ReviewWhere is the vitamin D receptor?
Highlights
► VDR is highest in intestinal enterocytes, pancreatic islets, renal distal tubules, osteoblasts. ► The positive presence of VDR in other tissues is discussed. ► VDR is not found in mature muscle including heart and liver. ► Poor specificity, antibodies, lack of controls have confounded VDR reports.
Introduction
Vitamin D3 undergoes sequential 25- and 1α-hydroxylation to become the active hormone, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) [1]. 1,25(OH)2D3 is an important modulator of calcium and phosphate absorption in intestine, calcium re-absorption in kidney, and calcium mobilization in bone [2]. In addition to maintaining calcium/phosphate homeostasis, it promotes differentiation and inhibits proliferation of certain cells, suggesting a potential role in cancer chemoprevention [3]. 1,25(OH)2D3 has also been shown to suppress autoimmune diseases in several animal models [2], [4]. 1,25(OH)2D3 exerts its functions by binding to VDR,1 a member of the steroid hormone receptor superfamily [5], [6], [7], [8], [9], leading to transcriptional regulation of target genes [10]. Many genes are directly upregulated (e.g., CYP24A1, CaBP-D9k, CaBP-D28k, osteocalcin, and Rankl) or downregulated (e.g., PTH and CYP27B1) via activation of VDR [11], [12], [13], [14], [15], [16], [17], [18], [19]. Thus, VDR plays a central role in the biological actions of vitamin D.
Accurate identification of VDR in tissues is critical to understand the physiopathological significance of vitamin D and could be key to the development of novel therapeutic modalities targeting the receptor. Since VDR was discovered three decades ago, more than 50 targets have been identified involving a broad realm of vitamin D functions [2], [20], [21], [22]. However, contradictory results have been reported perhaps due to selection of methods. Although VDR immunohistochemistry was developed as a new powerful tool for determining the presence of VDR in tissues, great care must be exercised using appropriate positive and negative controls [23]. This review focuses on the tissue distribution and cellular localization of VDR.
Section snippets
Selection of tissues
Human and animal tissues are widely used for addressing VDR expression. A number of factors such as age, vitamin D status, calcium, and health can affect the expression of VDR gene in certain tissues. For example, vitamin D status and calcium regulate VDR expression in kidney [24] and bone [25], but not in intestine. In addition, VDR expression in tumors does not necessarily reflect that in normal tissues as seen in some breast and colon carcinomas, which seem to lose VDR expression [26], [27],
VDR is abundant in intestine
The nuclear component bound to 1,25(OH)2D3 was first identified in chick intestinal mucosa in 1975 [8] and later identified as VDR [5], [6], [53]. Since then, many studies have shown high abundance of the receptor in intestinal mucosa from animals and humans by autoradiography [21], in situ hybridization, and immunological methods [23], [33], [42]. VDR is widely distributed throughout small intestine from duodenum to ileum and large intestine including cecum and colon [21], [23], [33], [42],
VDR is undetectable in liver
Liver is generally considered negative for VDR [2], even though estrogens have been shown to induce the appearance of VDR in rat livers [59], [60]. Autoradiography failed to detect VDR in the hepatocytes [61], but an extremely low level of VDR was detected in normal rat liver (1300-fold lower than that in intestine) [44]. We found no detectable levels of VDR in human and mouse liver by immunohistochemistry (Fig. 3 and unpublished data), whereas others showed inconsistent expression of VDR in
VDR is strongly expressed in pancreatic beta cells
VDR was first detected by the ligand binding assay in normal chick pancreas [57]. A follow-up study showed concentrated autoradiographic signals in the nuclei of cells that were centrally located in adult rat pancreatic islets [63]. Using autoradiography and co-immunostaining, Clark et al. reported that the target cells of vitamin D were the insulin-containing cells, not those producing glucagon or somatostatin [64]. We also showed that VDR is only detected in the insulin-positive cells of
VDR is expressed in kidney tubular epithelial cells
In situ determination of VDR in kidney by immunohistochemistry and various other methods have shown that VDR is expressed in distal renal tubules and collecting ducts [21], [23], [33], [36], [37], [65], [66], [67], [68], [69], but at low levels in proximal renal tubules (24-fold lower than that in the distal tubules in mouse) (Fig. 3, Fig. 4) [34]. This is consistent with the VDR function in regulating calcium re-absorption from pre-urine, and the low abundance of VDR in proximal tubules seems
VDR is selectively expressed in bronchial epithelial cells
VDR is found in bronchial epithelial cells in human (Fig. 3), mouse (unpublished results), and rat fetus, but absent in alveolar cells in human lung as shown by immunohistochemical staining (Fig. 3) and autoradiography [33], [74].
VDR is selectively expressed in skin epithelial cells
The presence of VDR in skin was determined by ELISA, PCR, and in situ hybridization [44], [46], [75] and the target cells were identified by in situ immunohistochemistry [33], [72]. VDR seems to be restricted to the nuclei of epidermal epithelial cells (unpublished data). The epithelial cells of the hair root sheaths, sweat glands, and sebaceous glands also contain VDR [21], [76], [77], [78], [79].
VDR is detected in osteoblasts and chondrocytes
Bone is the first tissue identified as a target for vitamin D [80]. VDR was detected in the preparations of fetal rat bone and mature rat bone tissues by ligand binding assay and ELISA, respectively [9], [44]. qPCR analysis revealed that 1,25(OH)2D3 strongly induced VDR gene transcription in mouse bone [25], [81]. VDR was detected in osteoprogenitor cells, osteoblasts, lining cells, osteocytes, and chondrocytes in bone [33], [80], [82], [83], [84], [85], [86]. The presence of VDR in
VDR is undetectable in muscle
Stumpf et al. was not able to show [3H]-1,25(OH)2D3 localization in muscle by autoradiography [21], [57], [89], [90], [91], and no mRNA encoding VDR was detected in heart and liver [5]. Immunoassays also failed to detect VDR in mature skeletal and heart muscles [44]. Using immunoblotting, qPCR, and immunohistochemical staining, we showed that VDR was not detected in smooth muscle, heart muscle or skeletal muscle in human (Fig. 3) and in vitamin D deficient, normal and 1,25(OH)2D3 treated
T-lymphocytes
Nuclear intake of [3H]-1,25(OH)2D3 by lymphocytes is evident for the presence of VDR in these cells [21], [97], [98]. VDR has been shown present in T-lymphocytes after activation, but absent in isolated resting human T cells [99], [100]. An early clinical study reported that 76% seropositive patients with rheumatoid arthritis had lymphocytes that possessed VDR (without in vitro activation) compared to only 18% (3 of 17) in normal individuals [101]. Presumably, these patients have more activated
Parathyroid and thyroid glands
VDR is highly expressed in the parathyroid epithelial cells, detected by ligand binding [57], autoradiography [69], [89], [122], lacZ reporter assay [38], and immunohistochemistry (Fig. 5). 1,25(OH)2D3 acts on VDR in parathyroid to increase VDR expression and suppress transcription of PTH gene [123], [124], [125]. VDR is undetectable in thyroid (Fig. 5) [38], [122].
Pituitary gland
The presence of VDR in pituitary gland has been demonstrated by co-localization with the pituitary hormones [126], autoradiography
VDR is undetectable in brain tissue
ELISA and immunohistochemical staining showed undetectable levels of VDR in cerebrum and cerebellum in rat and human (Fig. 3) [44]. Similarly, VDR was not detected in mouse neurons and glia (unpublished data). Historically, reports of VDR expression in brain were mainly derived from autoradiographic studies [132], [133], in situ hybridization [134], and immunohistochemistry [42], [134], [135], [136], [137], [138], [139], [140]. But be aware that the antibodies used for direct measurement of VDR
Spermatozoa
VDR has been detected in testes by autoradiography [141], [142], [143], [144], RT-PCR [145], and immunohistochemistry [146], [147]. Our study showed that in human testes, VDR is predominantly expressed in the cells located at the center of efferent ducts, where more matured spermatozoa exist (Fig. 3), consistent with the previous finding that VDR is mainly located on the head/nucleus of human sperm and mid-piece [147].
Prostate gland secretory epithelial cells
Numerous studies have revealed the presence of VDR in prostate gland [33],
Discussion
VDR is clearly present in cells of the intestinal epithelium, renal tubules, parathyroid gland cells, skin (keratinocytes), mammary epithelium, pancreas (beta islet cells), pituitary gland, skeleton (osteoblasts and chondrocytes), immune system (monocytes, macrophages, and T-lymphocytes), and germ tissues (Table 1) [2]. The tissues with the highest VDR content are intestine, kidney, parathyroid gland, and bone, all of which are associated with maintenance of calcium homeostasis. The functions
Acknowledgments
This work was supported by a fund from the Wisconsin Alumni Research Foundation. We sincerely thank Pat Mings for her assistance in preparation and submission of manuscript.
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