The vitamin D deficiency pandemic and consequences for nonskeletal health: mechanisms of action

Abstract

Vitamin D, the sunshine vitamin, is important for childhood bone health. Over the past two decades, it is now recognized that vitamin D not only is important for calcium metabolism and maintenance of bone health throughout life, but also plays an important role in reducing risk of many chronic diseases including type I diabetes, multiple sclerosis, rheumatoid arthritis, deadly cancers, heart disease and infectious diseases. How vitamin D is able to play such an important role in health is based on observation that all tissues and cells in the body have a vitamin D receptor, and, thus, respond to its active form 1,25-dihydroxyvitamin D. However, this did not explain how living at higher latitudes and being at risk of vitamin D deficiency increased risk of these deadly diseases since it was also known that the 1,25-dihydroxyvitamin D levels are normal or even elevated when a person is vitamin D insufficient. Moreover, increased intake of vitamin D or exposure to more sunlight will not induce the kidneys to produce more 1,25-dihydroxyvitamin D. The revelation that the colon, breast, prostate, macrophages and skin among other organs have the enzymatic machinery to produce 1,25-dihydroxyvitamin D provides further insight as to how vitamin D plays such an essential role for overall health and well being. This review will put into perspective many of the new biologic actions of vitamin D and on how 1,25-dihydroxyvitamin D is able to regulate directly or indirectly more than 200 different genes that are responsible for a wide variety of biologic processes.

Figure 1

Once vitamin D is made in the skin or ingested from the diet, it travels to the liver where it is converted to 25-hydroxyvitamin D [25(OH)D]. This major circulating form of vitamin D is then converted in the kidneys to its active form 1,25-dihydroxyvitamin D [1,25(OH)₂D]. The renal production of 1, 25(OH)₂D is for regulating calcium and phosphorus metabolism. 25(OH)D is also converted in many tissues including prostate, colon, breast, lung, immune cells including monocytes and macrophages to 1, 25(OH)₂D. The local production of 1, 25(OH)₂D is to regulate cell growth, control immune function as well as affect up to 200 different genes responsible for health. Reproduced with permission. Holick copyright 2008.

Figure 2

Colon, prostate, skin, monocytes among other tissues and cells can convert 25-hydroxyvitamin D [25(OH)D] to 1, 25-dihydroxyvitamin D [1,25(OH)₂D]. Once formed within the cell, it can induce a wide variety of genes by interacting with its vitamin D receptor (VDR) in the nucleus to regulate proliferation, differentiation and apoptosis. Once it completes this process, it then induces its own destruction by enhancing the 24-hydroxylase activity (24-OHase). Reproduced with permission. Holick copyright 2008.

Figure 3

Figure 3a. Prostate cells that have 25-hydroxyvitamin D-1-hydroxylase activity when incubated with either 25(OH)D₃ or 1,25(OH)₂D₃ are able to inhibit proliferation in a dose dependent fashion. Reproduced with permission. Holick copyright 2008. Figure 3b. Panel A, effect of 25(OH)D₃ (10-⁸M) on ³H-thymidine incorporation into DNA of LNCaP cells with or without transient transfection with PCR 3.1 vector, anti-sense (AS) or sense PCR 3.1-1α-OHase cDNA (S). Panel B, effect of 25(OH)D₃ (10-⁸M) on ³H-thymidine incorporation into DNA of LNCaP cells stably transfected with vector PCR 3.1 or with sense PCR 3.1-1α-OHase cDNA. Bars indicate the standard deviation of eight determinations, *P < 0.05. Reproduced with permission. Whitlatch, et. al, 2002.

Figure 3

Figure 3a. Prostate cells that have 25-hydroxyvitamin D-1-hydroxylase activity when incubated with either 25(OH)D₃ or 1,25(OH)₂D₃ are able to inhibit proliferation in a dose dependent fashion. Reproduced with permission. Holick copyright 2008. Figure 3b. Panel A, effect of 25(OH)D₃ (10-⁸M) on ³H-thymidine incorporation into DNA of LNCaP cells with or without transient transfection with PCR 3.1 vector, anti-sense (AS) or sense PCR 3.1-1α-OHase cDNA (S). Panel B, effect of 25(OH)D₃ (10-⁸M) on ³H-thymidine incorporation into DNA of LNCaP cells stably transfected with vector PCR 3.1 or with sense PCR 3.1-1α-OHase cDNA. Bars indicate the standard deviation of eight determinations, *P < 0.05. Reproduced with permission. Whitlatch, et. al, 2002.

Figure 4

When the 25(OH)D is > 30 ng/ml, it is believed to have a multitude of effects including regulating activated T and B cell activity, enhancing the destruction of infectious agents by increasing the production of cathelicidin (CD). It alters smooth muscle cell proliferation, decreases low density lipoproteins (LDL) and increases high density lipoproteins (HDL) as well as decreasing renin production and enhancing insulin production all for helping preventing cardiovascular disease. Reproduced with permission. Holick copyright 2008.