Hypotheses and Emerging Facts: the Vitamin D Receptor Capacitor, Rheumatoid Arthritis and Beyond

Yue Zhang

Yue Zhang, Arthritis Program, Division of Genetics and Development, The Toronto Western Research Institute, Toronto Western Hospital, University Health Network, 60 Leonard Avenue, Toronto, Ontario, Canada

Correspondence to: Yue Zhang, PhD, Arthritis Program, Division of Genetics and Development, The Toronto Western Research Institute, Toronto Western Hospital, University Health Network, 60 Leonard Avenue, Toronto, Ontario, Canada.
Email: zy1001@yahoo.com
Telephone:+1-416-603-5800 Ext 4797
Received: April 10, 2014
Revised: May 17, 2014
Accepted: May 23, 2014
Published online: June 23, 2014
A part of this article has been selected for one invited lecture in 2014 India Healthcare summit.


As System-IN Failing, complex diseases such as autoimmune diseases (ADs) like rheumatic arthritis (RA), and the associated cancers remain as a challenge to thoroughly understand, though their common underlying mechanisms emerge. In this visionary article, we summarize some recent hypothesis-generating discussions on the Vitamin D and its receptor (VDR) capacitor for autoimmune diseases (ADs) and associated cancers, then update bioinformatics evidence along with latest progress in RA. We could conclude this may provide one unique angle to view the controversies surrounding the beneficial effects of Vitamin D supplementation.

© 2014 The Authors. Published by ACT Publishing Group Ltd.

Key Words: Rheumatoid arthritis; Autoimmune disaeses; Vitamin D receptor capacitor; Cancer; Prevention

Zhang Y. Hypotheses and Emerging Facts: the Vitamin D Receptor Capacitor, Rheumatoid Arthritis and Beyond. International Journal of Orthopaedics 2014; 1(1): 1-8 Available from: URL: http://www.ghrnet.org/index.php/ijo/article/view/742


Complex diseases such as autoimmune diseases (ADs) like rheumatoid arthritis (RA), ankylosing spondylitis (AS) and the associated cancers such as lung cancer and breast cancer are related to a reduction of mobility. Generally, RA is an autoimmune disease in which the body's own immune system mistakenly attacks patients' healthy tissue. This often causes pain, loss of joint shape and alignment, and consequently loss of movement. Currently, no single cause for RA has been assigned, but patients seem to be genetically predisposed to the disease. AS is a chronic, progressive inflammatory disease involving primarily the sacroiliac joints and the axial skeleton. Understanding the causes behind these diseases and then addressing them properly may allow patients to live a more active life.

Beyond bone health, basically, although we are still lacking convincing data [namely, if any, but very few facts and mainly bioinformatics dry evidence], in order to better understand their pathophysiology, the Vitamin D and its receptor (VDR) capacitor hypothesis for ADs and associated cancers has been developed. Vitamin D might only improve diseases status of patients with marginally insufficiency, for which high doses as 400-1,000 IU daily might be required. Beyond certain points, there would be not any beneficial effect with vitamin D supplementation. It does not mean that the vitamin D is sufficient in those individuals and/or generally no beneficial effect for vitamin D supplementation. For decades, it remains debatable for beneficial effects and even definition of sufficiency of vitamin D. Rather than to resolve all these issues, this hypothesis may provide one viewpoint/interpretation for such controversy. Such capacitor (like the electronic device) has preventive effects and only slight side-effects at a rational range along with supplementation. Human beings are speculatively good at surviving the challenges of genetic variations and environmental factors, and rely on the robustness of complex genetic regulatory networks, possibly including the VDR as a capacitor, similar to its homologue DAF-12 in Caenorhabditis elegans. Besides, decoding the genetics of the complex diseases associated with the aging process with which that DAF-12 contribution was proven is critical in understanding the controversies surrounding the beneficial effects of Vitamin D supplementation. In this visionary article, we summarize some recent hypothesis-generating discussion as well as analyze latest bioinformatic indirect evidence from RA. In turn, this increased understanding has also heightened our awareness of current gaps in our knowledge. We conclude it by considering possible explanations, and suggesting future lines of experiments.


(1) This hypothesis is distilled from the comparative advantages of different model systems, data from genome-wide association studies (GWAS), and chromatin immunoprecipitation (ChIP)-seq/ChIP-chip studies[1-6] (Table 1).

(2) It hypothesizes that the evolutionarily conserved roles of Vitamin D and the VDR may shed light on the important role of human VDR[1-9].

(3) Similar to DAF- 21/HSP90VDR may buffer disease-causing genetic mutations and/or variations, the diseased phenotype may occur with polygenic genetic mutations and/or variations plus a deficiency of Vitamin D and a lack of UVB. In these circumstances, mal-functional DAF-12/VDR loses of its buffering ability as a capacitor[1-9].

(4) Environmental factor-induced malfunctional DAF-12/VDR may be postulated to cause the dys-regulation of expression of an array of its target genes; supposedly, the citrullination of such dys-regulated genes might be tightly mediated by VDR-orchestrated processes and consequently end with autoimmunity[4].

(5) Human VDR studies[1-4] show VDR binding loci to be enriched near AD-associated genes[2,4] (Table 1 ) and to overlap many conserved targets of the homologous DAF-12/VDR in C. elegans[5]. VDR ChIP-seq assays in primary CD4+ cells have related serum 25-hydroxyvitamin D levels to ADs[6].

(6) Regarding the signalling pathways, when VDR function is down-regulated due to genetic defects or by Vitamin D unavailability, it may remodel many different processes and make adjustments to multiple signal transducers, thereby simultaneously disturbing several developmental pathways. If DAF-12/VDR loses its buffering capability, ADs and associated cancers may arise in patients[4].

(7) At a systems biology level, the age-related genetic regulatory network (GRN) of VDR, the human homologue of DAF-12 in C. elegans, may play a central role as being the common basis preventing some ADs and associated cancers. In fact, the GRN of DAF-12/VDR combines microRNA regulations, autophagy, longevity and cellular reprogramming, and forward or feedback loops. Our recent ChIP-chip screening for DAF-12/VDR target genes[5,7,8], along with NCBI Aceview, may reveal many translatable targets that overlap with validated homologues identified in human VDR studies that are significantly enriched near genes that are pathologically associated with ADs[4,9], including phospholipase C-like 1 (PLCL1), B lymphoid tyrosine kinase (BLK) (i.e. pll-1 and src-1 respectively; Table 1). Vitamin D3 regulates matrix metallopeptidase (MMP3) in cultured human cells[10].

(8) Hypothesis: some of targets of vitamin D and VDR -associated “loci” identified by GWAS for ADs and associated cancers collectively have significance for gene function. Namely, some of them may contribute to producing self-antigens or the machinery of producing of autoantibodies; others may responsible for the quantity of either self-antigens, auto-antibodies and/or immune machinery capacitor[1-9,19].

(9) Different genetic backgrounds would create personalized Vitamin D insufficiencies and necessities of personalized Vitamin D supplementation.

(10). A Vitamin D deficiency status of a “system robustness failure” may lead to a “one-way” street and thus be irreversible for ADs, including RA. Vitamin D insufficiency might lead to a “system in failing”[4].


One GWAS reveals that, strikingly, an allelic VDR variant may link to clinical autoimmune antibodies including the anti-p150 (TIF-1γ)/p140 (TIF-1α )[11] and TIF-1γ/α genes’ C. elegans homologues, flt-1 and nhl-2, which are also direct targets of DAF-12/VDR (Table 1)[5].

One of our recent experiences is as follows: when the new key regulators for ADs were published online, we predicted that they would be putative target candidates of Vitamin D-VDR signalling (and DAF-12/VDR signalling); amazingly, for most, if not all, this turned out to be the case. For instance, the key regulator fibrillin-1/FBN1, which is responsible for fibrosis and autoimmunity in mouse models of scleroderma, turns out to be the homologue of fbl-1 in C. elegans, the putative target of DAF-12/VDR[12].

Another GWAS identified genetic variants for joint damage progression in autoantibody-positive RA[13], where three key genes (sperm-associated antigen 16 (SPAG16), and matrix metallopeptidase 1 and 3 (MMP1 and MMP3) are among human homologue candidates of DAF-12/ VDR target genes[7,5,14-16]. Vitamin D regulates matrix MMP3 in cultured human cells[10] The latest case is POLR3A gene/ rpc-1, which is responsible for both scleroderma and cancer[17]. Moreover, Miller FW et al[18] reporting on a GWAS of dermatomyositis (DM), revealed a genetic overlap with other ADs, the first identification of genetic predispositions towards ADs shared with DM. Likely, a malfunction of VDR could affect the pathogenesis of RA and associated cancers[9,19,20] and expand to many other ADs, paraneoplastic neurological diseases and DM[18,21-23] (Table 1). Further patterns of genetic overlap across ADs have emerged[18,24]. A malfunction in VDR could thus affect the pathogenesis of RA and possibly associated cancers[9,19]. Importantly, MMP3 contributes to this process[3,7,25]. In closing, the pathophysiology of ADs (or at least a subgroup of ADs) may share the common underlying mechanism of the GRN of VDR.

To seek for novel support of this emerging concept, we have extended these observations by looking into GWAS-identified AS (in preparation), such as endoplasmic reticulum aminopeptidase 1/ERAP-1 for AS mapping to the pam-1, one C. elegans DAF-12/VDR target genes), particularly RA risk loci as follows:

A recent study[26] reported the discovery of 42 novel rheumatoid arthritis (RA) risk loci, providing insights into RA biology, contributing to drug discovery. Indeed, Vitamin D-VDR signalling (VITAMIN D-VDR) may act as a upstream master of the risk gene candidates found in RA and VITAMIN D-VDR studies over the last few decades[1,2,4,5,25,27-31].

As VITAMIN D-VDR targets, some RA risk genes (e.g. PTPN22) may alter adaptive immunity and initiate abnormal responses. VITAMIN D-VDR studies relate 25-hydroxyvitamin D levels to ADs. Given that ~80% of the novel risk locus-associated candidate genes in Okada et al[26] are VD3/VDR targets (Table 1 ) and one-third of them have homologous putative DAF-12/VDR targets[5] (Table 1), about 80% (273/377, regardless of species[1,4-5,7,27-31]) of 377 genes included in 101 loci[26] (~⅓ (127/377) of their rat homologues[27]) merge with VITAMIN D-VDR targets[26]( Table 2), as do all (29/29) the highlighted RA drug target genes[1,5,26,30,31]. This suggests that VITAMIN D-VDR may play a central role in RA pathogenesis[2]. Further, multilayered regulatory networks benefit us in preventing RA alongside using protein–protein interactions, including those applied for identifying RA drug target genes[26] and complexes between VDR and its targets (e.g. MED1).

Innate immunity is important in RA pathogenesis. However, stating that there is no overlap in innate immunity[26] may convey a biased message. Several innate immunity participants are actually among the latest highlighted 98 genes in a recent study[26] (e.g. interleukin-1 receptor-associated kinase 1/IRAK1[1], CD40[4], colony stimulating factor 2 /CSF2[30], complement component 5/C5 and interferon regulatory factor 8/IRF8[4]). Some drugs targeting innate immunity may be repurposed for RA. Since DAF-12/VDR and its targets are required for innate immunity in C. elegans, other innate immunity-related genes within 101 risk loci with a biological score of <2[26] highlighted in that study[26] but which overlap DAF-12/VDR targets (such as rpn-3/PSMD3 and MAK-2/MAPKAPK5[5,32]) may be investigated for drug discovery. Indeed, GLPG0259, an inhibitor of MAPKAPK5, is a new target for treating RA that is undergoing trial[33]. Lastly, half (34/66) of the VITAMIN D-VDR targets with a biological score of 1[26] (e.g. rhotekin 2/RTKN2)[34] may be possibly re-designated as risk genes because of their role in certain ADs.

As mentioned previously, the VITAMIN D-VDR capacitor is an extension from its homologous DAF-12/VDR development “capacitor”[5], similar to the HSP90 capacitor[35], likely masking minor genetic variations, mutations and environmental insults[2,7]. If UVB and Vitamin D are insufficient or if mutations in VDR occur, this feature could become overtaxed, leading to RA[2,4,35]. Many VITAMIN D-VDR (DAF-12/VDR) targets, such as POLY3A/rpc-1, may encode self-antigens that possibly elicit autoantibodies[2,17] (Table 1).

Further investigation is needed for improving our understanding of RA, genetics and the role of Vitamin D. A fraction of ~1500 VITAMIN D-VDR targets[4] may switch to context-dependent RA risk genes at certain points and democratically contribute to “system failure” RA. Vitamin D supplementation may prevent ADs by its buffering capability; outside these contexts, disease status becomes independent of it[35], entering a “one-way street”.

In closing, VITAMIN D-VDR regulation is critical for identifying RA risk genes and drug discovery. For healthcare, RA prevention with personalized Vitamin D optimization rather than disease reversal could be pursued, since therapies targeting a single RA risk gene may have a limited effect, e.g. RA therapy fails with the anti- TNF (a VITAMIN D-VDR target) alone[25,26]; better inhibition of human Th17-mediated synovial inflammation is achieved by combining it with Vitamin D3[25].

Therefore, we may draw the following conclusions. (1) The preventive effects of Vitamin D supplementation on such complex diseases may well need to be considered and we should avoid Vitamin D insufficiency in patients; (2) We predict that combination therapy with Vitamin D will likely benefit the treatment of ADs such as RA and AS.


Analysis of Vitamin D/VDR context-dependent targets is based on data from several recent studies including microarray, ChIP-chip/ChIP-seq publications and some references therein[1,25,27,31,42]. NCBI Aceview is used to identify homologues of VDR downstream ADs-related target gene candidates alongside published DAF-12/VDR binding sites[7]. For comprehensive identification of gene candidates, both sides of the DAF-12/VDR binding sites are considered, as some ADs-related gene homologues may be missed (the original online supplementary material may describe their neighbouring genes only). For BlastP, the P <10-04 is defined as the cut-off for the identification of significant homologue candidates; otherwise, they are considered “exceptional”.


There are no conflicts of interest with regard to the present study.


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Peer reviewer: Vladimir Palicka, MD, PhD, Professor, Osteocentre, UKBD, Charles University in Prague, School of Medicine Hradec Kralove, University Hospital, Sokolska 581, CZ-500 05 Hradec Kralove, Czech Republic.


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