20S-Hydroxyvitamin D3, a Secosteroid Produced in Humans, Is Anti-Inflammatory and Inhibits Murine Autoimmune Arthritis.

Arnold E Postlethwaite,Syamal K Bhattacharya,Robert C Tuckey,Linda K Myers,Tae-Kang Kim,Andrzej T Slominski,David D Brand,Wei Li

doi:10.3389/fimmu.2021.678487

Abstract

The ability to use large doses of vitamin D3 (D3) to chronically treat autoimmune diseases such as rheumatoid arthritis (RA) is prohibitive due to its calcemic effect which can damage vital organs. Cytochrome P450scc (CYP11A1) is able to convert D3 into the noncalcemic analog 20S-hydroxyvitamin D3 [20S(OH)D3]. We demonstrate that 20S(OH)D3 markedly suppresses clinical signs of arthritis and joint damage in a mouse model of RA. Furthermore, treatment with 20S(OH)D3 reduces lymphocyte subsets such as CD4+ T cells and CD19+ B cells leading to a significant reduction in inflammatory cytokines. The ratio of T reg cells (CD4+CD25+Foxp3+ T cells) to CD3+CD4+ T cells is increased while there is a decrease in critical complement-fixing anti-CII antibodies. Since pro-inflammatory cytokines and antibodies against type II collagen ordinarily lead to destruction of cartilage and bone, their decline explains why arthritis is attenuated by 20(OH) D3. These results provide a basis for further consideration of 20S(OH)D3 as a potential treatment for RA and other autoimmune disorders.

Highlights

Rheumatoid arthritis (RA) is one of the more common autoimmune diseases
The histologic scores reflecting inflammation, cartilage damage and subchondral bone erosion in joints harvested at sacrifice on Day 40 post CII immunization were significantly reduced in 20S(OH) D3 treated versus S.O. treated CIA mice (Figure 1E), reflecting the ability of 20(OH)D3 to protect joints from damage in this model
On Day 21 under the conditions we employ, arthritis is highly inflammatory and driven by complement fixing anti-CII antibodies. This suggests 20S(OH)D3 has anti-inflammatory effects. This is the first demonstration that a natural noncalcemic D3 analog, 20S(OH)D3, which is normally produced in humans, suppresses the CIA model of human rheumatoid arthritis (RA), both clinical arthritis and joint destruction, providing a rationale for further consideration of 20S(OH)D3 as a potential mono or adjunctive therapy for RA and other autoimmune diseases

Summary

Introduction

Rheumatoid arthritis (RA) is one of the more common autoimmune diseases Standard disease modifying anti-rheumatic drugs, (DMARDs), such as methotrexate (MTX) and “biologics” that target specific cytokines (e.g., TNFa) or surface molecules on immune cells (e.g., CTLA-4 on T cells), do reduce both joint damage and certain systemic complications of RA. Their use occasionally triggers adverse events such as increased infections and development of certain neoplasms, other autoimmune diseases, or interstitial lung disease [5,6,7,8]. D3, which is inert as a pro-hormone, undergoes two hydroxylation steps: first in the liver (or skin itself)

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Conclusion