The Biological Activities of Vitamin D and Its Receptor in Relation to Calcium and Bone Homeostasis, Cancer, Immune and Cardiovascular Systems, Skin Biology, and Oral Health

Abstract

Vitamin D plays an important role in calcium homeostasis and bone metabolism, with the capacity to modulate innate and adaptive immune function, cardiovascular function, and proliferation and differentiation of both normal and malignant keratinocytes. 1,25(OH)₂D, the biologically active form of vitamin D, exerts most of its functions through the almost universally distributed nuclear vitamin D receptor (VDR). Upon stimulation by 1,25(OH)₂D, VDR forms a heterodimer with the retinoid X receptor (RXR). In turn, VDR/RXR binds to DNA sequences termed vitamin D response elements in target genes, regulating gene transcription. In order to exert its biological effects, VDR signalling interacts with other intracellular signalling pathways. In some cases 1,25(OH)₂D exerts its biological effects without regulating either gene expression or protein synthesis. Although the regulatory role of vitamin D in many biological processes is well documented, there is not enough evidence to support the therapeutic use of vitamin D supplementation in the prevention or treatment of infectious, immunoinflammatory, or hyperproliferative disorders. In this review we highlight the effects of 1,25(OH)₂D on bone and calcium homeostasis, on cancer, and refer to its effects on the cardiovascular and immune systems.

Figure 1

Synthesis of vitamin D precursors and metabolites. Photosynthesis in the skin, dietary intake, and supplements are the sources of vitamin D. Melanin and sunblock preparations, which protect the skin from sunlight damage, reduce the UVB penetration resulting in decreased cutaneous photoconversion of 7-dehydrocholesterol to vitamin D [6]. Older persons have a decreased capacity to produce cutaneous previtamin D₃ [2]. CYP2R1 is the major enzyme responsible for hydroxylation of vitamin D in the liver into 25(OH)D. 25(OH)D is then hydroxylated by the enzyme CYP27B1 in the kidney to become hormonal 1,25(OH)₂D. CYP27B1 is also expressed by nonrenal tissues [, –6]. 1,25(OH)₂D, the biologically active form of vitamin D, acts on target cells including cells of the parathyroid glands, osteoblasts, dendritic cells, T cells, and keratinocytes. Small amounts of 1,25(OH)₂D can also be produced locally in the skin by cutaneous keratinocytes, but only insignificantly contributing to the blood levels of 1,25(OH)₂D. Usually 25(OH)D and 1,25(OH)₂D are metabolized by CYP24A1 into water soluble inactive forms which are secreted in bile [7, 8].

Figure 2

Schematic representation of the functions of vitamin D in bone and calcium homeostasis. Low serum calcium triggers the production and secretion of parathyroid hormone (PTH) by the parathyroid glands, which in turn induces the synthesis of 1,25(OH)₂D in the kidney by CYP27B1. FGF 23 can inhibit renal tubular reabsorption of phosphate and CYP27B1 activity and can stimulate CYP24A1 [7, 8, 26, 27]. Vitamin D regulates calcium homeostasis by promotion of calcium absorption in the intestine, by reabsorption of calcium by the kidney, and by mobilization of calcium from the bone. 1,25(OH)₂D through a negative feedback loop regulates the synthesis of PTH and of CYP27B1 (a) [–6, 10]. Lower 25(OH)D is associated with increased PTH levels and lower bone density. This is owing to PTH/Vitamin D-induced increase in bone turnover, which results in increased bone resorption. Persistent vitamin D deficiency may result in osteopenia and osteomalacia [5]. 1,25(OH)₂D promotes the production of CYP24A1, the enzyme that degrades 1,25(OH)₂D (b) [1, 5], and low calcium and low PTH levels inhibit the production of CYP24A1 (c) [4]. Thus levels of circulating 1,25(OH)₂D are regulated, in part, by CYP27B1-mediated production and by CYP24A1-mediated degradation [4].