Vitamin D and barrier function: a novel role for extra-renal 1α-hydroxylase

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Abstract

Much recent attention has focused on the positive health benefits of vitamin D beyond its established role in calcium homeostasis. Epidemiology has highlighted the link between vitamin D deficiency and prevalent diseases such as common cancers and autoimmune disease. Furthermore, studies in vitro have shown that the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) is a potent antiproliferative and immunosuppressive agent. The net effect of this has been the generation and analysis of synthetic analogues of vitamin D for potential use in the treatment of cancers and other disorders including psoriasis. However, there is increasing interest in the impact that vitamin D may have on normal physiology above and beyond its classical effects on calcium homeostasis and bone metabolism. We have postulated that these ‘non-calcemic’ effects of vitamin D are dependent on extra-renal synthesis of 1,25(OH)2D3 via the enzyme 1α-hydroxylase at barrier sites throughout the body. Here we present a review of the mechanisms associated with extra-renal 1α-hydroxylase, and we also speculate on how this ‘new’ physiological role for vitamin D may actually reflect an ancient function for this pluripotent secosteroid.

Introduction

Over the last 20 years our view of how vitamin D influences human physiology has changed dramatically. On the one hand studies of naturally occurring mutations and targeted ablation of vitamin D-associated genes have helped to define the molecular and cellular mechanisms associated with rickets and osteomalacia (Malloy et al., 1999, Miller and Portale, 2000, Dardenne et al., 2001, Panda et al., 2001). On the other hand studies elsewhere have documented non-classical effects of vitamin D ranging from anti-cancer properties to the regulation of hypertension and immunosuppressive actions (Jones et al., 1998). Whilst much of this work has focused on the therapeutic exploitation of synthetic vitamin D analogues, there is now growing interest in the mechanisms by which naturally occurring vitamin D can impact on cellular function in a wide variety of tissues. The aim of the current review is to first provide an overview of the non-calciotropic actions of vitamin D. Second we will argue that these actions are dependent on extra-renal expression of the enzyme 25-hydroxyvitamin D3-1α-hydroxylase (1α-hydroxylase) which acts to increase tissue concentrations of the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). Lastly we will propose a new role for locally synthesized 1,25(OH)2D3 as a modulator of barrier integrity involving the regulation of both epithelial and immune cell function.

Section snippets

Beyond rickets—non-calciotropic effects of vitamin D

Active, hormonal vitamin D in the form of 1,25(OH)2D3 is generated from parental vitamin D3 by sequential hydroxylation steps catalyzed by mitochondrial cytochrome P450 enzymes (see Fig. 1) (Omdahl et al., 2001, Omdahl et al., 2002). The first of these takes place in the liver and involves addition of a 25-hydroxyl group catalyzed by the enzyme vitamin D-25-hydroxylase (25-hydroxylase). The resulting molecule, 25-hydroxyvitamin D3 (25OHD3), is the major circulating metabolite of vitamin D,

Expression of 1α-hydroxylase in extra-renal tissues

Until recently one of the major hurdles to the analysis of the tissue distribution of 1α-hydroxylase was that in the absence of antibodies or molecular probes the enzyme was only detectable by relatively insensitive metabolic assays. However, since the cloning of the cDNA for human 1α-hydroxylase (Fu et al., 1997) there has been a more thorough appraisal of the distribution of the enzyme. In studies carried out by our group we have developed specific antisera which showed for the first time the

Cells that synthesize 1,25(OH)2D3

The studies outlined above have shown clearly that 1α-hydroxylase is expressed to varying degrees throughout the body: in some cases such as the distal nephron, colon and skin mRNA, and protein levels are on a par with those observed in the proximal tubules. The question then arises as to what effect, if any, this has on global synthesis of 1,25(OH)2D3 relative to the kidney as the classical endocrine activator of vitamin D. The simple answer is that, in most cases, extra-renal synthesis of

Vitamin D and human health—the importance of serum 25OHD3

The significance of 1,25(OH)2D3 production by dendritic cells is two-fold. First, this demonstrates that cells associated with normal immune surveillance are as capable of synthesizing active vitamin D as pathological macrophages. Second, it is likely that the ability of both dendritic cells and macrophages to produce 1,25(OH)2D3 is at least in part dependent on the availability of substrate for 1α-hydroxylase, namely 25OHD3. The evidence for this stems from analysis of circulating vitamin D

Vitamin D and barrier integrity—a new function or an ancient function?

We and other groups have shown that the enzyme 1α-hydroxylase is expressed at barrier sites throughout the body, not only by macrophages but also by normal cells involved in immune surveillance. Prominent amongst these are dendritic cells but the enzyme is also expressed by key epithelial cells. Active 1,25(OH)2D3 has potent functional effects on dendritic cells suggesting that these cells may act as the main conduit for vitamin D within the immune system. We have shown that this is mediated in

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