Efficacy and mechanisms of action of vitamin D in experimental polyarthritis

Abstract

Vitamin D (vit D) status has been linked to the occurrence and severity of auto-immune and inflammatory diseases. This study evaluates the effects of vit D status on adoptive transfer of adjuvant-induced arthritis (ATA). Rats maintained on diets replete or deficient in vit D3 received arthritogenic thoracic duct cells and were monitored for severity of arthritis. CD45 + cells obtained by collagenase digestion of hind-paw synovium-rich tissues (SRTs) were analysed to observe the effects of dietary vit D3 on the inflammatory process. Arthritis was more severe in vitamin D-deficient (vit-D À ) rats compared with vitamin D-replete (vit-D + ) rats. Resolution was delayed in vit-D À rats compared with vit-D + rats, or rats fed standard chow. During the acute phase of ATA, numbers of CD45 + cells were significantly increased in the SRTs of vit-D À rats compared with vit-D + rats. This increase involved T-cells, polymorphonuclear leukocytes, macrophages, dendritic cells (DCs) and MHC II hi cells that resemble activated monocytes. A major difference between the dietary groups was that most DCs at the peak of inflammation in vit-D À rats were CD4 -, whereas in convalescent vit-D + rats most expressed CD4. Multiple categories of genes expressed by DCs differed between deficient and replete rats, with deficiency being associated with relative upregulation of certain pro-inflammatory genes and replete status being associated with upregulation of genes associated with resolution of inflammation. The findings indicate that ATA is more severe and prolonged in vit-D deficiency, that vit-D deficiency promotes accumulation of CD4 À DCs in synovium during ATA and that a gene-expression profile is likely to contribute to the observed increased severity and duration of arthritis. The role of vitamin D (vit D) in calcium homeostasis and maintenance of skeletal health has long been recognised. 1 The vit D receptor has been found on more than 35 cell types 2 and more recently the immuno-regulatory effects of vit D have been appreciated. The latter properties have been observed in experimentally induced animal models of autoimmune diseases, including experimental autoimmune encephalomyelitis, 3 collagen-induced arthritis, 4 autoimmune type 1 diabetes, 5 T-cell-mediated colitis 6 and murine lupus. 7 Epidemiological studies have linked vit D insufficiency with frequency of a number of autoimmune diseases, including multiple sclerosis, 8 rheumatoid arthritis (RA), 9 type 1 diabetes, 10 Bechet's syndrome 11 and inflammatory bowel disease. 12 Epidemiological evidence has also associated higher dietary intake of vit D with protection from autoimmune diseases. 13,14 The present study was undertaken to explore the effects of vit D status in a well-characterised model of immune-mediated arthritis. Adjuvant-induced arthritis (AIA) is a T-cell-mediated disease 15 that has similarities to rheumatoid arthritis in distribution (predominantly peripheral and symmetrical) and in histopathology. 16 We have shown that ATA, induced using thoracic duct (TD)...

The Vitamin D Receptor Regulates Rheumatoid Arthritis Synovial Fibroblast Invasion and Morphology

“…Vitamin D deficiency correlates with increased disease severity and joint damage in RA (9,10) and in rodent models of arthritis (11). Treatment with vitamin D and analog VDR agonists have been shown to reduce disease severity and joint damage in experimental arthritis (12,32), including collageninduced arthritis (33,34).…”

Acute Erythemal Ultraviolet Radiation Causes Systemic Immunosuppression in the Absence of Increased 25-Hydroxyvitamin D3 Levels in Male Mice

“…Indeed, the role of UVR-induced vitamin D in modulating immune-driven diseases has not (until the current study) been examined in vitamin D-deficient mice. Through dietary restriction, vitamin D deficiency enhanced the pathogenesis of immune-driven disorders such as diabetes [14], colitis [15] and arthritis [16] in rodent models. However, Becklund et al (2010), observed that UVR suppressed experimental autoimmune encephalomyelitis (EAE) in mice (a murine model of multiple sclerosis) when there were minimal changes in serum 25(OH)D 3 , suggesting that vitamin D 3 may not be a central mediator of UVR-induced systemic immunosuppression [17].…”

Vitamin D deficiency leads to sensory and sympathetic denervation of the rat synovium

“…A number of studies have suggested that vitamin D deficiency increases the susceptibility and severity of rheumatoid arthritis (Kroger et al, 1993, Cantorna et al, 1998, Larsson et al, 1998, Cutolo et al, 2006, Patel et al, 2007, Haque and Bartlett, 2010, Rossini et al, 2010, Kerr et al, 2011, Turhanoglu et al, 2011, Zwerina et al, 2011, Attar, 2012, Moghaddami et al, 2012, Moghimi et al, 2012, Song et al, 2012). At least in the short time frame of our study, vitamin D deficiency did not appear to cause overt rheumatoid arthritis; however we can make some significant comparisons.…”

“…A positive association has been observed between vitamin D deficiency and undifferentiated inflammatory arthritis (Heidari et al, 2012), a condition which frequently progresses to active RA, which suggests that vitamin D deficiency may play a role in initiation or early stage of the disease. In rodents, vitamin D deficiency or vitamin D receptor deletion increased disease severity and delayed resolution of inflammatory arthritis (Zwerina et al, 2011, Moghaddami et al, 2012). Conversely, supplementation with the active hormone, 1,25-dihydroxyvitamin D3 or a vitamin D analog prevented development or halted progression of collagen-induced arthritis, and reduced the severity of Lyme-induced arthritis (Cantorna et al, 1998, Larsson et al, 1998).…”