Adriana S Dusso, Alex J Brown, & Eduardo Slatopolsky
Renal Division, Washington University School of Medicine, St. Louis, Missouri, USA

https://doi.org/10.36866/pn.64.28

Vitamin D was discovered early in the 20th century as the component of fish oil essential for the prevention and cure of rachitic bone disease. Vitamin D3 or cholecalciferol can be produced in adequate amounts by skin exposure to sunlight. Vitamin D2 or ergocalciferol, a related compound with very similar activities, is found in a few plants
(Dusso et al. 2005).

Vitamins D3 and D2 have little intrinsic activity and must be metabolised to exert biological effects (see Fig. 1). Hydroxylation of carbon 25 occurs primarily in the liver. 25­hydroxyvitamin D [25-OHD], the most abundant vitamin D metabolite in circulation, is used as the index of vitamin D status. 25-OHD is further metabolized by the 1α-hydroxylase to 1,25-dihydroxyvitamin D [1,25(OH)2D], the active (hormonal) form. Although the kidney is the primary source of the circulating 1,25(OH)2D, 1α-hydroxylase is also found in many cells throughout the body. Nonrenal 1,25(OH)2D production serves cell-specific functions (Dusso et al. 2005). In fact, the association between vitamin D deficiency and higher susceptibility to tuberculosis (Zasloff, 2006) and cancer (Zittermann, 2003) results from inadequate production of 1,25(OH)2D by nonrenal sources rather than systemic 1,25(OH)2D deficiency.

1,25(OH)2D acts as a steroid hormone. It binds with high affinity to a specific intracellular receptor, the vitamin D receptor (VDR), a member of the steroid receptor family. Upon 1,25(OH)2D binding, the VDR undergoes a conformational change allowing interaction with a number of other macromolecules. Typically, the liganded VDR forms a heterodimer the retinoid X receptor (RXR), which promotes binding to specific DNA sequences in the promoters of regulated genes. The DNA-bound complex then recruits coactivators that unwind chromatin and facilitate gene transcription, or corepressors that suppress gene transcription.

1,25(OH)2D-VDR control of gene transcription mediates classical vitamin D actions on calcium homeostasis and skeletal integrity as well as nonclassical actions on cell growth, differentiation and survival, immunomodulation, and endocrine regulation (Dusso et al. 2005).

Classical 1,25(OH)2D /VDR actions in bone, intestine, the parathyroid glands and the kidney maintain serum calcium levels within the narrow limit required for normal cellular physiology and the development and maintenance of a mineralized skeleton. The impaired 1,25(OH)2D production in chronic kidney disease decreases intestinal calcium absorption. The resulting hypocalcemia enhances the secretion of parathyroid hormone (PTH), which accelerates calcium release from bone in an effort to restore normal serum calcium. 1,25(OH)2D also acts as a skeletal anabolic agent, necessary to sustain bone forming activity, matrix mineralization, and the normal coupling of PTH-induced bone remodeling (Dusso et al. 2005).

Interestingly, nearly 70% of the USA population with suboptimal levels of 25(OH)D has increased serum PTH, despite normal 1,25(OH)2D. This suggests that adequate vitamin D supplementation should decrease the risk of osteoporosis and fracture in healthy individuals either by direct 25-OHD activation of the VDR, or as a result of local 1,25(OH)2D production by bone and parathyroid cells expressing 1α-hydroxylase.

Nonclassical 1,25(OH)2D/VDR actions include regulation of cell proliferation, differentiation and survival, immunomodulation, suppression of the renin- angiotensin system and enhancement of glucose-mediated insulin secretion. Accordingly, abnormalities in the vitamin D endocrine system have been linked to hypertension, diabetes, disturbed muscular and cardiovascular function, susceptibility to infections, autoimmune diseases and cancer (Zittermann, 2003; Dusso et al. 2005; Garland et al. 2006). Intriguingly, however, the higher incidence of these disorders correlates to 25-OHD deficiency rather than insufficient serum 1,25(OH)2D. This suggests that increased local production of 1,25(OH)2D upon adequate elevations in 25-OHD levels by vascular endothelial cells, immune cells, and pancreatic beta cells expressing 1α-hydroxylase could mediate the reduced incidence of hypertension, cardiovascular disease and diabetes in vitamin D-repleted individuals.

1,25(OH)2D /VDR actions in the immune system provide strong evidence of the contribution of adequate local 1,25(OH)2D production by immune cells to the association between 25-OHD deficiency rather than 1,25(OH)2D insufficiency with higher susceptibility to infections, autoimmune diseases and cancer (Hayes et al. 2003; Zittermann, 2003; Dusso et al. 2005; Garland et al. 2006).

The importance of adequate 25-OHD availability to the activated macrophage is evident in tuberculosis (Zasloff, 2006). As early as 1895, phototherapy was used to treat ‘lupus vulgaris’ (skin tuberculosis), but it was not until 2006, when local activation of 25­hydroxyvitamin D to 1,25(OH)2D by macrophages infected with the mycobacterium tuberculosis was proven mandatory for the potent anti­tuberculosis properties of vitamin D. More important was the discovery that the low serum 25-OHD levels, a common occurrence in the African American population, limited the mounting of an adequate anti­tuberculosis response, a defect which could be corrected upon vitamin D supplementation. Similarly, in vitamin D deficiency, impaired local 1,25(OH)2D production by dendritic cells appears to mediate abnormalities in the establishment and maintenance of immune self-tolerance, essential for prevention of autoimmune diseases as type I diabetes, multiple sclerosis, inflammatory bowel disease, encephalomyelitis and rheumatoid arthritis (Hayes et al. 2003; Zittermann, 2003; Dusso et al. 2005). Epidemiological studies associate vitamin D deficiency with the prevalence of these autoimmune disorders, and vitamin D supplementation can improve symptoms of rheumatoid arthritis and decrease relapse rates in multiple sclerosis (Zittermann, 2003).

Enhanced sunlight exposure is associated with lower death rates for breast, colon and prostate cancer (Garland et al., 2006). 1,25(OH)2D/VDR control of DNA repair, induction of differentiation and apoptosis of malignant cells as well as enhancement of macrophage immune surveillance could mediate vitamin D efficacy in cancer prevention. In cancer, 1,25(OH)2D/VDR suppression of angiogenesis and cell proliferation, and induction of macrophage antitumoral properties, and tumor cell apoptosis may ameliorate the severity of cancer progression. In cancer cells expressing 1-hydroxylase, local 1,25(OH)2D production could contribute to growth arrest since 25­hydroxyvitamin D, at concentrations insufficient to activate the VDR, suppresses cell proliferation. Tumor growth may also be suppressed by the 1,25(OH)2D produced by activated macrophages in the vicinity of a cancer cell or in the tumor microenvironment. Indeed, vitamin D supplementation may prevent cancer and improve the efficacy of conventional anticancer therapy.

In summary, adequate vitamin D status could prevent the onset or ameliorate the progression of many prevalent diseases. New recommendations for daily requirements are mandatory. Dietary sources, including vitamin D­fortified food and vitamin supplements (400 IU/day) have only a minimal effect on 25(OH)D levels. Sunlight exposure is much more effective, but moderation is necessary to reduce skin cancer risk. Ten minutes of arm and face exposure per day is usually sufficient. The daily intake of vitamin D can be increased safely to 1,200 U/day (Zittermann, 2003; Garland et al. 2006). These relatively inexpensive measures to improve vitamin D status can have a major impact on the prevalence and severity of osteoporosis, diabetes, cardiovascular disease, hypertension, tuberculosis, autoimmune disease and cancer.

References

Dusso AS, Brown AJ & SlatopolskY E (2005). Vitamin D. Am J Physiol Renal Physiol 289, F8-28.

Garland CF, Garland FC, Gorham ED, Lipkin M, Newmark H, Mohr SB & Holick MF (2006). The role of vitamin D in cancer prevention. Am J Public Health 96, 252-261.

Hayes CE, Nashold FE, Spach KM & Pedersen LB (2003). The immunological functions of the vitamin D endocrine system. Cell Mol Biol (Noisy-le-grand) 49, 277-300.

Zasloff M (2006). Fighting infections with vitamin D. Nat Med 12, 388-390.

Zittermann A (2003). Vitamin D in preventive medicine: are we ignoring the evidence? Br J Nutr 89, 552-572.