Vitamin D: Old Roles and New Discoveries

Abstract

Vitamin D is a fat-soluble vitamin that has various forms. It regulates bone protein formation and stimulates calcium absorption. There is a crucial receptor that helps vitamin D perform its functions and is termedvitamin D receptor (VDR) that has the chemical formula '1,25(OH)2D'. Vitamin D has many novel functions. Firstly, it has an anti-tumor activity that works through regulating the genes responsible for cell proliferation and differentiation. Secondly, it plays an immunological role by regulating different immune cells. Moreover, it helps in resisting cardiovascular diseases by regulating the function and structure of the heart. It also has a neuroprotective effect since vitamin D metabolites can pass through the blood-brain barrier. Besides, it contains anti-aging effects since vitamin D and VDR induce the formation of α-Klotho hormone which delays aging. Additionally, this research will discuss vitamin D deficiency diseases such as rickets in newborns and osteomalacia in adults.

Introduction and Objectives

Vitamins are organic substances that are needed in small amounts to perform several functions in the human body. Vitamin D, a fat-soluble secosteroid, was formally defined as a vitamin in the twentieth century. Vitamin D has two major forms; vitamin D2 (ergocalciferol), which plants and fungi produce from ergosterol, and vitamin D3 (cholecalciferol), which is the natural form of vitamin D that is produced in the human skin from 7-dehydrocholesterol (7-DHC). However, the differences between the two forms do not affect metabolism and activation since both forms have pro-hormone functions (Silva and Furlanetto, 2018).

Currently, many novel non-skeletal physiological functions exist foe vitamin D including cell proliferation, adaptive immune system regulation, and a preventive effects on neuron-degenerative and cardiovascular diseases (CVD). On the other hand, vitamin D deficiency increases the vulnerability to infections and autoimmune diseases. Because of the clinical importance of vitamin D and to enhance its tissue-specific clinical applications, many studies are recently established.

The current research attempts to illustrate the nature, structure and main classic functions of vitamin D with the recognition of its novel functions and disorders caused by vitamin D deficiency.

Research Review

Structure and Nature of Vitamin D

Vitamin D is a fat-soluble vitamin alongside vitamins A, E, and K. The human body can independently synthesize vitamin D, so it is not essential in our diet. Vitamin D has two major physiological forms: vitamin D2 and D3 which are the results of ultraviolet irradiation of ergosterol and 7-dehydrocholesterol, a precursor found in the skin, respectively. Classically, vitamin D deficiency causes rickets and osteomalacia.

Functions of Vitamin D3

To efficiently study and understand the biological roles of vitamin D in the human body, its receptors have been studied thoroughly in the last few decades. In the beginning, it was commonly a known fact that vitamin D is one of the most vital vitamins for bone regulation, bone formation, and calcium maintenance in the human body. However, recent researches have additionally found out that the hormonally active form of vitamin D, 1,25-dihydroxyvitamin D3, actually yields several additional extra-skeletal biological responses. These responses include (a) the inhibition of cancer cells in patients with breast, prostate and colon cancers; and (b) protection against cardiovascular diseases and various autoimmune diseases: Following the identification of its antirachitic uses, vitamin D is now chemically considered as a secosteroid.

Vitamin D deficiency and resultant disorders

In addition to the essential roles of vitamin D in absorbing essential ions (calcium ion primarily and phosphorus ions secondarily) and the skeletal growth, the deficiency of this vitamin specifically may lead to a decrease in the intestinal calcium absorption and the bone turnover rate (the resorption of the bone by osteoclasts and leakage of its minerals into the blood, then replacing the resorption by new bone). Those who isolate themselves from being exposed to sunlight or those with highly pigmented skin are at high risk of having vitamin D deficiency. Human milk is described to be the best food for human neonates unless it is deficient in vitamin D. Such deficiency may lead to rickets to the newborn baby. Unfortunately, this still occurs to this day, leading to a severe deficiency of the vitamin in the newborn infant.

Rickets is one of the most common diseases caused by vitamin D deficiency since calcium is not absorbed efficiently, causing a noticeable decrease in the calcium serum level. This triggers the calcium sensors in the parathyroid glands, causing the secretion of parathyroid hormones (PTH). The result of this is an increased osteoclast activity in bone erosion, causing extensive bone resorption; and an increase in the calcium absorption in the kidney tubules (in the proximal and distal parts). Moreover, PTH decreases the absorption of phosphorus from the kidney and leads to the expelling of it into the urine . Additionally, a severe deficiency of vitamin D causes osteomalacia, a disease that is characterized by softening of bones which may be associated with crippling deformities.

Novel Functions

Vitamin D has been quite known to be associated with bone health, growth, and reorganization through: (a) stimulating the intestinal calcium absorption, (b) regulating the serum calcium concentration, (c) regulating the phosphate levels. However, novel actions on multiple types of tissues have been recently discovered. What’s interesting is the fact that vitamin D can be used to protect against: (a) cardiovascular diseases; (b) nervous system diseases; (c) diabetes mellitus. This is because calcitriol’s (Vitamin D active metabolite) mode of action is mediated by the vitamin D receptor, a subfamily of nuclear receptors, which is found in nearly all types of cells.

Vitamin D effects on cell proliferation and differentiation

Vitamin D specific receptor (VDR) and calcitriol have been found to regulate the expression of genes linked with cellular proliferation differentiation, proposing their crucial role in the avoidance of cancer. Numerous analyses on publications of the prostate, breast, and ovarian cancer showed that vitamin D3 levels were concurrent with decreased incidence of cancer. This anti-cancer effect of calcitriol can be achieved through several mechanisms as suppression of metastases, angiogenesis and invasion, together with the promotion of apoptosis.

Vitamin D effects on the immune system

Calcitriol possesses key immune-regulatory actions. as increasing the defense capacity of macrophages, inhibiting the proliferation of monocytes, and promoting the differentiation of monocytes to macrophages Besides, calcitriol inhibits dendritic cell proliferation, maturation and immune stimulatory properties inducing regulatory T cells (T-reg cells). Furthermore, calcitriol inhibits the expression of antigen-presenting cells’ (APC) cytokines while also inducing T helper (Th2) cells; hence, Th1 cells are inhibited. Also, the B cell proliferation and antigen production are inhibited by calcitriol. Moreover, calcitriol can control immune mechanisms in target organs and secondary lymphoid organs.

Vitamin D correlation with cardiovascular diseases

Based on experimental studies, VDR and calcitriol are vital controllers of the cardiac structure and function. On the other hand, clinical researches have linked the CVD to vitamin D deficiency. According to developing evidence, CVD-related signaling pathways are greatly concerned with calcitriol. Experimentally, addition of calcitriol to cardiomyocyte cells demonstrated inhibition of cell proliferation, reduced expression of genes regulating cell cycle and promotion of cardiomyotubes formation.

Vitamin D Neuroprotective Effect

Naturally, metabolites of vitamin D cross the blood-brain barrier (BBB). Hence, vitamin D has several roles in a wide range of neuromuscular/neurological disorders. Calcitriol up- regulates glutathione, playing a role in neuroprotection and/or neuromodulation. Substantia nigra of the midbrain contains high levels of VDR and 1α-hydroxylase, the enzymes needed for calcitriol production. Therefore, vitamin D might be related to the insufficient neuronal dopamine observed in Parkinson’s disease.

Moreover, vitamin D has a role in the development of the nervous system, keeping the integrity of the BBB, axonal growth/regeneration, and myelination. Disturbance of all these effects is important in autoimmune demyelinating diseases of the nervous system, especially multiple sclerosis and neuromyelitis optica. Research is still needed to determine the true potential of vitamin D as the vital prophylaxis against these autoimmune attacks on the myelin sheath.

Vitamin D anti-aging Effect

Many studies showed that calcitriol induces a renal hormone called α-klotho which is an anti-aging enzyme/coreceptor protecting against skin atrophy, osteopenia, neuroendothelial dysfunction, memory defects, neurodegeneration and diminished hearing acuity. Both calcitriol and α-klotho help normal physical growth, healthy development, antioxidant effects and homeostasis, while protecting against malignancy.

Conclusion

Vitamin D is one of the most vital vitamins with complex structures and important functions. Some of these functions are classic and scientifically proved, while others are novel and discussable. However, these new functions show the great potential of vitamin D and how it could be used to prevent serious diseases. Finally, any deficiency in vitamin D may lead to serious diseases for both newborns and adults, so great care has to be taken to keep the vitamin D levels sufficient, especially in newborns.

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