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| Calcium Homeostasis |
Vitamin D is required to maintain normal blood levels of calcium and phosphate, that
are in turn needed for the normal mineralisation of bone, muscle contraction, nerve
conduction, and general cellular function in all cells of the body. Vitamin D achieves this after its conversion to the active form 1,25-dihydroxyvitamin D [1,25-(OH)2D], or calcitriol. This active form regulates the transcription of a number of vitamin D–dependent genes coding for calcium-transporting proteins and bone matrix proteins.
Vitamin D also modulates the transcription of cell cycle proteins, that decrease cell proliferation and increase cell differentiation of a number of specialised cells of the body (e.g., osteoclastic precursors, enterocytes, keratinocytes, etc.). This property may explain the actions of vitamin D in bone resorption, intestinal calcium transport, and skin. Vitamin D also possesses immuno-modulatory properties that may alter responses to infections in vivo. The cell differentiating and immuno-modulatory properties underlie the reason why vitamin D derivatives are now used successfully in the treatment of psoriasis and other skin disorders.
Clinical assays measure 1,25-(OH)2D2 and 1,25-(OH)2D3, collectively called 1,25-(OH)2D. Similarly, calcidiol is measured as 25-OH-D but it is a mixture of 25-OH-D2 and 25-OH-D3. For the purposes of this document, 1,25-(OH)2D and 25-OH-D will be used to refer to calcitriol and calcidiol, respectively.
Overview of the role of vitamin D
Vitamin D, a seco-steroid, can either be made in the skin from a cholesterol-like precursor (7-dehydrocholesterol) by exposure to sunlight or can be provided pre-formed in the diet. The version made in the skin is referred to as vitamin D3 whereas the dietary form can be vitamin D3 or a closely related molecule of plant origin known as vitamin D2. Because vitamin D can be made in the skin, it should not strictly be called a vitamin, and some nutritional texts refer to the substance as a prohormone and to the two forms as cholecalciferol (D3) or ergocalciferol (D2).
From a nutritional perspective, the two forms are metabolised similarly in humans, are equal in potency, and can be considered equivalent. It is now firmly established that vitamin D3 is metabolised first in the liver to 25-hydroxyvitamin-D (25-OH-D or calcidiol) and subsequently in the kidneys to 1,25-(OH)2D to produce a biologically active hormone. The 1,25-(OH)2D, like all vitamin D metabolites, is present in the blood complexed to vitamin D binding protein, a specific α-globulin. The 1,25-(OH)2D is believed to act on target cells similarly to the way a steroid hormone would act. Free hormone crosses the plasma membrane and interacts with a specific nuclear receptor known as the vitamin D receptor, a DNA-binding, zinc-finger protein with a molecular weight of 55,000. This ligand-receptor complex binds to a specific vitamin D–responsive element and, with associated transcription factors (e.g., retinoid X receptor), enhances transcription of mRNAs which code for calciumtransporting proteins, bone matrix proteins, or cell cycle–regulating proteins. As a result of these processes ,1,25-(OH)2D stimulates intestinal absorption of calcium and phosphate and mobilises calcium and phosphate by stimulating bone resorption. These functions serve the common purpose of restoring blood levels of calcium and phosphate to normal when concentrations of the two ions are low.
Lately, interest has focused on other cellular actions of 1,25-(OH)2D. With the discovery of 1,25-(OH)2D receptors in many classical non-target tissues such as brain, various bone marrow–derived cells, skin, thymus, etc., the view has been expressed that 1,25-(OH)2D induces fusion and differentiation of macrophages. This effect has been widely interpreted to mean that the natural role of 1,25-(OH)2D is to induce osteoclastogenesis from colony forming units–granulatory monocytes in the bone marrow. The 1,25-(OH)2D also suppresses interleukin 2 production in activated T lymphocytes, an effect which suggests the hormone might play a role in immuno-modulation in vivo. Other tissues (e.g., skin) are directly affected by exogenous administration of vitamin D, though the physiologic significance of these effects is poorly understood. The pharmacologic effects of 1,25-(OH)2D are profound and have resulted in the development of vitamin D analogues, that are approved for use in hyper proliferative conditions such as psoriasis.
In calcium homeostasis 1,25-(OH)2D works in conjunction with parathyroid hormone (PTH) to produce its beneficial effects on the plasma levels of ionised calcium and phosphate. The physiologic loop starts with calcium sensing by the calcium receptor of the parathyroid gland. When the level of ionised calcium in plasma falls, PTH is secreted by the parathyroid gland and stimulates the tightly regulated renal enzyme 25-OH-D- 1-α-hydroxylase to make more 1,25-(OH)2D from the large circulating pool of 25-OH-D. The resulting increase in 1,25-(OH)2D (with the rise in PTH) causes an increase in calcium transport within the intestine, bone, and kidney. All these events raise plasma calcium levels
back to normal, that in turn is sensed by the calcium receptor of the parathyroid gland. The further secretion of PTH is turned off not only by the feedback action of calcium, but also by a short feedback loop involving 1,25-(OH)2D directly suppressing PTH synthesis in the parathyroid gland.
Although this model oversimplifies the events involved in calcium homeostasis it is easy to see from it that sufficient 25-OH-D must be available to provide adequate 1,25- (OH)2D synthesis and hence an adequate level of plasma calcium and that vitamin D deficiency will result in inadequate 25-OH-D and 1,25-(OH)2D synthesis, inadequate calcium homeostasis, and a constantly elevated PTH level (termed: secondary hyperparathyroidism).
It becomes evident from this method of presentation of the role of vitamin D that the nutritionist can focus on the plasma levels of 25-OH-D and PTH to gain an insight into vitamin D status. Not shown but also important is the endpoint of the physiologic action of vitamin D, namely adequate plasma calcium and phosphate ions, that provide the raw materials for bone mineralisation.
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