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Regulation of Cellular Growth by 1,25-Dihydroxyvitamin D₃-Mediated Growth Factor Expression

Timothy D. Veenstra, Mark R. Pittelkow and Rajiv Kumar

T. D. Veenstra is in the Nephrology Research Unit; M. R. Pittelkow is in the Department of Dermatology and the Department of Biochemistry and Molecular Biology; and R. Kumar is in the Nephrology Research Unit and the Department of Biochemistry and Molecular Biology at the Mayo Clinic/Foundation, Rochester, MN 55905, USA.

	Abstract

 
Although the primary function of 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] is the regulation of calcium and phosphorus metabolism, it also regulates the growth and differentiation of several different cell types. Recent work suggests that 1,25(OH)₂D₃ regulates cellular growth by altering the synthesis of growth factors and growth factor responses.

	Introduction

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The purpose of this review is to discuss the mechanisms by which vitamin D analogs alter cellular growth, with an emphasis on 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃]-mediated regulation of growth factors and growth factor receptors. We believe this represents an important pathway by which vitamin D analogs change cellular growth in a variety of cells. It is well known that the primary function of 1,25(OH)₂D₃ is the regulation of calcium and phosphorus metabolism (6). The observation that 1,25(OH)₂D₃ reduces the rate of cellular growth and induces the differentiation of myeloblasts (M1 cells) and promyelocytes (HL-60 cells) into macrophages (1), and that 1,25(OH)₂D₃ inhibits the proliferation of cancer cells (4), initially showed that the sterol is capable of functioning in areas regulating cell functions distinct from transcellular calcium transport. The effects of 1,25(OH)₂D₃ on the growth and differentiation of several different cell types have now been reported and suggest that 1,25(OH)₂D₃, or noncalcemic vitamin D analogs, may be of therapeutic value in the treatment of disorders characterized by abnormal cell growth.

The effects of vitamin D₃ and its metabolites on cells maintained in culture, or the effects observed after the topical application of vitamin D analogs to the skin at relatively high concentrations, stand in contrast to the effects of vitamin D deficiency seen in the whole organism. In vitamin D deficiency, growth retardation is a striking feature (7). These observations can be reconciled if one realizes that growth retardation in vitamin D deficiency is a consequence of calcium and phosphorus deficiencies. In vitamin D-dependent rickets type II, a disorder characterized by resistance to 1,25(OH)₂D₃ because of mutations in the vitamin D receptor (VDR), calcium infusions increase the growth rate in affected children (2). Recently, VDR null mutant mice were shown to be similar to their wild-type or heterozygous littermates in size, growth rate, and behavior at birth (10) because during gestation, sufficient transfer of calcium and phosphorus occurs across the placenta. Symptoms typical of rickets were seen in the null mutant mice after weaning, when non-vitamin D-dependent calcium transport mechanisms in the intestine are known to disappear (10). Feeding null mutant mice a diet containing lactose and high concentrations of calcium overcomes the growth retardation seen in these animals. It should also be noted that the effects of 1,25(OH)₂D₃ on cell proliferation are variable. Although 1,25(OH)₂D₃ generally has an antiproliferative effect on cells maintained in culture, 1,25(OH)₂D₃ in some instances has been shown to accelerate growth in vivo or in vitro. Cell culture conditions, as well as direct responses mediated by 1,25(OH)₂D₃ through receptor or nonreceptor mechanisms, may account for the apparent divergent biological activity. For example, the presence or absence of serum in cell culture, or the concentrations of the sterol or calcium in the medium, have an effect on the response of a given cell type to 1,25(OH)₂D₃ (8).

1,25(OH)₂D₃ regulates the expression of growth factors such as ß-type transforming growth factors (TGF-ß), insulin-like growth factor (IGF), nerve growth factor (NGF), glial cell line-derived neurotrophic factor, interleukins, hepatocyte growth factor and vascular endothelial growth factor (14). Table 1 summarizes some of these effects; it is not comprehensive, and the reader is referred to other reviews for details (14). These growth factors are expressed in many vitamin D-sensitive organs. Although information concerning the regulation of growth factors by 1,25(OH)₂D₃ was previously available, there was until recently little direct proof of their role in 1,25(OH)₂D₃-mediated regulation of cell growth.

	1,25(OH)2D3, growth factors, and the skin

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	1,25(OH)2D3, growth factors, and bone

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TGF-ß, along with systemic hormones and cytokines, regulates bone remodeling, bone fracture repair, bone induction, and development (12). The amount of TGF-ß in the bone of vitamin D-deficient rats is selectively reduced because of a deficiency of vitamin D and not calcium. Recently, we have shown that 1,25(OH)₂D₃ causes a decrease in the growth of human osteoblasts, which is accompanied by an increase in the expression of TGF-ß2 but not TGF-ß1 (15). Addition of an antibody directed against TGF-ß partially blocks the growth inhibitory effects of 1,25(OH)₂D₃ suggesting that the upregulation of TGF-ß2 plays a role in the growth retardation seen after the treatment of osteoblasts with 1,25(OH)₂D₃. 1,25(OH)₂D₃-induced TGF-ß2 expression is regulated at the level of gene transcription and increased TGF-ß2 messenger RNA (mRNA) stability (15). Interestingly, an increase in the amount of TGF-ß type I and II receptor mRNA was also observed in osteoblasts treated with 1,25(OH)₂D₃ (14). Upregulation of TGF-ß type I and II receptors could significantly contribute to 1,25(OH)₂D₃ inhibition of osteoblast growth. In bone, the release of growth factors such as TGF-ß likely influences the activity of cells adjacent to osteoblasts such as osteoclasts and thus may play an important role in bone remodeling (12).

IGF-I and -II and insulin-like growth factor binding proteins (IGFBP) are regulated in bone by 1,25(OH)₂D₃ (11, 12). IGF-I and -II increase the synthesis of collagen in osteoblasts as well as increasing cell replication in bone (12). 1,25(OH)₂D₃ decreases IGF-I release from human bone cells maintained in culture; in mouse calvaria maintained in culture, 1,25(OH)₂D₃ increases IGF-II synthesis (11, 12). In addition to effects on the release of IGF, 1,25(OH)₂D₃ increases the number of type 1 IGF receptors in mouse clonal osteoblastic cells as well as upregulating the expression of IGFBP-2, -3, and -4 (11). The published findings do not allow a firm conclusion to be made as to how 1,25(OH)₂D₃ influences bone cell growth via the IGF system.

	1,25(OH)2D3, growth factors, and the prostate

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As previously mentioned, 1,25(OH)₂D₃ may be of therapeutic value in regulating disorders characterized by abnormal cell growth. In particular, 1,25(OH)₂D₃ has been shown to regulate prostate cell proliferation, and recent studies have implicated vitamin D deficiency as a potential risk factor in the etiology of prostate cancer (5). Although the precise mechanism is unclear, two recent studies suggest that TGF-ß and IGFBP play a role in 1,25(OH)₂D₃-regulated prostate cell growth. 1,25(OH)₂D₃ has been shown to increase TGF-ß2 and TGF-ß3 expression in NRP-152 cells, an epithelial cell line derived from rat prostate (5). Addition of a neutralizing TGF-ß antibody was able to block the production of other 1,25(OH)₂D₃-regulated metabolites, suggesting that the upregulation of TGF-ß plays a direct role in the effects of 1,25(OH)₂D₃ on this cell line. In addition, 1,25(OH)₂D₃ has been shown to increase the expression of IGFBP-6 in human prostate cells in a dose-dependent manner. It is possible that the mechanism for 1,25(OH)₂D₃-regulated prostate cell growth may ultimately involve both TGF-ß and IGFBP.

	1,25(OH)2D3, growth factors, and the nervous system

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1,25(OH)₂D₃ inhibits cell growth and induces NGF expression in cultured neuroblastoma cells, in glial cells, in rat brain in vivo, in cultured fibroblasts, and in osteoblasts (13). NGF is secreted in a target-derived, paracrine manner, and subsequent binding of NGF to cell surface receptors on sensory, sympathetic, and central nervous system neurons results in a pleiotropic response that has been shown to be important for neuronal development and survival (3). The effects of 1,25(OH)₂D₃ on mouse neuroblastoma cells are dependent on the expression of NGF, because antibodies neutralizing NGF activity partially blocked the antiproliferative effects of 1,25(OH)₂D₃. Recent results from our laboratory using osteosarcoma ROS 17/2.8 cells and a series of NGF promoter/human growth hormone reporter plasmids have shown that the activator protein-1 (AP-1) site located within the first intron of the NGF gene plays a critical role in 1,25(OH)₂D₃-induced NGF expression in this cell line (13). 1,25(OH)₂D₃ increases AP-1 binding activity in these cells, suggesting that 1,25(OH)₂D₃ regulates NGF expression indirectly by regulating members of the Fos and Jun protooncogene family, which constitute the AP-1 transcription factor (13). 1,25(OH)₂D₃ treatment also increases AP-1 binding activity in myelogenous leukemia cells by increasing the expression of JunD, a member of the Jun family (9).

	Conclusions

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Since the initial observation that 1,25(OH)₂D₃ influences breast epithelial cell growth and differentiation (1), numerous other cell types in vitro and in vivo have been shown to respond to 1,25(OH)₂D₃ treatment in a similar fashion. 1,25(OH)₂D₃ has been shown to affect the expression of growth factors, immediate-early response genes, and protein kinases. As we have shown above, an important mechanism by which 1,25(OH)₂D₃ influences cell growth is the altered expression of various growth factors. The mechanism by which 1,25(OH)₂D₃ alters cell growth via an alteration of growth factors needs further examination.

	Acknowledgments

 
This work was supported by National Institutes of Health Grant DK-25409.

	References

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