Page 45 - Vitamin D and Cancer

32 J. Thorne and M.J. Campbell

between different cellular-signaling systems. Furthermore, the arena for VDR
actions and interplay extends beyond the nucleus and integrates levels of cytoplas-
mic signal transduction, genomic and epigenomic regulation. Establishing the
specificity of function and selectivity of VDR interactions has to an extent been
limited by technical approaches. Unbiased approaches are now required to dissect
VDR interactions (in the membrane, cytoplasm, and nucleus) in either individual
cells or very pure populations, thereby to generate a comprehensive understanding
of the spatial temporal network of its interactions.

2.2 Integrated VDR Actions

2.2.1 Lessons from Murine Models

The VDR plays a well-established endocrine role in the regulation of calcium
homeostasis by regulating calcium absorption in the gut and kidney, and bone min-
eralization. 1a,25(OH) D status is dependent upon cutaneous synthesis initiated
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by solar radiation and also on dietary intake – a reduction of either one or both
sources leads to insufficiency, although UV-initiated cutaneous 1a,25(OH) D syn-
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thesis is the principal route in a vitamin D-sufficient individual. The importance of
the relationships between solar exposure and the ability to capture UV-mediated
energy is underscored by the inverse correlation between human skin pigmentation
and latitude. That is, the individual capacity to generate vitamin D in response to
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solar UV exposure is intimately associated with forebear environmental adaptation.
The correct and sufficient level of solar exposure and serum vitamin D are matters
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of considerable debate. Current recommendations for daily vitamin D intake are in
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the range of 400–800 IU/day [92]. More recently, reassessment of the 1a,25(OH) D
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impact on the prevention of osteoporosis has suggested that the correct level may
be as high as 2–3,000 IU/day, which may reflect more accurately “ancestral” serum
levels [93].
The importance of the relationship between UV exposure and calcium homeostasis
has driven the endocrine view of 1a, 25(OH) D synthesis and signaling. In paral-
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lel, local generation of 1a, 25(OH) D in target tissues has become apparent and
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supported a separate autocrine role to regulate cell proliferation and differentiation,
and other functions including the modulation of immune responses.
Key insights into these functions have been gained in Vdr-deficient mice
[94–96]. The Vdr is expressed widely during murine embryonic development in
tissues involved in calcium homeostasis and bone development. Vdr disruption
results in a profound phenotype in these models, which is principally observed
post-weaning and is associated with the alteration of duodenal calcium absorp-
tion and bone mineralization, resulting in hypocalcemia, secondary hyperpara-
thyroidism, osteomalacia, rickets, impaired bone formation, and elevated serum
levels of 1a,25(OH) D . In parallel, a range of more subtle effects are seen
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more clearly when the animals are rescued with dietary calcium supplementation