 1 attempts to show diagrammatically the concept described by Parfitt67 and discussed more fully in a recent review,68 of a pool of exchangeable calcium in equilibrium with bone, the efflux of which seems to be governed by PTH, with the influx probably occurring down a physicochemical gradient. To our knowledge, there is no evidence that calcitonin affects the latter, but a greater effect on calcium efflux in states of high bone turnover is consistent with its inhibitory actions on osteoclasts, and perhaps osteocytes.46, 52 The ability of calcitonin to reduce serum calcium following an exogenous calcium load is at least partly explained by reducing the efflux of calcium from bone, rather than affecting its influx. Indeed, CT/CGRPKO mice also showed a greater calcemic response to exogenous PTH administration than controls due to increased bone resorption, which was prevented by treatment with calcitonin but not CGRP.30 Evidence from studies in global-CTRKO and osteoclast-CTRKO mice suggest that this effect of calcitonin to protect against hypercalcemia is largely mediated via the CTR on osteoclasts. Hypercalcemia induced by treatment with 1,25(OH)2D3 results in a higher hypercalcemic response in global-CTRKO and osteoclast-CTRKO mice compared to littermate controls, attributable to increased bone resorption.39, 41 Of interest, the peak serum calcium levels following 1,25(OH)2D3–induced hypercalcemia were greater in global-CTRKOs than osteoclast-CTRKOs, suggesting a hypocalcemic action of calcitonin at a site or sites in addition to the osteoclast.39 This view is supported by observations of increased tubular reabsorption of calcium in the kidney (TmCa) in global-CTRKOs following induced hypercalcemia, whereas TmCa was unchanged in osteoclast-CTRKOs. These data are consistent with the renal actions of calcitonin to inhibit calcium reabsorption, in order to rapidly improve severe hypercalcemia, being mediated directly via the CTR.69 The precise contribution of the renal actions of the CTR in protecting against hypercalcemia, however, remains to be determined.

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Figure 1. Proposed model by which calcitonin (CT) protects the skeleton by regulating bone turnover. These actions appear to be most important when bone turnover is high. CT limits calcium flux from bone by (a) inhibiting osteoclastic bone resorption and (b) perilacunar/canalicular remodeling by osteocytes. CT may act to (c) regulate coupling between osteoclasts and osteoblasts. CT inhibits bone formation by (d) stimulating the production of sclerostin from osteocytes and (e) by acting via the CTR in the arcuate nucleus of the hypothalamus to activate a yet unidentified efferent neural pathway. Pathways indicated by dashed lines represent hypothesized mechanisms of CT action requiring further investigation.

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Physiological situations that impose a significant calcium stress on mammals are pregnancy and lactation, which require a relatively large transfer of calcium from the mother to the fetus and neonate.70 Calcium demand during pregnancy seems to be met largely by increased calcium absorption across the gut. However, calcium for milk is sourced from the maternal skeleton, together with renal calcium conservation.70 The mechanism controlling calcium efflux from the skeleton during lactation is not fully understood; however, it is thought to be mediated, at least in part, by PTHrP. PTHrP expression is upregulated in mammary tissue during lactation and is released into the maternal circulation, where it acts as an endocrine mediator of bone resorption.70 Deletion of the PTHrP gene specifically in the mammary gland in mice results in a reduction of plasma PTHrP levels and lower bone turnover, with a relative preservation of bone mass.71 Circulating calcitonin levels are elevated during pregnancy and lactation,72, 73 supporting the concept that calcitonin, via its inhibitory actions on osteoclasts, oppose these actions of PTHrP, thereby protecting the maternal skeleton from excessive resorption during lactation. In fact, Woodrow and colleagues74 showed that CT/CGRPKO mice exhibit greater losses in skeletal mass and more trabecular thinning during lactation compared with the wild-type littermates. Importantly, administration of exogenous salmon CT, but not αCGRP, to CT/CGRPKOs normalized the bone loss to those observed in the wild-type mice, suggesting that calcitonin and not CGRP protects bone mass during lactation. An elegant study by Qing and colleagues52 has further interrogated the mechanism of calcium removal from bone during lactation and found that this is contributed to by a process termed osteocytic osteolysis (reviewed in Ref. 68) whereby osteocytes remove their surrounding bone matrix. Osteocyte expression of the PTH receptor was shown to be critical for lactation-induced osteocytic osteolysis because its deletion attenuated the decrease in BMD that occurs in lactation and prevented the increase in osteocyte lacunae area seen in wild-type animals.52 Given that the CTR has been identified in osteocytes, it is tempting to speculate that calcitonin may act at the level of the osteocyte to modulate osteocyte-mediated calcium release. Until now, the action of calcitonin to protect the maternal skeleton during lactation was thought to be mediated solely via inhibition of osteoclast resorption. As reviewed by Miller,75 calcitonin is produced in large amounts in the mammary gland and in the pituitary gland, where it may have paracrine functions in the regulation of prolactin secretion. This author therefore described a “breast, brain, and bone circuit” in the regulation of mineral and skeletal metabolism during the reproductive cycle. Precisely how calcitonin might interact with these processes, summarized in Fig. 2, remains to be elucidated.

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Figure 2. Potential actions of calcitonin (CT) to protect the skeleton during lactation: (1) circulating CT derived from the thyroid and mammary tissue act via the calcitonin receptor (CTR) in the pituitary to decrease prolactin secretion, which in turn decreases the production of PTHrP by the breast; (2) CT acting via the CTR to oppose the actions of PTHrP by inhibiting (A) osteoclastic bone resorption and (B) perilacunar/canalicular remodeling by osteocytes, in order to limit the amount of calcium released from the bone matrix.

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Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. CTRs and Intracellular Signaling
  5. The Physiological Role of Calcitonin
  6. Conclusion
  7. Disclosures
  8. Acknowledgements
  9. References
  10. Supporting Information

Since its discovery 50 years ago, the physiological role of calcitonin in regulating bone and calcium homeostasis has been vigorously debated, with some describing calcitonin as an “enigmatic” or even “vestigial” hormone. Regulatory concerns have arisen recently regarding a putative link between calcitonin therapy and the progression of some cancers76; nonetheless, elucidating the physiology of calcitonin is important in appreciating the totality of calcium homeostasis in the body. From the knowledge obtained to date, we are proposing two distinct but related roles for calcitonin, first to protect the skeleton by regulating bone turnover, and second to maintain calcium homeostasis. Although these actions represent a significant advance in our understanding of the physiological role of calcitonin and the CTR, many questions relating to their mechanism of action and the physiological importance of these actions remain unanswered. Based on the current literature, studies of particular importance will be those addressing the potential actions of calcitonin centrally and within bone at the level of the osteocyte.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. CTRs and Intracellular Signaling
  5. The Physiological Role of Calcitonin
  6. Conclusion
  7. Disclosures
  8. Acknowledgements
  9. References
  10. Supporting Information

This work was supported by grant support from the National Health and Medical Research Council of Australia, The University of Melbourne, and The Austin Health Medical Research Foundation (to RD and DF).

Authors' roles: Both authors contributed to the design and writing of this manuscript.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. CTRs and Intracellular Signaling
  5. The Physiological Role of Calcitonin
  6. Conclusion
  7. Disclosures
  8. Acknowledgements
  9. References
  10. Supporting Information
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Supporting Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. CTRs and Intracellular Signaling
  5. The Physiological Role of Calcitonin
  6. Conclusion
  7. Disclosures
  8. Acknowledgements
  9. References
  10. Supporting Information

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