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*Hormones
Endocrinology Vol. 140, No. 4 1869-1874
Copyright © 1999 by The Endocrine Society

ARTICLES

Evidence for Stanniocalcin Gene Expression in Mammalian Bone1

Yuji Yoshiko, Aoi Son, Shuji Maeda, Akira Igarashi, Shoichi Takano, Jianguo Hu and Norihiko Maeda

Department of Oral Anatomy (Y.Y., A.S., S.M., N.M.), Hiroshima University School of Dentistry, Minami-ku, Hiroshima 734-8553, Japan; and R & D Center, BML, Inc. (A.I., S.T., J.H.), Kawagoe, Saitama 350-1101, Japan

Address all correspondence and requests for reprints to: Norihiko Maeda, Department of Anatomy, Hiroshima University School of Dentistry, Minami-ku, Hiroshima 734-8553, Japan.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Stanniocalcin (STC) acts as a regulator of calcium and phosphate homeostasis in an endocrine manner in bony fish. Recently, complementary DNAs encoding human and mouse STC have been characterized, and the messenger RNA (mRNA) expression was identified in various tissues, such as kidney, small intestine, prostate, thyroid, and ovary. Because previous studies concerning the effects of fish STC on mammalian bone have been discussed, there is a good possibility that mammalian STC is a local factor in bone. Here, we demonstrated STC mRNA expression in neonatal mouse calvaria, the primary cultured mouse osteoblast-rich fractions, and human and mouse osteoblastic cell lines. We also mapped the cellular distribution of the STC mRNA in femur and calvaria in developing mice. Several transcripts with a major 4-kb band were detected in all samples. The cellular distribution of the mRNA expression corresponded closely to osteoblasts in both femur and calvaria. Significant labeling of the STC mRNA was also identified in chondrocytes but not in osteoclasts and other bone marrow elements. These results are the first evidence that hormone may be actually expressed in osteoblasts and chondrocytes, and they strongly implicate the involvement of local STC in both endochondral and membrane bone as an autocrine/paracrine factor.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
HUMAN STANNIOCALCIN (STC) was first identified in a study aimed at identifying genes involved in the control of cellular proliferation, using a simian virus 40 early region-transfected human fibroblast culture (1), and in a process of random sequencing of a human tissue complementary DNA (cDNA) library (2). Recently, its genomic structure and chromosomal localization have been determined also in humans (3). It had been widely assumed that STC is a calcium-regulating hormone presented only in bony fish. Fish STC is synthesized and secreted by the corpuscles of Stannius (CS), unique endocrine glands associated with kidney (4, 5) and embryologically derived from nephric ducts (6). The fish hormone is a homodimeric glycoprotein with a molecular mass of approximately 50 kDa, and no sequence similarity with calcitonin (CT), PTH, or other known molecules in vertebrate had been observed. However, there are interesting parallels between STC in fish and CT in mammals, with respect to stimulus-secretion coupling and function (4). The primary function of fish STC is the prevention of hypercalcemia by targeting gill (7) and gastrointestinal tract (8) Ca2+ transport. A second important action of the hormone is stimulation of phosphate reabsorption by renal proximal tubule (9).

The predicted human STC is 247 amino acids long, and it shares 80% amino acid sequence similarity with fish STC (1, 2). Human STCs from both baculovirus-infected insect cells and recombinant Chinese hamster ovary (CHO) cells are secreted as glycosylated proteins and as disulfide-linked homodimers, with physiological and chemical properties similar to those of the fish STC (10). These properties were identified in native STC derived from human tissue (11). However, the human STC messenger RNA (mRNA) was expressed in various tissues, with high levels in ovary, prostate, and thyroid (1). Immunoreactivity, using a specific antiserum to fish STC and a polyclonal antibody to bacterial synthesized recombinant human STC, was identified in renal cortex tubule immediately adjacent to glomerulus and serum in humans (12) and in the specific segments of renal tubule in rats (13), respectively. Lastly, native hormone was localized to principal and {alpha}-intercalated cells in the distal half of nephron (11). As in human, mouse STC cDNA was isolated, and it encoded a predicted protein of the same length as its human counterpart, with a very high level of amino acid sequence similarity, and the mRNA was also expressed in various tissues (14). Bacterial or CHO cell-synthesized recombinant human STC increases phosphate reabsorption in renal cortical brush-border membrane vesicle of rats (15) and decreases calcium absorption and increases phosphate absorption in duodenum of swine and rats (16), respectively. These findings suggest that mammalian STC acts as a regulator of calcium and phosphate homeostasis and has an autocrine/paracrine (rather than a specialized) endocrine role.

Possible effects of fish STC or CS extracts on serum calcium levels and bone metabolism in mammals have been discussed (17, 18, 19, 20, 21). The fish STC and its N-terminal peptide fragment are similar, in terms of biological activity, to PTH (17, 18, 19) and CT (20), respectively. If the activities of fish STC do apply to those of mammalian STC, and if mammalian STC does act as a regulator of calcium and phosphate homeostasis, there is a good possibility of STC mRNA expression in bone cells. The present study provides solid evidence for STC mRNA expression in neonatal mouse calvaria and its primary cultured osteoblast-rich fractions and human and mouse osteoblastic cell lines. These results also enabled us to determine the cellular distribution of the STC mRNA in bone. In situ hybridization (ISH) analysis revealed that the STC mRNA was strongly expressed in osteoblasts in both femur and calvaria of developing mice. Chondrocytes were also stained with ISH histochemistry. These results suggest that the specific bone cells actually synthesize STC and that the hormone may act as an autocrine/paracrine factor in both endochondral and membrane bone.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
Pregnant or normal ddY mice of appropriate age for the study were purchased from Shizuoka Laboratory Animal Center (Hamamatsu, Japan).

Primary bone cell and osteoblastic cell line culture
Bone cell fractions were obtained from calvaria of 20 ddY mice, at postnatal day 1, by sequential collagenase digestions (22, 23), which resulted in 6 cell fractions. An identification of the osteoblastic phenotype in the fractions was made by an assay of alkaline phosphatase activity, as described (23). Human osteosarcoma lines, Saos-2, MG-63, and U-2 OS were purchased from American Type Culture Collection (Rockville, MD). HOS human osteogenic sarcoma line was obtained from Riken Cell Bank (Tsukuba, Japan). MC3T3-E1 mouse normal osteoblast-like cell line was kindly donated by Prof. M. Kumegawa (Meikai University, Saitama, Japan). The 6 cell fractions and the cell lines were cultured in appropriate medium (MEM for MG-63; DMEM for SAOS-2 and U-2; and MEM-{alpha} for primary cultured cells, HOS, and ME3T3-E1 cells, Gibco BRL, Grand Island, NY) supplemented with 10% FBS (Upstate Biotechnology, Inc. Lake Placid, NY) and antibiotics. Cultures were maintained, up to confluence, at 37 C in a humidified atmosphere of 5% CO2.

Northern blot analysis
The riboprobes for STC and alkaline phosphatase (ALP) were synthesized and labeled by in vitro transcription using digoxigenin (DIG)-11-uridine 5'-triphosphate (nonradioactive RNA labeling and detection kit, Boehringer Mannheim, Mannheim, Germany). Recombinant plasmids, including human STC cDNA and mouse placental ALP cDNA (positions 628-1258 of the cDNA sequence), were generously provided by Dr. R. R. Reddel (Children’s Medical Research Institute, Sydney, Australia) and Dr. Y. Ishizuka (Sumitomo Pharmaceutical Co., Osaka, Japan), respectively. Total cellular RNA from calvaria (at postnatal day 1) and kidney, spleen, and liver of 6-week-old ddY mice, as well as cultured cells, were obtained by acid-guanidinium thiocyanate-phenol-chloroform extraction (24). Total RNA (20 µg for the tissues and 10 µg for the cultured cells) was electrophoresed on a 1% agarose-17% formaldehyde gel, then transferred to a positively charged nylon membrane (Boehringer Mannheim). After immobilization by baking at 120 C for 30 min, the membrane was prehybridized, hybridized with 100 ng/ml antisense or sense riboprobes. Hybridization and washing conditions were as recommended by the manufacturer. After washing, an ALP-conjugated anti-DIG antibody was applied, and chemiluminescence detection was carried out using disodium 3-(4-methoxyspiro{1,2-dioxetane-3,2'(5'-chloro)tricycro[3.3.1.13,7]decan}4-yl)phenyl phosphate (CSPD) substrate (Boehringer Mannheim). The signals were determined using Kodak scientific imaging film (BIOMAX MS, Rochester, NY). The adequacy of RNA loading was assessed by rehybridization with the ß-actin riboprobe. The data represent results analyzed from tissues (six independent pools of calvaria, two independent pools of each of kidney, spleen and liver) and cultured cells, and analyzed (each in at least two experiments).

Tissue preparation
Twenty- or 30-day-old ddY mice were anesthetized with a 25-mg/kg ip injection of pentobarbital sodium. Femur and calvaria were preserved by in vivo vascular perfusion of 0.1 M phosphate buffer (pH 7.4) for 5 min, followed by perfusion with 4% paraformaldehyde in the same buffer for 10 min. The femur and calvaria were then removed, immersed in the fixative overnight at 4 C, and decalcified with 10% EDTA at 4 C. The specimens were then dehydrated in a graded series of ethanol, defatted in chloroform, and embedded in paraffin. Sections, 6-µm thick, were placed on 3-aminopropyltriethoxysilane-treated slides and stored at 4 C.

ISH
ISH analysis was carried out as previously described (25), with slight modification. In brief, the sections were deparaffinized in xylene, rehydrated, and treated with proteinase K (5 µg/ml, Boehringer Mannheim) for 15 min at 37 C. After postfixation with 4% paraformaldehyde in phosphate buffer for 10 min, further permiabilization was carried out in 0.1 N HCl for 10 min. The sections were then acetylated in 0.25% acetic anhydride in 0.1 M triethanolamine-HCl (pH 8.0) for 5 min, dehydrated, and air dried. Subsequently, the sections were incubated in hybridization buffer (50% formamide, 200 µg/ml yeast transfer RNA, 1x Denhardt’s solution, 10% dextran sulfate, 600 mM NaCl, 0.25% SDS, and 1 mM EDTA in 10 mM Tris-HCl, pH 7.6) for 16 h at 42 C with 1 µg/ml riboprobes. Posthybridization treatment consisted of washing in 2 x SSC and 50% formamide at 42 C, and incubation in ribonuclease A (RNase A; 1–10 µg/ml; Sigma Chemical Co., St. Louis, MO) for 20 min at 37 C, followed by washing once in 2 x SSC for 20 min and twice in 0.2 x SSC for 20 min at 42 C. The sections were then incubated with blocking reagent (Boehringer Mannheim), followed by an ALP-congugated anti-DIG antibody (Boehringer Mannheim). Next, they were washed and incubated in color substrate solution (nitro blue tetrazolium chloride and 5-bromo-4-chloro-3-indolyl phosphate, toluidine salt Boehringer Mannheim) for 15–120 min. After the ISH histochemical procedure, the sections were counterstained with methyl green. The adjacent sections were hybridized with riboprobe for ALP, as described above, or stained for tartrate-resistant acid phosphatase (TRAP) activity, as previously described (26), and counterstained with hematoxylin. The specificity of antisense riboprobe for STC was identified by the pretreatment of RNase A (10 µg/ml) before ISH and by the negative control tissue (liver), in which STC mRNA had not been detected by Northern blot analysis. The data represent results from three animals, each analyzed in at least two independent experiments.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Northern blot analysis
We first determined whether STC mRNA is expressed in bone and identified the size and pattern of the transcripts, compared with those of kidney or spleen, in which the mRNA transcripts have been established (14); and Northern blot analysis (on neonatal mouse calvaria, adult mouse kidney, spleen, and liver) was carried out using DIG-labeled riboprobes for STC (Fig. 1Go). In all samples except for liver, several transcripts were clearly detected by the antisense riboprobe, and the 1.4-kb band was most abundant in the spleen (lane 1) and the 4-kb transcript in the kidney (lane 2), as previously described (13). The major 4-kb transcript and fainter bands (smaller transcripts), which were similar in size and pattern to those of the kidney, were detected in calvaria (lane 3). No signal was detected in the liver (lane 4) and in all the samples by the sense riboprobe (the result is represented, in lane 5, by the calvaria).



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  		Figure 1. Expression pattern of STC mRNA transcripts in mouse spleen, kidney, calvaria, and liver. Total RNA from adult mouse spleen, kidney and liver, and neonatal mouse calvaria was extracted by a guanidine isothiocyanate method. Twenty micrograms of total RNA was subjected to Northern blot analysis. The blot was hybridized with a DIG-labeled antisense (lanes 1–4) and sense (lane 5) riboprobe for STC. Lane 1, spleen; lane 2, kidney; lanes 3 and 5, neonatal calvaria; lane 4, liver. Molecular sizes of markers, in kb, are indicated to the left of the blot.

 
We next attempted to identify the specific cell type expressing the STC mRNA in the primary cultured bone cells. The results are illustrated in Fig. 2AGo. Neonatal calvaria was sequentially digested by collagenase (22, 23), and six bone cell fractions were obtained. STC mRNA transcripts, in close agreement with the kidney types, were apparently detected in fractions 1–4. The level was highest in fractions 2 and 3 (followed by fractions 1 and 4) and was low in fractions 5 and 6. The high levels of STC mRNA closely correlated with those of ALP mRNA (Fig. 2AGo) and its activity (data not shown), indicating that osteoblast-rich fractions abound in the STC mRNA accumulation. These results enabled us to estimate that the STC mRNA expression is specific to osteoblasts. Then, we examined whether the STC mRNA is expressed in each osteoblastic cell line, in which the osteoblastic phenotypes differs, or not. Unexpectedly, the STC mRNA was expressed in all the human and mouse osteoblastic cell lines, MG-63, SAOS-2, U2-OS, HOS, and MC3T3-E1, similar to the transcripts of primary cultured bone cells and calvaria (Fig. 2BGo).



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  		Figure 2. Expression pattern of STC transcripts in primary cultured mouse bone cells, and human and mouse osteoblastic cell lines. Total RNA from primary cultured mouse bone cells and osteoblastic lines was extracted by a guanidine isothiocyanate method. Ten micrograms of total RNA was subjected to Northern blot analysis with DIG-labeled STC (for A and B) or ALP riboprobe (for A), and then reprobed with a ß-actin riboprobe (for A). A, STC and the ALP mRNA transcripts in the primary cultured cells: lane 1, fraction 1; lane 2, fraction 2; lane 3, fraction 3; lane 4, fraction 4; lane 5, fraction 5; lane 6, fraction 6 of enzymatically digested cells from neonatal mouse calvaria. B, STC mRNA transcripts in human and mouse osteoblastic cell lines: lane 1, MG-63 cells; lane 2, Saos-2 cells; lane 3, U-2 OS cells; lane 4, HOS cells; lane 5, MC3T3-E1 cells. Molecular sizes of markers, in kb, are indicated on the left.

 
ISH
We determined STC mRNA expression levels in primary cultured bone cells and osteoblastic cell lines, as well as neonatal calvaria. These results suggested that osteoblasts actually express STC mRNA. We, therefore, examined the cellular distribution of the STC mRNA in femur and calvaria of developing mice, by ISH histochemistry using the DIG-labeled riboprobes. The sections were studied with sense and antisense probes for STC and ALP. Hybridization with the sense riboprobes, and the pretreatment of RNase A before hybridization with the antisense riboprobes, did not establish significant labeling of any structures (data not shown). We also identified the specificity of the antisense riboprobe for STC by no labeling of liver in which STC mRNA had not been detected by Northern blot analysis (data not shown). Hybridization with the antisense riboprobe yielded strong labeling of both femur (Fig. 3Go; A, B, D, E, and F) and calvaria (Fig. 3HGo). In the femur, signal for STC was rich in epiphysis and metaphysis. The cellular identification of the strong labeling corresponded with osteoblasts, in contact with trabecular (A, B, E, and F) and cortical (D) bone. These findings corresponded to the labeling patterns of ALP mRNA, as illustrated in C, the adjacent section of B. As shown in E, significant labeling of the STC mRNA was also observed in osteoblasts in contact with trabecular bone of secondary marrow cavity. Furthermore, the same could apply to chondrocytes in the superficial site of articular cartilage and epiphyseal plate (E). In subsequent histological and histochemical cell identification, using adjacent sections, no staining pattern for TRAP-positive multinucleated cells identical to the labeling of the STC mRNA was observed (F and G). The signal was relatively poor in diaphysis because the cavity was filled with STC mRNA-negative bone marrow cells. The labeling of vascular tissue and other tissue elements was also not significant. In calvaria, strong labeling was detected in the layer of osteoblasts in contact with bone at the endocranial site (Fig. 3IGo).



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  		Figure 3. Cellular distribution of STC mRNA in the bone of 20- or 30-day-old developing mice. A–G and H, Femur of 30-day-old mice and calvaria of 20-day-old mice, respectively. The sections were hybridized with a DIG-labeled antisense cRNA encoding human STC (A, B, D, E, F, and H) and mouse ALP (C) and were counterstained with methyl green. A, Longitudinal section of metaphysis; B, a high magnification view of trabeculare in the metaphysis; C, the adjacent section of B; D, a high-magnification view of cortical bone in the metaphysis; E, longitudinal section of epiphysis; F, a high-magnification view of multinucleated cells on the trabecular bone surface in the metaphysis; G, the adjacent section of F, the section was stained for TRAP activity and counterstained with hematoxylin; H, transverse section of calvaria. Labeling of STC mRNA is shown in osteoblasts (black arrows in B, D, and H) and chondrocytes (white arrows in E) but not in TRAP-positive cells (asterisks in F and G). Labeling of ALP mRNA was rich in osteoblasts (black arrows in C), characterized by the close parallel to STC mRNA expression (B). Bar, 60 µm.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this paper, we examined whether STC mRNA is expressed in mammalian bone, and we mapped the cellular distribution of STC mRNA in bone using developing mice. We clearly demonstrated that the STC mRNA was expressed in all neonatal calvaria, primary cultured osteoblast-rich fractions (which were determined by ALP activity and mRNA expression) and osteoblastic cell lines (by Northern blot analysis). There were several transcripts with a high level of 4-kb and fainter bands common to these samples. For ISH analysis, the labeling was rich in a specific cell type, characterized by the correlation to ALP mRNA expression, by contact with bone surface, and by being TRAP-negative. Osteoblasts show increased ALP expression as they mature before the mineralization phase (27). Therefore, it is reasonably suggested that the mRNA is strongly expressed in osteoblasts. This is the case in both femur and calvaria. Trabecular and cortical bone of the metaphysis and the endocranial site of calvaria was abounding with the strong labeling of STC mRNA. In addition, the labeling was identified in chondrocytes, suggesting that the STC mRNA expression is involved in cartilage, as well as in bone. No significant labeling was detected in osteoclasts, blood vessels, or other marrow elements.

STC mRNA expression has been identified in heart, placenta, lung, skeletal muscle, pancreas, kidney, thymus, prostate, testis, ovary, thyroid, small intestine, colon, and adrenal cortex in humans (1) and in heart, spleen, liver, kidney, small intestine, colon, and ovary in mice (14) but not in brain, liver, spleen, peripheral blood leucocytes, and adrenal medulla in humans (1) and not in liver in mice (14). Skeletal results have not been reported on the STC mRNA expression. Transcripts of 2- and 4-kb, and at least four transcripts have been reported in human and mouse STC mRNA, respectively. Different STC transcripts predominate in different tissues, suggesting that tissue-specific alternative splicing occurs (14). In the present study, bone was added at one of the possible STC synthesis sites in mice, and the major 4-kb and fainter bands were similar in size and pattern to those of kidney but different from those of spleen. These results suggested that each product of the STC transcripts in bone, kidney, spleen, and other tissues is restricted to tissue-specific function, as is shown in a previous report (14). Recently, a second STC (STC-2) cDNA in mouse and human has been identified (28). STC-2, like STC, is expressed in a wide variety of tissues, but the predicted amino acid sequence of STC-2 contains a cluster of histidine residues, which suggests that STC-2 may interact with metal ions (28).

Milet and co-workers (17) first reported that an extract of eel CS, which synthesizes and secretes STC, caused an increase in serum levels of calcium and resulted in the activation of osteoclastic bone resorption at the periosteum of femur in rats. A bone resorption assay, using organ culture of rat fetal calvaria, revealed that extracts of eel (17) and trout (18) CS and purified trout STC (19) stimulated the release of calcium from the bone in the same manner as PTH. These effects were not observed in salmon STC (20), but its specific peptide fragment, which was highly conserved in amino acid sequence of fish STCs, inhibits a PTH-dependent stimulation in the calvarial bone resorption and in cAMP production in ROS17/2.8 rat osteoblastic cell line (21). In the light of the great sequence and structural similarity between fish and mammalian STC, mammalian STC may prove to be effective in the regulation of bone cell properties as an autocrine/paracrine factor. Previous studies in mammalian systems reported that renal phosphate (15) and intestinal calcium and phosphate transport (16) can be regulated by recombinant human STC. These observations imply that STC may play a significant role in mammalian calcium homeostasis, by reducing net calcium absorption and promoting calcium deposition into bone in the presence of increased plasma phosphate levels (16). This hypothesis is well matched to the present results identifying STC mRNA expression in osteoblasts and chondrocytes in developing mice.

In conclusion, this is the first report of STC mRNA expression in mammalian bone. STC mRNA in developing mouse bone is expressed with a pattern similar to that in kidney. Strong signal for the mRNA is restricted to osteoblasts and chondrocytes. In kidney, STC-immunoreactive and STC mRNA-expressing cells have been identified in specific segments of nephron in humans (11) and rats (13), and in mice (29), respectively. Recombinant STC caused a reduction in phosphate extraction in rat kidney (15). These results are strong evidence of a direct effect of STC as an autocrine/paracrine factor on mammalian tissues. Although the present results cannot reveal whether STC regulates calcium and phosphate levels or has other functions in bone, the identification of STC mRNA expression in bone cells supports the hypothesis that STC acts in an autocrine/paracrine manner during both endochondral and intramembraneous ossification, and their bone metabolism in mammals.


   Footnotes
 
1 This work was supported, in part, by a grant-in-aid from the Ministry of Education, Science, and Culture of Japan. Back

Received July 3, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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