INVITED REVIEW
Prospect of a stanniocalcin endocrine/paracrine system in mammals

Kenichi Ishibashi and Masashi Imai

Department of Pharmacology, Jichi Medical School, Tochigi 329-0498, Japan


    ABSTRACT
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DISCOVERY OF THE SECOND...
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Stanniocalcin (STC) is a calcium- and phosphate-regulating hormone produced in bony fish by the corpuscles of Stannius, which are located close to the kidney. It is a major antihypercalcemic hormone in fish. As the corpuscles of Stannius are absent, and antihypercalcemic hormones are basically not necessary, in mammals, the discovery of a mammalian homolog, STC1, was surprising and intriguing. STC1 displays a relatively high amino acid sequence identity (~50%) with fish STC. In contrast to fish STC, STC1 is expressed in many tissues, including kidney. More recently, a human gene encoding the second stanniocalcin-like protein, STC2, was identified. STC2 has a lower identity (~35%) with STC1 and fish STC. Similar to STC1, STC2 is also expressed in a variety of tissues. Research into the functions of STCs in mammals is still at an early stage, and the ultimate physiological and pathological roles of STCs have not yet been established. A few studies indicate that STC1, similar to fish STC, stimulates phosphate absorption in the kidney and intestine, but the function of STC2 is still unknown. However, several interesting findings have been reported on their cellular localization, gene structure, and expression in different physiological and pathological conditions, which will be clues in elucidating the functions of STCs in mammals. STC1 expression is enhanced by hypertonicity in a kidney cell line or by ischemic injuries and neural differentiation in the brain. STC1 expression in the ovary is also enhanced during pregnancy and lactation. Calcitriol upregulates STC1 and downregulates STC2 expression in the kidney. Interestingly, STC1 and STC2 are expressed in many tumor cell lines, and the expression of STC2 is enhanced by estradiol in breast cancer cells. STC2 is also expressed in pancreatic islets. These results suggest that the biological repertoires of STCs in mammals will be considerably larger than in fish and may not be limited to mineral metabolism. This brief review describes recent progress in mammalian STC research.

phosphate transport; calcium homeostasis; hypertonicity; ischemia


    INTRODUCTION
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INTRODUCTION
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STANNIOCALCIN (STC; previously named hypocalcin or teleocalcin) is a glycoprotein hormone that was thought to be unique to teleostean and holostean fish (reviewed in Ref. 1). STC is secreted by specialized organs, the corpuscles of Stannius (CS), which are located adjacent to the kidney or scattered throughout the kidney proper. CS cells may be derived from nephric ducts (24). One pair is found in most fish, and the removal of these glands produces hypercalcemia. Therefore, the main function of STC, similar to that of calcitonin, appears to be the prevention of hypercalcemia. In fish, both STC and calcitonin are antihypercalcemic, but the capacity of STC surpasses that of calcitonin. The main targets of STC are the entry routes of Ca: the gills and intestines. In seawater, where Ca2+ concentration is 40 mg/dl, which is 10 times higher than that of extracellular fluid, hypercalcemia is a continuous threat to the fish because Ca will enter the body by diffusion across the gills and skin as well as via the intestines. STC seems to prevent Ca entry from the gills and intestines (13, 38). The mechanism of this inhibition remains unclear. It is proposed that the decrease in cAMP by STC inhibits Ca channels at the gill epithelial cells (1). However, other investigators speculate that STC modulates the number and/or size of Ca-transporting cells but not the membrane density of Ca transporters (42). In the marine environment, with high Ca levels, STC was believed to play an important role in mineral homeostasis. However, even in freshwater fish, the Ca concentration of the surrounding water is higher than that in cells, so the regulation of Ca entry at the gills and intestines is important. In fact, there is no difference between freshwater and marine salmon in the blood level and sensitivity of STC to Ca (44). Moreover, the net Ca flux in freshwater fish is positive possibly by the active absorption of Ca from the intestine (13). Therefore, STC is an important regulator of Ca in both marine and freshwater fish. Interestingly, roles of STC other than Ca homeostasis are reported: phosphate homeostasis (25) and ovarian function (39). Presently, active research on fish STC continues because its receptor and signaling mechanisms have not yet been clarified.

In terrestrial animals, the primary hormone for the homeostatic control of extracellular Ca is parathyroid hormone (PTH). However, PTH is hypercalcemic whereas STC is antihypercalcemic. This difference may be caused by the fact that Ca concentrations in the bodily fluids of terrestrial animals are dependent on internal stores (bones) to prevent the constant threat of hypocalcemia. Therefore, the presence in terrestrial animals of STC homologs as antihypercalcemic hormones was doubted because they may be unnecessary for these animals, as terrestrial animals seldom face the threat of hypercalcemia and they do not spontaneously become hypercalcemic. Their plasma Ca concentrations increase only transiently after the ingestion of foods containing Ca. In response to such postprandial hypercalcemia, calcitonin is secreted to facilitate the net Ca transfer to bone to decrease plasma Ca concentration to a normal level. Moreover, no homologous organs for CS have been identified in higher vertebrates. However, some reports suggested the presence of a functional receptor for STC homologs because the injection of fish STC in frogs, birds, and rats induced hypocalcemia (26, 28, 36). More directly, it was reported that human kidney cells cross-reacted with anti-salmon STC antibody (43). The molecular identity of STC homologs in these animals and humans were unknown until the discovery of a mammalian homolog, STC1 (3, 4, 32).

It is possible that STC is conserved through the evolution of fish to mammals and that STC homologs may also be present in amphibia, reptilia, and birds. Presently, however, only mammalian STC homologs have been identified. The role of STC homologs in terrestrial animals seems to have changed through evolution. For example, STC1 seems to have the effect more preferentially on phosphate metabolism than on Ca metabolism: STC1 has been shown to stimulate phosphate reabsorption in the small intestine and proximal tubules of the kidney (26, 46). Moreover, human STC1 expression is not limited to a single organ but is expressed in many tissues, most abundantly in the ovary, prostate, and thyroid gland (4, 32). Such a wide expression pattern is also shown in mice (3) and rats (Fig. 1), suggesting a paracrine rather than a classic endocrine role of STC1. Recent identification of the second homolog (STC2) has introduced more complexity into this field. This review will focus on STC2 and recent progress in our understanding of the mammalian STC system.


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Fig. 1.   Northern blot of mammalian stanniocalcin homolog (STC1) in rat tissues. Two micrograms of poly(A)+ RNA from various rat tissues (Clontech) were hybridized with 32P-labeled rat STC1 cDNA. The positions of the RNA markers (kb) are indicated. Ht, heart; Br, brain; Sp, spleen; Lg, lung; Ms, skeletal muscle; Kd, kidney; Te, testis.


    DISCOVERY OF THE SECOND GENE FOR MAMMALIAN STANNIOCALCIN
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As only one STC is known in fish, it is somewhat surprising to find the second gene for STC (STC2) in mammals. However, recent analyses of marine salmon and white suckers suggest that another STC may also be present in fish (27, 45). Whether it is similar to STC2 is presently unknown. The putative fish STC2 will provide some clues to clarify the physiological role of STC2 in mammals. The human STC2 cDNA was found by four independent investigators based on the search for STC homologs in EST database (6, 11, 19, 30). The presently known mammalian STCs are aligned with two fish STCs (Fig. 2). STC2 is longer than STC1 and fish STC. STC2 has only ~35% identity with both STC1 and fish STC, whereas STC1 has ~55% identity with fish STC. Therefore, STC2, rather than STC1, is more distantly related to fish STC. The NH2-terminal half of STC2 is cysteine rich, suggesting that STC2 may also form dimers, as is the case with STC1 and fish STC. Indeed, native hamster STC2 has been shown to form a disulfide-linked homodimer with a subunit size of 35-40 kDa (30). The sites of a consensus glycosylation sequence [Asn-X-Thr(Ser)] are conserved among STCs, suggesting that STC2 is also a glycoprotein and that the glycosylation is responsible for the diffuse band in Western blots (30). Hydropathy profiles indicate that the NH2 termini of STCs are hydrophobic and may be the signal peptide sequences for secretory proteins. Thus the first 24 amino acids of STC2 are cleaved off to produce a secretory form, as shown in fish STC. In fish STC, the subsequent ~14 amino acids are also cleaved off to produce a mature form. It is unknown at present whether there is a prosegment in STC2 that would be cleaved off to produce an active form. Hydropathy analyses of STC2, STC1, and fish STC revealed that they share similar hydropathy profiles at the NH2-terminal half but differ at the COOH-terminal half: STC2 has a longer hydrophilic stretch at the COOH terminus. The COOH terminus of STC2 also has a cluster of histidines (HHxxxxHH), which may interact with divalent metal ions such as Zn, Co, Ni, and Cu. In fact, this histidine cluster was used for binding STC2 to the Ni column to purify STC2 (30). The functional significance of this cluster remains to be clarified. The locations of 10 cysteines are conserved among STCs (Fig. 2, cap ). However, at the COOH terminus, STC2 has four more cysteines than STC1 and fish STC. Moreover, the eleventh cysteine conserved in STC1 and fish STC is not spatially conserved in STC2 (Fig. 2, N). This cysteine appears to be important for the disulfide-linked homodimer formation (18). Therefore, STC2 may undergo a different modification of its tertiary structure compared with STC1 and fish STC. The presently known features of STC1 and STC2 are summarized in Table 1. As both STC1 and STC2 are widely expressed and their expressions overlap in some tissues, it is conceivable that they form a heterodimer, as is the case for activin and inhibin. They may be secreted by the same cells in some tissues. In fact, a human fibrosarcoma cell line, HT1080, has been shown to secrete both STC1 and STC2 as phosphoproteins in the medium (21). However, it is not known whether STC1 and STC2 can form heterodimers.


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Fig. 2.   Multiple sequence alignment of 8 mammalian and 2 fish STCs. Ten conserved cysteine residues are indicated (cap ). N, 11th cysteine in STC2. The accession nos. in the Entrez Protein database at the National Center for Biotechnology Information as follows: human STC2 (hSTC2; NP 003705); rat STC2 (rSTC2; BAA85251); mouse STC2 (mSTC2; NP 035621); macaque STC2 (macSTC2; AAD02027); human STC1 (hSTC1; NP 003146); rat STC1 (rSTC1; AAB39541); mouse STC1 (mSTC1; NP 033311); bovine STC1 (bSTC1; AAF68996); eel STC1 (angSTC; P18301); and salmon STC (samSTC; I 51197).


                              
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Table 1.   Comparison of 2 mammalian homologs of stanniocalcin


    STRUCTURE OF STANNIOCALCIN GENES
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The genes for STC1 have been reported in humans, rats, and mice (5, 41). They are composed of four exons. Interestingly, they have CAG repeats at the 5'-untranslated region. Specifically, 33-bp additional CAG repeats were found in 2 of 198 chromosomes in humans. Although length polymorphisms such as CAG repeats are sometimes associated with the pathogenesis of diseases, as documented in Huntington's disease (35), the significance of CAG repeats in the STC1 gene is presently unknown. However, such a length polymorphism may be a clue in identifying individuals with different phenotypes due to putative different levels of STC1 gene expression.

In contrast, such CAG repeats are not found in the STC2 gene (19). Neither TATA boxlike sequences are found in the STC2 gene, although a TATA box is present in the STC1 gene. The STC2 gene is also composed of four exons, and the exon-intron boundaries are completely conserved between the STC2 and STC1 genes (19), suggesting that they were produced by gene duplication. However, the chromosomal locations of these genes are different in humans: STC1 is located at chromosome 8p11.2-p21 (5), whereas STC2 is located at chromosome 5q35 (47). Therefore, this gene duplication may be a relatively remote event. The chromosomal mappings of these genes await the analysis of their potential involvement in some genetic disorders. The identification of such diseases will reveal the function of human STCs.


    TISSUE DISTRIBUTION OF STANNIOCALCINS
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STC1 is widely expressed in humans and mice. However, among investigators, the major organs expressing STC1 detected by Northern blot differ. A recent report indicated high expression of 4-kb STC1 mRNA in humans in the thyroid gland, kidney and heart, with diminished expressions in the lung, placenta and trachea, but very little expression in the ovary (30). In contrast, others reported the highest expression of STC1 mRNA and protein in the ovary (4, 41, 49). Although the species difference may explain some of these differences, hormonal states may also affect the amount of STC1 expression in the ovary (49). In fact, STC1 expression in mouse ovary is regulated by gestation and lactation (10). In the ovary, STC1 mRNA is highly expressed at the secondary interstitial and the theca interna cells (10, 41). In bone, STC1 mRNA is expressed in osteoblasts and chondrocytes but not in osteoclasts (52). STC1 protein is also localized in developing bones and muscles of the fetal mouse (22). In the brain, the most intense staining was observed, with immunohistochemistry, in the pyramidal cells of the cerebral cortex and the hippocampus and in the Purkinje cells of the cerebellum (54). STC1 is also expressed in the choroid plexus (14). The expression of STC1 in brain neurons appears to be linked to their terminal differentiation: STC1 expression in human neural crest-derived tumor cells is enhanced after PMA-induced neural differentiation at both mRNA and protein levels, and strong STC1 expression was observed in fully differentiated large neurons but not in fetal and newborn mice (54). Interestingly, STC1 is expressed in many cancer cell lines and tumor tissues, including adrenal tumors (29). STC1 expression was even detected in blood samples from cancer patients (15). Some tissue injuries may shed endothelial cells into the circulation to complicate the results because normal vascular endothelial cells also express STC1 when stimulated (33). Therefore, the aforementioned results may not directly indicate that STC1 can be a molecular marker for the detection of tumor cells in the blood from patients with malignancies. Further studies are necessary to confirm this potentially important finding.

The results on STC1 localization in the kidney are controversial. The presently available results are summarized in Table 2. STC1 gene expression was examined by in situ hybridization and STC1 protein expression by immunohistochemistry. Overall, STC1 is expressed in tubular epithelial cells. As STC-producing cells in fish arise from pronephric/mesonephric ducts (24), STC1 production in kidney epithelia may indicate a common embryological origin of STC1 and fish STC. With detailed analyses, however, it should be noted that there is a discrepancy between STC1 mRNA and protein localization. In rat kidney, the STC1 gene was expressed selectively in the collecting ducts, specifically, in the principal cells and the alpha -intercalated cells (48). STC1 protein was also expressed in distal nephron segments (16, 48). One report, however, showed STC1 protein expression in the proximal tubules (proximal straight tubules), although in situ hybridization study of rat kidney failed to document STC1 gene expression in the proximal tubules (48). A similar discrepancy was noted in embryonic mouse kidneys (37). Therefore, in rat and mouse kidneys, the STC1 gene is expressed in distal segments, but STC1 protein is expressed in both proximal and distal segments. Interestingly, STC1 protein in human kidney appears to distribute similarly to the STC1 gene in rodent kidney. Unfortunately, STC1 gene expression has not yet been examined in human kidney. Curiously, in mouse kidney, STC1 gene was reported to be expressed widely with less expression in the collecting ducts (51). Another report on rat kidney failed to detect STC1 protein in the proximal tubules (16). At present, there is no obvious way to reconcile these divergent observations.

                              
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Table 2.   STC1 localization in the kidney

It is noteworthy that a similar discrepancy between STC1 gene and protein expression has been reported in the ovary. STC1 immunostaining was intense in the oocyte cytoplasm and in some granulosa cells. However, both did not appear to express the STC1 gene (10). STC1 protein in these cells may be sequestrated from the surrounding primary theca. Alternatively, these cells may express the STC1 gene below the detection level of in situ hybridization. Therefore, care must be taken when STC1 expression is evaluated. For this reason, STC1 gene expression sites in the brain, muscle, and heart are still unknown because presently only immunohistochemical studies have been reported in these organs.

STC2 is also widely expressed. Two STC2 transcripts (2 and 4.4 kb) are present in different tissues: heart, placenta, lung, muscle, pancreas, and spleen (11, 30). However, much wider expression has been reported by other investigators (6, 19). It is possible that the STC2 expression pattern may reflect the different physiological states of factors that regulate its expression. In contrast to STC1, STC2 expression in the kidney is negligible, which suggests that STC2 may be derived from an unknown hormone secreted by organs other than CS in fish. Interestingly, the expression of 2.2- and 5-kb STC2 transcripts was reported in embryonic tissues of the kidney, lung, liver, and brain (11). Also reported was its expression in many tumor cell lines, with an especially high level in those from the lung, colon, and mammary glands, as well as in Hela cells. These tumor cell lines express an additional 4.3-kb transcript. As is the case with STC1, STC2 expression in embryos and tumor cell lines suggests its role in organogenesis and cell proliferation.

Presently, only one report is available on the cellular level of STC2 expression. Immunohistochemical studies revealed that STC2 is expressed at alpha -cells in pancreatic islets and colocalizes with glucagon-secreting cells (30). This result agrees with the relatively high level of STC2 mRNA expression in the pancreas (30). This provocative result suggests a role for STC2 in glucose homeostasis.


    PHYSIOLOGICAL ROLES OF STANNIOCALCINS
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The function of STC1 has only been partially clarified. We may expect more functions of STC1, as it is expressed in a wide range of tissues. Similarly, several functions of STC2 are also expected. However, our knowledge of its function is totally null. Therefore, one should be cautioned that what follows in this section will be highly speculative and that completely different views may be presented in the near future. STC1 and/or STC2 overproduction by transgenic animals and their inactivation in knockout mice by targeting disruption will reveal their unexpected functions.

Recombinant human STC1, when injected into rats, reduced renal phosphate excretion (46). This may be due to the stimulation of the phosphate transport in the proximal tubules, as the rate of Na-phosphate cotransport was 40% higher in vesicles from STC1-treated rats. However, the change in phosphate excretion in the urine by STC1 was marginal and not dose dependent. Moreover, the plasma phosphate concentration was not affected, suggesting that STC1 may not be the major determinant of the phosphate transporters. On the other hand, STC1 had no effect on Ca excretion in the urine and on plasma Ca concentration (46). Therefore, STC1 appears to participate in renal phosphate regulation and have little effect on Ca metabolism. However, the effect of STC1 on Ca metabolism in rats may be masked by PTH, a dominant regulator of extracellular Ca concentration. Furthermore, the interaction between PTH and STC1 may have complicated the results. For example, the NH2 terminus of fish STC inhibited the cAMP accumulation induced by PTH (50). If there is a similar interaction between STC1 and PTH, the effect of STC1 will be more pronounced in the absence of PTH. In fact, in vitro studies with pig and rat duodenal mucosa showed that administration of STC1 to the serosal surface reduced Ca absorption and stimulated phosphate absorption (26). These results suggest that the function of STC1 in mammals seems to be similar to that of fish STC. Because STC1 has 56-66% identity with fish STC, the conserved function of STC1 is not surprising. As STC1 expression in chondrocytes and osteoblasts has been shown (52), bone may also be an important target for STC1 in mammals. The effect of STC1 on bone is the most promising area for studying the function of STC1. Moreover, if the cellular uptake of phosphate in tumor cells is also enhanced by STC1, as shown in kidney proximal tubular cells, high STC1 expression in tumor cells may reflect a higher metabolic demand for phosphate in these cells, with STC1 acting in a paracrine/autocrine manner. On the other hand, it is unknown whether STC1 inhibits the cellular uptake of Ca as does fish STC in the gills. If STC1 has such a function, inhibition of Ca entry into cells by STC1 may protect them under the stress of hypertonicity or ischemia (34, 53). This issue will be discussed later.

As STC2 has only ~34% identity with STC1 and fish STC, the biological activities of STC2 may not be the same as those of STC1 and fish STC. Presently, only an indirect effect of STC2 on the kidney phosphate transporter was examined (19). The culture medium of STC2-transfected Chinese hamster ovary cells inhibited the promoter activity of the type II Na-phosphate cotransporter by 38%. Such an inhibitory effect on the type II Na-phosphate transporter accounts for the 26% reduction of phosphate uptake by a kidney cell line (opossum kidney cells). As the type II Na-phosphate cotransporter is a major phosphate uptake mechanism of the apical membrane of the kidney proximal tubules, the results suggest that STC2 may inhibit phosphate transport on a long-term basis through the transcriptional control of the phosphate transporter. Therefore, STC1 and STC2 seem to have opposite effects on phosphate transport in the kidney. However, this result was indirect and should be considered with reservation until the direct effect of recombinant STC2 on kidney phosphate transport is examined. In HYP mice with hypophosphatemia, STC2 mRNA expressions in most of the tissues are downregulated, except in the spleen (19). The downregulation of STC2 expression in rat kidney by calcitriol is also reported (17). Moreover, a preliminary study reported the upregulation of STC2 mRNA expression in mouse kidney with the use of a high-phosphate diet (31). Hence, these results suggest, albeit indirectly, that STC2 may also play a role in phosphate metabolism. As STC2 was cloned from a human osteosarcoma cDNA library and its expression in bone was abundant in mice (19), STC2 may also play a role in bone metabolism, including Ca homeostasis.


    REGULATION OF STANNIOCALCIN EXPRESSION
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Fish STC is induced by a high-Ca environment. This is consistent with an antihypercalcemic effect of STC. Similarly, STC1 is also upregulated by an increase in ambient Ca concentration: the expression of STC1 abruptly increased at an incubated ionic Ca concentration of >5.4 mM in cultured cells (4). However, the threshold of Ca for this response was unphysiologically high. This may be due to the change in the threshold modulated by culture conditions such as osmolarity (34), although the mechanism that defines the threshold has not been clarified. STC1 gene induction may be due to the increased ambient Ca concentration detected by sensors like the Ca-sensing receptor. In the culture condition, it is possible that there is a progressive decline in the number of putative Ca-sensing receptors per cell, resulting in the diminished cell sensitivity and responsiveness to Ca reported in PTH cells (2). Alternatively, STC1 gene induction may be due to the increase in intracellular Ca concentration, as the Ca ionophore was shown to stimulate fish STC secretion. Similarly, the upregulation of STC1 expression by calcitriol in the kidney (17) may well be due to a high serum Ca concentration, although it is also possible that calcitriol directly stimulated STC1 expression. The increase in STC1 mRNA may also be due to the enhanced stability of the STC1 transcript, as ambient high Ca has been shown to stabilize the transcript of STC in primary cultured cells from trout CS (12).

Of particular interest, STC1 expression in Madin-Darby canine kidney cells was also induced by hypertonicity, suggesting the role of STC1 in osmoregulation (34). STC1 expression was also stimulated in rat kidney by dehydration (Ishibashi K, unpublished observations). It is unknown whether the effect of osmolarity on STC1 expression is specific to the kidney or a more general phenomenon. In fact, the role of fish STC in water balance was suggested: stanniectomy has been shown to enhance the drinking rate in eels (40), and plasma osmolarity was decreased in stanniectomized fish (1). Therefore, further studies are warranted on the role of STC1 in water metabolism.

In neural cells, hypoxia induces STC1 (53), which may stimulate phosphate uptake by these cells through a paracrine/autocrine mechanism as is the case in kidney proximal tubules. Phosphate may buffer the toxic high intracellular free Ca and stimulate ATP synthesis in a hypoxic environment. Alternatively, STC1 may inhibit cytotoxic Ca entry into the cells in the ischemic condition, as fish STC inhibits Ca entry into the epithelial cells in gills. A dramatic induction of STC1 was also reported in human umbilical vein endothelial cells by lysophosphatidylcholine, a proatherogenic factor (33). A similar induction of the STC1 gene was also reported in serum-stimulated fibroblasts (20). These results suggest the role of STC1 in wound healing, possibly by mediating inflammation and/or angiogenesis (23). The mechanism of STC1 gene induction by hypoxia, hypertonicity, lysophosphatidylcholine, and serum is presently unclear but may be caused by the increase in intracellular Ca concentration. Whatever the mechanism, the transfection of STC1 to a neural crest-derived cell line (Paju cell) increased the resistance to the ischemic challenge, suggesting a beneficial therapeutic application of STC1 in some clinical settings (53). Clarification of its underlying resistance mechanism will reveal a novel function of STC1. A recent report on a blood-level assay of STC1, however, showed that STC1 does not normally circulate in the blood, having a short half-life and/or fast degradation (9), and that STC1 is detectable in the blood only during gestation (10). Hence, the mechanism of this degradation should be clarified before the therapeutic usage of STC1 is contemplated.

Reports on the regulation of the STC2 gene expression are more limited. The downregulation of STC2 mRNA by calcitriol treatment and its upregulation by a low-phosphate diet in mouse kidney were already described above (17, 31). Interestingly, both STC1 and STC2 expression are not affected by calcitriol in the ovary (17). The results suggest the tissue-specific regulation of mammalian STCs or indirect effects of calcitriol on their gene expression. The results also suggest paracrine roles of mammalian STCs. The researchers of mammalian STCs seem to be biased by the reports on the function of fish STC, because the function of fish STC as a regulator of mineral metabolism is relatively well established. However, the expression of fish STC is also modulated by factors seemingly unrelated to mineral metabolism. For example, estradiol increases fish STC, and prolactin induces the hypertrophy of CS (1). Neural regulation of STC release is also possible, as carbachol stimulates the production and release of fish STC (1). Interestingly, STC2 expression was enhanced by 17beta -estradiol in estrogen receptor-positive breast cancer cells (7). Potentially, STC2 may serve as a breast cancer biomarker. More importantly, the role of STC2 in mammary gland morphogenesis should be examined. Similarly, it was reported that ovarian STC1 expression is enhanced during the estrous cycle, regulated by luteinizing hormone and the high level of progesterone (10). Furthermore, STC1 production in the ovary is upregulated during lactation. Prolactin may stimulate this STC1 expression. Therefore, although it is highly speculative, mammary gland development may be regulated by locally produced STC2 and distantly produced STC1.


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Work in the last couple of years has provided molecular identification and the first insights into the function of mammalian STCs. The present knowledge of the STC system in mammals is at a very early stage. Its physiological functions are still unknown. Obviously, further studies are required to clarify and establish the role of the STC system in mammals. These include identification of cell types producing STCs, the regulation of their expression in each cell and each organ, the modes of action on specific cells through specific receptor(s), the cloning of their receptor(s), and the signaling events producing physiological effects and their physiological and pathological functions. As the studies of the STC system in fish become more advanced, the knowledge obtained from studies of fish STC will definitely be beneficial in the research on the STC system in mammals. However, as mammals have two STC isoforms and are devoid of specialized organs that secrete STCs, it is anticipated that the STC system in mammals deviates from that in fish. This system will provide another dimension of the regulation of bone and mineral metabolism and be a target for a therapeutic intervention in the treatment of metabolic bone diseases. Moreover, its role in water metabolism should be examined, as a recent report on stanniectomized eels showed stimulated water intake and induction of STC1 in Madin-Darby canine kidney cells by hypertonicity. Furthermore, a much wider biological repertoire in this system is expected, as ischemic injuries induced STC1 in mammalian brain and high STC2 expression at alpha -cells of the pancreatic islet. Clarification of the postulated protective effect of the STC system against a high intracellular Ca concentration will lead to the development of new treatments for cellular injuries induced by inflammatory, ischemic, and hypertonic stresses. Finally, as STCs are highly expressed in tumor cells and embryonic organs, their roles in tumor biology and embryology should be clarified in the near future.


    ACKNOWLEDGEMENTS

This work was supported in part by The Mochida Memorial Foundation for Medical and Pharmaceutical Research and by The Ryoichi Naito Foundation for Medical Research.


    FOOTNOTES

Address for reprint requests and other correspondence: K. Ishibashi, Dept. of Pharmacology, Jichi Medical School, Minamikawachi, Tochigi 329-0498, Japan (E-mail: kishiba{at}jichi.ac.jp).

10.1152/ajprenal.00364.2000


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REFERENCES

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