Vitamin D Deficiency and Reduction of Sympathetic and Sensory Innervation in Arthritis

Vitamin D Deficiency Sympathetic Arthritis
Vitamin D Deficiency – Rheumatoid Arthritis

A new study published in Neuroscience demonstrates that vitamin D deficiency in experimental animals is related to sensory and sympathetic denervation and reduced neurotrophin levels in the synovium.

Vitamin D is a secosteroid hormone involved in bone and calcium metabolism. It is involved in the regulation of calcium homeostasis, as it regulates calcium absorption from the gastrointestinal system. The hormone is synthesized in the skin by the action of ultraviolet irradiation. Vitamin D has extraskeletal effects as well.

Vitamin D has been found to have immunomodulatory actions. Vitamin D deficiency has been shown to be correlated with the appearance of autoimmune diseases, such as diabetes mellitus type 1 and multiple sclerosis.

Rheumatoid arthritis (RA) is a debilitating inflammatory joint disease that can be influenced by environmental factors, including dietary vitamin D deficiency. While the underlying pathology is complex, a prequel to RA is loss of autonomic and sensory synovial innervation.

Several studies have associated vitamin D levels with rheumatoid arthritis (RA) development in humans. Thus, low levels of vitamin D are documented in patients with active RA.

Merlino and colleagues found that greater intake of vitamin D might be associated with a lower risk of RA. Through 11 years of follow up, 152 cases of RA were reported. Greater intake of this hormone was found to be inversely associated with risk of RA. Inverse associations were apparent for both dietary and supplemental hormone .

Also vitamin D levels inversely correlate with the activity, pain scores and disabilities profiles in RA, whereas vitamin supplementation delays the onset and progression of arthritis models in rodents (MT Cantorna et al., 1998). In a study involving 1191 patients with RA and 1019 controls, Rossini and colleagues found an inverse association between hormone levels and disease activity in RA.

Peripheral nerves express vitamin D receptors and the hormone can regulate nerve growth and neurotrophin expression, suggesting a link between vitamin D, joint innervation and RA.

However, little is known as to the mechanism of how vitamin D deficiency influences RA development. Of note, the hormone can bind to receptors located in sensory and sympathetic neurons, possibly affecting joint homeostasis and innervation.

Also, partial degeneration of sympathetic and sensory synovial axons is observed in RA patients and in the early phases of many rodent inflammatory arthritis models. In addition, previous research indicates that this innervation also is important to the regulation of immune cells.

In the Neuroscience study SE Tague and PG Smith, from the University of Kansas Medical Center, Kansas City, KS, USA, analyzed the density of synovial nerve fibers in ovariectomized rats on a vitamin D-deprived diet. The authors showed that 4 weeks of vitamin D deprivation decreased sensory and sympathetic innervation in rat synovium.

Of note, the intimal synovial nerves are sensory and most contain both CGRP & GFRα2.  Vitamin D deficiency reduces subintimal density of sympathetic (TH-ir) nerves. Nerve growth factor (NGF) was primarily expressed by intimal CD163-negative type B synoviocytes, while neurturin, a ligand selective for non-peptidergic sensory neurons, was expressed by synovial mast cells.

In hormone-deficient rats, there were significant reductions in sensory nerves in the intima and sympathetic nerves in the subintima. While there was no significant change in NGF-immunoreactivity, the vitamin deficiency reduced the levels of neurturin, a potent neurotrophic factor, in synovial mast cells. This suggests a role in nerve nurturing, as mast cells are well known to be in an intimate contact with synovial nerves fibers (M Hukkanen et al., 1991).

The study of Tague & Smith suggests that vitamin D deficiency may increase arthritis onset and development via reduction in synovial innervation and neurotrophin levels. It may also indicate that a simple vitamin monitoring program and supplementation in inflammatory diseases such as rheumatoid arthritis could be useful as a complement to the actual anti-inflammatory therapies.

Source: Neuroscience, 2014, 279: 77-93. doi: /10.1016/j.neuroscience.2014.08.035
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