With the action of a steroid hormone, 1,25-dihydroxycholecalciferol is involved in quite a few metabolic processes. Calcitriol is bound to an intracellular receptor protein at the target organ – intestine, bone, kidney, and parathyroid gland – and transported into the nucleus. Subsequently, the vitamin-receptor complex exerts an influence on DNA. It alters the transcription (first step of protein biosynthesis – formation of m-RNA) of various hormone-sensitive genes. Eventually, this process leads to changes in protein biosynthesis with corresponding biological effects. A major function of vitamin D3 is the regulation of calcium and phosphate metabolism together with parathyroid hormone and calcitonin. In relation, vitamin D3 has four classic target organs – bone, small intestine, kidney and parathyroid gland.
Bone
Bone tissue is composed of osteoclasts (bone-degrading cells) and osteoblasts (bone-forming cell structures). Osteoclasts carve a lacuna into the bone surface via the formation of an “extracellular lysosome,” which in turn is filled and re-mineralized by osteoblasts. Accordingly, both osteoclasts and osteoblasts are essential for bone renewal, remodeling and repair. 1,25-Dihydroxycholecalciferol is thought to play an essential role in bone metabolism through its ability to influence resorption and mineralization in the physiological process of bone tissue formation and degradation. By leading to increased synthesis of osteoclasts from hematopoietic cells (cells of blood formation) and stimulating osteoblasts to secrete a resorption factor that promotes osteoclast activity, 1,25(OH)2D3 increases bone resorption. The stimulation of bone mineralization is based on the increased provision of calcium and phosphate through calcitriol-induced increased intestinal absorption. In this process, 1,25(OH)2D3 acts synergistically with parathyroid hormone. Furthermore, 1,25(OH)2D3, together with parathyroid hormone, promotes the mobilization of calcium – as calcium levels fall – and phosphate from bone into the extracellular space.Through increased intestinal absorption as well as mobilization from bone, 1,25-dihydroxycholecalciferol maintains blood calcium and phosphate concentrations. Since osteoblasts possess receptors for the vitamin D hormone, it can regulate the synthesis of alkaline phosphatase (AP) and osteocalcin in osteoblast cultures. In addition, under the influence of 1,25(OH)2D3 in osteoblasts, other components of the extracellular matrix (ECM) of bone tissue are secreted, such as osteopontin, type 1 collagen and hCYR61. These in turn exhibit specific effects important for bone formation. By promoting resorption and mineralization in the physiological process of bone tissue formation and degradation, vitamin D hormone causes an increase in bone turnover and, in conjunction with small intestine effects, a positive calcium and bone balance.
Small intestine
Among the major roles of vitamin D hormone is the regulation of calcium and phosphate uptake in the small intestine. 1,25(OH)2D3 leads to increased synthesis of the calcium-binding protein calbindin-D in cells of the small intestinal mucosa via a transcriptional increase of the corresponding gene. Furthermore, 1,25(OH)2D3 is able to activate intestinal calcium transport within a few minutes, independent of gene activation. Finally, under the influence of 1,25-dihydroxycholecalciferol, both intestinal calcium absorption and plasma calcium transport are increased.
Immune System
Vitamin D contributes to normal immune system function and a healthy inflammatory response. Vitamin D plays a regulatory role in the functioning of the immune system. Vitamin D receptors (VDR) have been detected in monocytes and in both T helper 1 (Th1) and T helper 2 (Th2) cells (cells of the immune system). The active form of vitamin D decreases the inflammatory response of Th1 cells, suppresses antigen presentation by dendritic cells and proliferation and immunoglobulin production. Kidney
Vitamin D hormone occupies an important position in the hydroxylation reaction in the kidney. It inhibits the hydroxylation of 25(OH)D3 in the 1alpha position. In parallel, calcitriol stimulates hydroxylation at the 24-position. It is assumed that vitamin D hormone influences renal reabsorption and renal excretion of calcium and phosphorus, respectively.
Parathyroid
Via a calcium sensor of the organism, the parathyroid gland senses the current calcium concentration in the serum. Parathyroid hormone, which is produced in the parathyroid gland, is responsible for maintaining calcium levels. Its secretion depends on the current calcium concentration. When calcium levels are low, parathyroid hormone is released from the parathyroid gland within minutes. It stimulates the expression of 1alpha-hydroxylase at the kidney and thus the formation of vitamin D hormone. By promoting intestinal calcium absorption and mobilization of calcium from bone to the extracellular space together with parathyroid hormone, 1,25(OH)2D3 increases serum calcium concentration.The increased plasma 1,25(OH)2D3 level in return inhibits parathyroid hormone secretion. This mechanism proceeds via parathyroid vitamin D3 receptors. If 1,25(OH)2D3 occupies these receptors specific to itself, the vitamin can influence the metabolism of the target organ.
Other effects of 1,25-dihydroxycholecalciferol
In addition to the four classic target organs, numerous tissues and cells also possess receptors for 1,25(OH)2D3, through which the steroid hormone exerts specific effects.In general, vitamin D hormone is an antiproliferative and differentiation-inducing substance:
- Growth and differentiation of epidermal and hematopoietic (blood-forming) cells.
- Differentiation and maturation of bone marrow cells
- Influence endocrine glands – in addition to insulin and parathyroid hormone also secretion of thyroid hormones.
- Skin – influence on cell growth and differentiation (creation and growth of hair follicles, differentiation of keratinocytes)
- Endocrine pancreas (pancreas) – modulation of insulin secretion
- Certain brain sections – increase in the activity of choline acetyltransferase.
- Muscle – differentiation and maturation of chondrocytes (cells of cartilage tissue) in callus formation (emerging replacement bone) after fractures (broken bones), direct influence on calcium transport and protein biosynthesis in muscle – ultimately leads to improvement of muscle strength -, coordination of muscle contraction, tendency to sway.
- Various tumor cells – inhibition of cell proliferation
