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  • Study protocol
  • Open Access
  • Open Peer Review

Role of vitamin D3 in Treatment of Lumbar Disc Herniation—Pain and Sensory Aspects: Study Protocol for a Randomized Controlled Trial


  • Received: 29 April 2014
  • Accepted: 4 September 2014
  • Published:
Open Peer Review reports



Vitamin D receptors have been identified in the spinal cord, nerve roots, dorsal root ganglia and glial cells, and its genetic polymorphism association with the development of lumbar disc degeneration and herniation has been documented. Metabolic effects of active vitamin D metabolites in the nucleus pulposus and annulus fibrosus cells have been studied. Lumbar disc herniation is a process that involves immune and inflammatory cells and processes that are targets for immune regulatory actions of vitamin D as a neurosteroid hormone. In addition to vitamin D’s immune modulatory properties, its receptors have been identified in skeletal muscles. It also affects sensory neurons to modulate pain. In this study, we aim to study the role of vitamin D3 in discogenic pain and related sensory deficits. Additionally, we will address how post-treatment 25-hydroxy vitamin D3 level influences pain and sensory deficits severity. The cut-off value for serum 25-hydroxy vitamin D3 that would be efficacious in improving pain and sensory deficits in lumbar disc herniation will also be studied.


We will conduct a randomized, placebo-controlled, double-blind clinical trial. Our study population will include 380 cases with one-level and unilateral lumbar disc herniation with duration of discogenic pain less than 8 weeks. Individuals who do not have any contraindications, will be divided into three groups based on serum 25-hydroxy vitamin D3 level, and each group will be randomized to receive either a single-dose 300,000-IU intramuscular injection of vitamin D3 or placebo. All patients will be under conservative treatment. Pre-treatment and post-treatment assessments will be performed with the McGill Pain Questionnaire and a visual analogue scale. For the 15-day duration of this study, questionnaires will be filled out during telephone interviews every 3 days (a total of five times). The initial and final interviews will be scheduled at our clinic. After 15 days, serum 25-hydroxy vitamin D3 levels will be measured for those who have received vitamin D3 (190 individuals).

Trial registration

Iranian Registry for Clinical Trials ID: IRCT2014050317534N1 (trial registration: 5 June 2014)


  • Inflammation
  • Lumbar disc herniation
  • Pain
  • Sensory
  • Vitamin D3


Medical treatment is the first step in therapy for lumbar disc herniation (LDH), except for patients who require immediate surgical decompression. Drugs that are utilized in treatment of LDH pain and sensory deficits include muscle relaxants [13], analgesics [1, 2, 49], corticosteroids [1, 2, 10], antidepressants [4, 8, 11, 12] and antiepileptics [4, 8, 1117].

Vitamin D is a secosteroid hormone that has many skeletal and nonskeletal functions [1894]. In addition to its classic action on bone metabolism and osteoporosis [18, 19], its links and roles in relation to other diseases have been addressed in the literature (diabetes mellitus [18, 2023], hypertension [24, 25], cardiovascular diseases [18, 2629], multiple sclerosis [3035], neurodegenerative diseases [3639], neuropsychiatric diseases [3944], inflammatory bowel disease [33, 4549], dermatologic diseases [5058], rheumatoid arthritis [47, 53, 5961], systemic lupus erythematosus [60, 6267], transplant rejection [6870], cancer [18, 52, 68, 7173], postherpetic neuralgia [74], corneal neuralgia [75], respiratory diseases [7679], pregnancy complications [8082], human reproductive issues [8385], migraine headache [86], chronic low back pain [87, 88], chronic painful conditions and fibromyalgia [89, 90] and diabetic neuropathy [9193]). Studies that have shed light on areas that have given us the scientific underpinning for our present proposal are described below.
  1. 1.

    Vitamin D has been called a neurosteroid hormone [39, 74, 94109], given its protective role against neurotoxicity and detoxification pathways [74, 94, 96108] and also its receptors in different parts of the central nervous system [36, 9496, 106114].

  2. 2.

    Vitamin D receptors are present in the spinal cord, nerve roots, dorsal root ganglia and glial cells [94, 96, 97, 113, 115118].

  3. 3.

    Vitamin D receptor gene polymorphism has a role in the development of lumbar disc degeneration and herniation [119123].

  4. 4.

    Discs are composed largely of avascular tissue with a great sensitivity to its nutritional supply and excretion of waste products, and the balance between these two processes is an important factor that could lead to disc degeneration [124127]. The effects of active vitamin D metabolites in nucleus pulposus and annulus fibrosus cells have been studied [128]. Vitamin D inhibits and decreases production of monocyte chemoattractant protein 1, thrombopoietin, vascular endothelial growth factor and angiogenin by human annulus cells in vitro [129]. As mentioned above, vitamin D affects detoxification pathways which are of importance in disc cell nutritional balance.

  5. 5.

    Vitamin D possesses immune regulatory properties which can downregulate proinflammatory cytokines and upregulate anti-inflammatory cytokines [22, 32, 36, 4648, 58, 67, 70, 74, 78, 90, 94, 96, 130146].

  6. 6.

    Vitamin D has properties that defend against cell injury caused via free radicals, reactive oxygen species, glutathione and glutamate [74, 94, 96108, 136, 147149].

  7. 7.

    Vitamin D has a role in pain by downregulating inflammatory cytokines that produce pain (a) directly, (b) by stimulating release of pain mediators, (c) by upregulating anti-inflammatory cytokines to help the body combat inflammation, (d) by its role in eliminating toxic metabolites or (e) by increasing the antioxidant pool. It also affects sensory neurons to modulate pain [114], influences neuron excitability [96] and acts at the level of substantia gelatinosa and spinal ganglion in the process of sensory perception [118]. In addition, its status affects pain sensitivity and opiate activity [150].

  8. 8.

    The role of the vitamin D receptor in skeletal muscles [151155] and its effects on muscle strength and function have been identified [156159].

In addition to the information described above, many studies about changes that occur in LDH have been done, as outlined below.
  1. 1.

    The contribution of inflammatory cytokines in the pathogenesis of LDH has been widely addressed in the literature. The herniated nucleus pulposus, either with immunogenic properties itself or by inducing an immunologic response in the nerve roots, dorsal root ganglia and surrounding muscles, is the starting point for the cascade of inflammation initiated through immune cell activation and infiltration and cytokine release [160184].

  2. 2.

    Neuropathic pain involves the activation of neurons, glial cells and the immune system [185, 186]. Dorsal root ganglia and dorsal roots play important roles in LDH, not only by the effect of released inflammatory cytokines but also by actively amplifying inflammation by producing proinflammatory cytokines and pain mediators that affect pain perception and nociception. Among these substances is brain-derived neurotrophic factor. Its receptor has been identified in intervertebral discs, with its expression being increased during inflammatory conditions such as LDH and its neuroimmunomodulatory role in the dorsal root of the spinal cord [185, 187204]. The other factor is glial cell–derived neurotrophic factor (GDNF). It has been shown that GDNF reduces neuropathic pain states [188, 190, 205208]. Interestingly, vitamin D affects neuropathic pain by directly suppressing inducible nitric oxide that is expressed in glial cells [96, 136] or by affecting other substances, such as reactive oxygen species or glutamate. Given the immunomodulatory action of vitamin D, it is possible that it could downregulate inflammatory chemokines released by glial cells [96, 185189, 209215]. It has been suggested that vitamin D attenuates ischemia-induced brain injury that is thought to be mediated through upregulation of GDNF, in addition to its role in nitric oxide (NO) suppression [216]. The results of other studies support the hypothesis that GDNF is upregulated by vitamin D [90, 94, 96, 190, 217]. Interleukin 6 (IL-6) and tumor necrosis factor α produced by glial cells were shown to be downregulated by vitamin D [94, 96, 136], as were glial cell release of NO [188, 218, 219], prostaglandin [188], IL-1 and IL-6 [218], which, as described below, could be suppressed by vitamin D administration. Glial cells have glutamate receptors that are important in the process of nociception [220224]. Therefore, vitamin D, through its immunoregulatory properties, affects another important cell population that is inflamed in disc herniation, either through suppressing neurotoxic agents or by its action on neurotrophins.

Some specific inflammatory cytokines and pain mediators that are involved in LDH and vitamin D immunomodulatory effects with regard to these specific substances are described in Table 1.
Table 1

Vitamin D effects on substances involved in lumbar disc herniation

Vitamin D actions [references]

LDH [references]

IFN-γ: D [46, 65, 72, 88, 94, 144]

E [160, 171, 179, 180]

IL-1: D [46, 65, 72]

E [173, 225227]

IL-2: D [46, 65, 72, 88, 92, 94, 139]


IL-4: D [46]

E [179]

IL-5: D [67]


IL-6: D [32, 46, 72, 92, 94, 136, 141]

E [165, 176, 181, 228230]


E [164, 225, 231]

IL-10: U [32, 47, 67, 74, 90, 94, 96, 144, 226, 227]


IL-12: D [22, 32, 67, 139, 140]

E [181, 182]

IL-17: D [47, 90]

E [181]

MCP: I [129]

E [164, 175]

MMP: I [232240]

E [176, 190, 228, 241243]

ROS: I [98, 101, 102, 106, 238]

E [244]

NO: I [245]

E [126, 148, 176, 190, 228, 246249]

Glutamate: I [101, 147]

E [220, 221]

Glutathione: I [96, 106, 148]


PG: I [250]

E [176, 190, 228, 243, 251, 252]

D, Downregulation; E, Expression; I, Inhibition; IFN-γ, Interferon γ; IL, Interleukin; LDH, Lumbar disc herniation; MCP, Monocyte chemoattractant protein; MMP, Matrix metalloproteinase; NO, Nitric oxide; PG, Prostaglandin; ROS, Reactive oxygen species; U, Upregulation.

  1. 3.

    Detailed study of inflammatory cytokines and subsequent pain mediators released in LDH has shown that there is a shift toward type 1 T-helper cell activity [164, 177, 181, 182, 228].

  2. 4.

    Vitamin D decreases the number and function of type 1 T-helper cells [47, 48, 67, 90, 253].

  3. 5.

    Muscle changes associated with low back pain have been studied [254258]. Studies have shown how muscles are affected by LDH [259266]. Atrophy of type II muscle fibers [259261, 263] or atrophy of both types I and II muscle fibers [260] and adipocyte enlargement are examples of how muscles are targeted by LDH [264]. Vitamin D deficiency–associated histochemical changes in muscles somehow resemble those seen in LDH-affected muscles with atrophy of type II muscle fibers [267271] and enlarged interfibrillar spaces and fat infiltration and glycogen granules [271274]. Another interesting aspect of vitamin D deficiency is how it promotes skeletal muscle hypersensitivity and sensory hyperinnervation [275]. Vitamin D supplementation was shown to increase the diameter of type II muscle fibers [181, 276]. It also influences transdifferentiation of muscle cells to adipose cells [277]. With regard to the presence of vitamin D receptor in skeletal muscles [151155], its effect on muscle growth and proliferation [278282] and the changes seen in muscles after LDH, we propose that vitamin D supplementation also influences muscle changes in this condition.



Design of the study

We will conduct a randomized, placebo-controlled, double-blind clinical trial.

Statement of ethical approval

This study was approved by the local research ethics committee of Shiraz University of Medical Sciences, Shiraz, Iran (CT-P-92-6632).

Informed consent

Informed consent will be obtained from all participants.


We will recruit patients who have appointments at the neurosurgery outpatient departments of the university-affiliated hospitals of Shiraz, Iran.


We will recruit 380 patients with LDH proven by physical examination and confirmed by magnetic resonance imaging.


Patients in the intervention arm will receive single-dose intramuscular injections of 300,000 IU of vitamin D3 (1 ml). Individuals will be informed about the nature of this study.

Inclusion criteria

The following are the inclusion criteria:
  1. 1.

    Single-level LDH

  2. 2.

    No coexistent or preexisting spine pathology (for example, spondylolysis, spondylolisthesis, infection, tumors, fracture)

  3. 3.

    Discogenic pain duration less than 8 weeks from onset to physician’s evaluation

  4. 4.

    Compliance with the study protocol

  5. 5.

    Normal laboratory studies that do not contraindicate vitamin D3 injection


Exclusion criteria

The following are the exclusion criteria:
  1. 1.

    Daily supplementation of more than 800 IU of vitamin D3

  2. 2.

    Serum calcium level above 10.5 mg/dl

  3. 3.

    Hypercalciuria (spot urine calcium/creatinine ratio above 0.4)

  4. 4.

    Lymphoma, sarcoidosis, tuberculosis (TB), hyperparathyroidism, celiac disease or malabsorption syndromes

  5. 5.

    History of kidney stones

  6. 6.

    History of inflammatory back pain

  7. 7.

    Impaired renal function tests (glomerular filtration rate less than 30 ml/min/1.73 m2)

  8. 8.

    Impaired hepatic function tests

  9. 9.

    Abnormal serum phosphorus, alkaline phosphatase and parathyroid hormone values

  10. 10.

    Fasting blood sugar above 126 mg/dl

  11. 11.

    Previous spine surgery

  12. 12.

    History of trauma

  13. 13.

    Taking anticonvulsant, anti-TB medications or vitamin D3 analogues

  14. 14.

    Cauda equine syndrome that requires emergency surgical decompression


Laboratory Assessments

The following laboratory workups will be performed for all included participants: serum 25-hydroxy vitamin D3 level, serum calcium, serum phosphorus, alkaline phosphatase, parathyroid hormone, liver function tests (bilirubin (direct and total), alanine transaminase, aspartate transaminase, total protein, total albumin), blood urea nitrogen, creatinine, spot urine for calcium and fasting blood sugar. Clinic-based pre-intervention interviews and physical examinations will include the following:
  1. 1.

    McGill Pain Questionnaire: The McGill Pain Questionnaire is used to evaluate different pain qualities and intensities. This questionnaire consists of four major descriptors: sensory, affective, evaluative and miscellaneous. Each descriptor has its own rank value. The sum of these rank values is the pain rating index. Present pain intensity is measured on scale from 0 to 5 [281].

  2. 2.

    Visual analogue scale (VAS) to evaluate low back pain and radicular pain: A VAS is a pain measurement scale that incorporates numbers and faces to depict the severity of pain. It is usually a 100-mm line. Its ends show the pain extremes [229, 282].

  3. 3.

    A physical examination to detect any sensory deficits.



Patients will be categorized on the basis of their serum 25-hydroxy vitamin D3 levels into three groups:

  •  Group 1: Optimum 25-hydroxy vitamin D3 level (32 to 50 ng/ml)

  •  Group 2: Deficient 25-hydroxy vitamin D3 level (less than 10 ng/ml)

  •  Group 3: Insufficient 25-hydroxy vitamin D3 level (less than 32 ng/ml)

Each of the groups will be randomized, based on randomly computer-generated numbers, into two groups to receive intramuscular injection of either 300,000 IU of vitamin D3 (1 ml) or distilled water (1 ml). All patients will be prescribed daily 15 mg Meloxicam capsules. Our study population will be warned verbally and in writing about the potential for severe adverse side effects of vitamin D3 (nausea, vomiting, abdominal pain, metallic taste, breathing difficulties). They will have access to emergency department care should side effects occur.

The study will last 15 days. After vitamin D3 injection, patients will be contacted by telephone every 3 days to assess the sensory and pain effects of vitamin D3 with the McGill Pain Questionnaire and the VAS (a total of five times). Participants will be provided with the VAS so that they can look at the scale and report their pain severity during the telephone interviews.

The following are the final post-treatment evaluations that will be carried out at the clinic:
  1. 1.

    McGill Pain Questionnaire

  2. 2.

    VAS (for low back pain and radicular pain)

  3. 3.

    Physical examination to detect any sensory deficits


Post-treatment 25-hydroxy vitamin D3 levels (after 15 days) will be measured for those participants who have received vitamin D3 (N = 190).

Statistical analysis

Data will be assessed by analysis of variance and paired tests.


On the basis of the inflammatory nature of disc herniation and the immunomodulatory effects of vitamin D, as well as the existence of vitamin D receptors in various parts of areas that are affected in the process of disc herniation, we propose a novel role for vitamin D in the treatment of discogenic pain and sensory deficits related to this pathology. We hypothesized that vitamin D3 plays a role in reducing the severity of discogenic pain and that vitamin D3 can improve discogenic-related sensory deficits.

The following are our general objectives in this trial:
  1. 1.

    Effect of vitamin D3 on discogenic pain

  2. 2.

    Effect of vitamin D3 on discogenic sensory deficits

  3. 3.

    Effect of posttreatment 25-hydroxy vitamin D3 level on pain and sensory deficit severity

  4. 4.

    Determining a cut-off level of 25-hydroxy vitamin D3 that is efficient in improving pain and sensory deficits

The following are our applicative objectives:
  1. 1.

    Proposing vitamin D3 as part of medical treatment for LDH

  2. 2.

    Improving LDH patients’ quality of life

  3. 3.

    Decreasing the economic and health burden of LDH


Our ultimate goal in this study is to introduce a new treatment strategy for the treatment of discogenic pain.

Trial status

The study protocol has been approved by the Vice-Chancellor for Research of Shiraz University for Medical Sciences. Recruitment has not been initiated.



Alanine transaminase


Aspartate transaminase










Interferon γ


Lumbar disc herniation


Monocyte chemoattractant protein


Matrix metalloproteinase


Nitric oxide




Reactive oxygen species





We appreciate Mohsen Akbarpour of Shiraz University of Medical Sciences for his contribution to the study statistical design and analysis. This study currently has no funding, but we are in the process of applying for grants.

Authors’ Affiliations

Department of Neurosurgery, Shiraz Medical School, Shiraz University of Medical Sciences, PO Box 71345-1536, Shiraz, Iran
Department of Neurosurgery, Shiraz Medical School, Shiraz University of Medical Sciences, PO Box 71345-1536, Shiraz, Iran


  1. Smeal WL, Tyburski M, Alleva J: Discogenic/radicular pain. Dis Mon. 2004, 50: 636-669.PubMedGoogle Scholar
  2. Valat J-P, Genevay S, Marty M, Rozenberg S, Koes B: Sciatica. Best Pract Res Clin Rheumatol. 2010, 24: 241-252.PubMedGoogle Scholar
  3. Legrand E, Bouvard B, Audran M, Fournier D, Valat JP: Sciatica from disk herniation: Medical treatment or surgery?. Joint Bone Spine. 2007, 74: 530-535.PubMedGoogle Scholar
  4. Stafford MA, Peng P, Hill DA: Sciatica: a review of history, epidemiology, pathogenesis, and the role of epidural steroid injection in management. Br J Anaesth. 2007, 99: 461-473.PubMedGoogle Scholar
  5. Van Boxem K, Cheng J, Patijn J, Van Kleef M, Lataster A, Mekhail N, Van Zundert J: 11. Lumbosacral radicular pain. Pain Pract. 2010, 10: 339-358.PubMedGoogle Scholar
  6. Koes BW, Van Tulder MW, Peul WC: Diagnosis and treatment of sciatica. BMJ. 2007, 334: 1313-1317.PubMedPubMed CentralGoogle Scholar
  7. Tarulli AW, Raynor EM: Lumbosacral radiculopathy. Neurol Clin. 2007, 25: 387-405.PubMedGoogle Scholar
  8. Pinto RZ, Maher CG, Ferreira ML, Ferreira PH, Hancock M, Oliveira VC, McLachlan AJ, Koes B: Drugs for relief of pain in patients with sciatica: systematic review and meta-analysis. BMJ. 2012, 344:Google Scholar
  9. Ito T, Takano Y, Yuasa N: Types of lumbar herniated disc and clinical course. Spine. 2001, 26: 648-651.PubMedGoogle Scholar
  10. Green LN: Dexamethasone in the management of symptoms due to herniated lumbar disc. J Neurol Neurosurg Psychiatry. 1975, 38: 1211-1217.PubMedPubMed CentralGoogle Scholar
  11. Chou R: Treating sciatica in the face of poor evidence. BMJ-British Med J. 2012, 344: 12.Google Scholar
  12. Levin KH: Nonsurgical interventions for spine pain. Neurol Clin. 2007, 25: 495-505.PubMedGoogle Scholar
  13. Kasimcan O, Kaptan H: Efficacy of gabapentin for radiculopathy caused by lumbar spinal stenosis and lumbar disk hernia. Neurol Med Chir. 2010, 50: 1070-1073.Google Scholar
  14. Eisenberg E, Damunni G, Hoffer E, Baum Y, Krivoy N: Lamotrigine for intractable sciatica: correlation between dose, plasma concentration and analgesia. Eur J Pain. 2003, 7: 485-491.PubMedGoogle Scholar
  15. Zaremba PD, Bialek M, Blaszczyk B, Cioczek P, Czuczwar Sa J: Non-epilepsy uses of antiepileptic drugs. Pharmacol Rep. 2006, 58: 1-12.PubMedGoogle Scholar
  16. Saldaña MT, Navarro A, Pérez C, Masramón X, Rejas J: Patient-reported-outcomes in subjects with painful lumbar or cervical radiculopathy treated with pregabalin: evidence from medical practice in primary care settings. Rheumatol Int. 2010, 30: 1005-1015.PubMedGoogle Scholar
  17. Leo RJ: Treatment considerations in neuropathic pain. Curr Treat Options Neurol. 2006, 8: 389-400.PubMedGoogle Scholar
  18. Holick MF: Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. Am J Clin Nutr. 2004, 79: 362-371.PubMedGoogle Scholar
  19. Holick MF: The vitamin D epidemic and its health consequences. J Nutr. 2005, 135: 2739S-2748S.PubMedGoogle Scholar
  20. Pittas AG, Lau J, Hu FB, Dawson-Hughes B: The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis. J Clin Endocrinol Metab. 2007, 92: 2017-2029.PubMedPubMed CentralGoogle Scholar
  21. Mathieu C, Badenhoop K: Vitamin D and type 1 diabetes mellitus: state of the art. Trends Endocrinol Metab. 2005, 16: 261-266.PubMedGoogle Scholar
  22. Arnson Y, Amital H, Shoenfeld Y: Vitamin D and autoimmunity: new aetiological and therapeutic considerations. Ann Rheum Dis. 2007, 66: 1137-1142.PubMedPubMed CentralGoogle Scholar
  23. Kamen DL, Tangpricha V: Vitamin D and molecular actions on the immune system: modulation of innate and autoimmunity. J Mol Med (Berl). 2010, 88: 441-450.Google Scholar
  24. Forman JP, Giovannucci E, Holmes MD, Bischoff-Ferrari HA, Tworoger SS, Willett WC, Curhan GC: Plasma 25-hydroxyvitamin D levels and risk of incident hypertension. Hypertension. 2007, 49: 1063-1069.PubMedGoogle Scholar
  25. Li YC, Qiao G, Uskokovic M, Xiang W, Zheng W, Kong J: Vitamin D: a negative endocrine regulator of the renin–angiotensin system and blood pressure. J Steroid Biochem Mol Biol. 2004, 89: 387-392.PubMedGoogle Scholar
  26. Dror Y, Giveon SM, Hoshen M, Feldhamer I, Balicer RD, Feldman BS: Vitamin D levels for preventing acute coronary syndrome and mortality: evidence of a nonlinear association. J Clin Endocrinol Metab. 2013, 98: 2160-2167.PubMedGoogle Scholar
  27. Nemerovski CW, Dorsch MP, Simpson RU, Bone HG, Aaronson KD, Bleske BE: Vitamin D and cardiovascular disease. Pharmacother: J Human Pharmacol Drug Ther. 2009, 29: 691-708.Google Scholar
  28. Wang TJ, Pencina MJ, Booth SL, Jacques PF, Ingelsson E, Lanier K, Benjamin EJ, D’Agostino RB, Wolf M, Vasan RS: Vitamin D deficiency and risk of cardiovascular disease. Circulation. 2008, 117: 503-511.PubMedGoogle Scholar
  29. Lee JH, O'Keefe JH, Bell D, Hensrud DD, Holick MF: Vitamin D DeficiencyAn Important, Common, and Easily Treatable Cardiovascular Risk Factor?. J Am Coll Cardiol. 2008, 52: 1949-1956.PubMedGoogle Scholar
  30. Mahon BD, Gordon SA, Cruz J, Cosman F, Cantorna MT: Cytokine profile in patients with multiple sclerosis following vitamin D supplementation. J Neuroimmunol. 2003, 134: 128-132.PubMedGoogle Scholar
  31. Cantorna MT, Hayes CE, DeLuca HF: 1,25-Dihydroxyvitamin D3 reversibly blocks the progression of relapsing encephalomyelitis, a model of multiple sclerosis. Proc Natl Acad Sci U S A. 1996, 93: 7861-7864.PubMedPubMed CentralGoogle Scholar
  32. Correale J, Ysrraelit MC, Gaitan MI: Immunomodulatory effects of Vitamin D in multiple sclerosis. Brain. 2009, 132: 1146-1160.PubMedGoogle Scholar
  33. Cantorna MT: Vitamin D and its role in immunology: multiple sclerosis, and inflammatory bowel disease. Prog Biophys Mol Biol. 2006, 92: 60-64.PubMedGoogle Scholar
  34. VanAmerongen BM, Dijkstra CD, Lips P, Polman CH: Multiple sclerosis and vitamin D: an update. Eur J Clin Nutr. 2004, 58: 1095-1109.PubMedGoogle Scholar
  35. Cantorna MT, Woodward WD, Hayes CE, DeLuca HF: 1,25-dihydroxyvitamin D3 is a positive regulator for the two anti-encephalitogenic cytokines TGF-beta 1 and IL-4. J Immunol. 1998, 160: 5314-5319.PubMedGoogle Scholar
  36. de Abreu DAF, Eyles D, Feron F: Vitamin D, a neuro-immunomodulator: implications for neurodegenerative and autoimmune diseases. Psychoneuroendocrinology. 2009, 34 (Suppl 1): S265-S277.Google Scholar
  37. Przybelski RJ, Binkley NC: Is vitamin D important for preserving cognition? A positive correlation of serum 25-hydroxyvitamin D concentration with cognitive function. Arch Biochem Biophys. 2007, 460: 202-205.PubMedGoogle Scholar
  38. Buell JS, Dawson-Hughes B: Vitamin D and neurocognitive dysfunction: preventing "D"ecline?. Mol Aspects Med. 2008, 29: 415-422.PubMedPubMed CentralGoogle Scholar
  39. Stewart A, Wong K, Cachat J, Elegante M, Gilder T, Mohnot S, Wu N, Minasyan A, Tuohimaa P, Kalueff AV: Neurosteroid vitamin D system as a nontraditional drug target in neuropsychopharmacology. Behav Pharmacol. 2010, 21: 420-426.PubMedGoogle Scholar
  40. Eyles DW, Burne TH, McGrath JJ: Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Front Neuroendocrinol. 2013, 34: 47-64.PubMedGoogle Scholar
  41. Jorde R, Waterloo K, Saleh F, Haug E, Svartberg J: Neuropsychological function in relation to serum parathyroid hormone and serum 25-hydroxyvitamin D levels. The Tromso study. Neurol Psychiatry. 2006, 253: 464-470.Google Scholar
  42. Hoogendijk WJ, Lips P, Dik MG, Deeg DJ, Beekman AT, Penninx BW: Depression is associated with decreased 25-hydroxyvitamin D and increased parathyroid hormone levels in older adults. Arch Gen Psychiatry. 2008, 65: 508-512.PubMedGoogle Scholar
  43. Anglin RE, Samaan Z, Walter SD, McDonald SD: Vitamin D deficiency and depression in adults: systematic review and meta-analysis. Br J Psychiatry. 2013, 202: 100-107.PubMedGoogle Scholar
  44. Spedding S: Vitamin D and depression: a systematic review and meta-analysis comparing studies with and without biological flaws. Nutrients. 2014, 6: 1501-1518.PubMedPubMed CentralGoogle Scholar
  45. Liu N, Nguyen L, Chun RF, Lagishetty V, Ren S, Wu S, Hollis B, DeLuca HF, Adams JS, Hewison M: Altered endocrine and autocrine metabolism of vitamin D in a mouse model of gastrointestinal inflammation. Endocrinology. 2008, 149: 4799-4808.PubMedPubMed CentralGoogle Scholar
  46. Zhu Y, Mahon BD, Froicu M, Cantorna MT: Calcium and 1α, 25‒dihydroxyvitamin D3 target the TNF‒α pathway to suppress experimental inflammatory bowel disease. Eur J Immunol. 2005, 35: 217-224.PubMedGoogle Scholar
  47. Guillot X, Semerano L, Saidenberg-Kermanac'h N, Falgarone G, Boissier MC: Vitamin D and inflammation. Joint Bone Spine. 2010, 77: 552-557.PubMedGoogle Scholar
  48. Cantorna MT, Mahon BD: Mounting evidence for vitamin D as an environmental factor affecting autoimmune disease prevalence. Exp Biol Med (Maywood). 2004, 229: 1136-1142.Google Scholar
  49. Cantorna MT, Zhu Y, Froicu M, Wittke A: Vitamin D status, 1, 25-dihydroxyvitamin D3, and the immune system. Am J Clin Nutr. 2004, 80: 1717S-1720S.PubMedGoogle Scholar
  50. Kragballe K: Treatment of psoriasis with calcipotriol and other vitamin D analogues. J Am Acad Dermatol. 1992, 27: 1001-1008.PubMedGoogle Scholar
  51. Holick MF: Vitamin D: A millenium perspective. J Cell Biochem. 2003, 88: 296-307.PubMedGoogle Scholar
  52. Holick MF: Vitamin D deficiency. N Engl J Med. 2007, 357: 266-281.PubMedGoogle Scholar
  53. Atwa MA, Balata MG, Hussein AM, Abdelrahman NI, Elminshawy HH: Serum 25-hydroxyvitamin D concentration in patients with psoriasis and rheumatoid arthritis and its association with disease activity and serum tumor necrosis factor-alpha. Saudi Med J. 2013, 34: 806-813.PubMedGoogle Scholar
  54. Reichrath J: Vitamin D and the skin: an ancient friend, revisited. Exp Dermatol. 2007, 16: 618-625.PubMedGoogle Scholar
  55. Benson AA, Toh JA, Vernon N, Jariwala SP: The role of vitamin D in the immunopathogenesis of allergic skin diseases. Allergy. 2012, 67: 296-301.PubMedGoogle Scholar
  56. Samochocki Z, Bogaczewicz J, Jeziorkowska R, Sysa-Jedrzejowska A, Glinska O, Karczmarewicz E, McCauliffe DP, Wozniacka A: Vitamin D effects in atopic dermatitis. J Am Acad Dermatol. 2013, 69: 238-244.PubMedGoogle Scholar
  57. Searing DA, Leung DYM: Vitamin D in atopic dermatitis, asthma and allergic diseases. Immunol Allergy Clin N Am. 2010, 30: 397.Google Scholar
  58. Adorini L: Intervention in autoimmunity: the potential of vitamin D receptor agonists. Cell Immunol. 2005, 233: 115-124.PubMedGoogle Scholar
  59. Cutolo M, Otsa K, Uprus M, Paolino S, Seriolo B: Vitamin D in rheumatoid arthritis. Autoimmun Rev. 2007, 7: 59-64.PubMedGoogle Scholar
  60. Pelajo CF, Lopez-Benitez JM, Miller LC: Vitamin D and autoimmune rheumatologic disorders. Autoimmun Rev. 2010, 9: 507-510.PubMedGoogle Scholar
  61. Adorini L, Penna G: Control of autoimmune diseases by the vitamin D endocrine system. Nat Clin Pract Rheumatol. 2008, 4: 404-412.PubMedGoogle Scholar
  62. Kamen DL, Cooper GS, Bouali H, Shaftman SR, Hollis BW, Gilkeson GS: Vitamin D deficiency in systemic lupus erythematosus. Autoimmun Rev. 2006, 5: 114-117.PubMedGoogle Scholar
  63. Kamen DL, Aranow C: The link between vitamin D deficiency and systemic lupus erythematosus. Curr Rheumatol Rep. 2008, 10: 273-280.PubMedGoogle Scholar
  64. Ben-Zvi I, Aranow C, Mackay M, Stanevsky A, Kamen DL, Marinescu LM, Collins CE, Gilkeson GS, Diamond B, Hardin JA: The impact of vitamin D on dendritic cell function in patients with systemic lupus erythematosus. PLoS One. 2010, 5: e9193.PubMedPubMed CentralGoogle Scholar
  65. Cutolo M, Otsa K: Review: vitamin D, immunity and lupus. Lupus. 2008, 17: 6-10.PubMedGoogle Scholar
  66. Ruiz-Irastorza G, Egurbide MV, Olivares N, Martinez-Berriotxoa A, Aguirre C: Vitamin D deficiency in systemic lupus erythematosus: prevalence, predictors and clinical consequences. Rheumatology (Oxford, England). 2008, 47: 920-923.Google Scholar
  67. Szodoray P, Nakken B, Gaal J, Jonsson R, Szegedi A, Zold E, Szegedi G, Brun JG, Gesztelyi R, Zeher M, Bodolay E: The complex role of vitamin D in autoimmune diseases. Scand J Immunol. 2008, 68: 261-269.PubMedGoogle Scholar
  68. Deluca HF, Cantorna MT: Vitamin D: its role and uses in immunology. FASEB J. 2001, 15: 2579-2585.PubMedGoogle Scholar
  69. DeLuca HF: Overview of general physiologic features and functions of vitamin D. Am J Clin Nutr. 2004, 80: 1689S-1696S.PubMedGoogle Scholar
  70. Hayes CE, Nashold FE, Spach KM, Pedersen LB: The immunological functions of the vitamin D endocrine system. Cell Mol Biol. 2003, 49: 277-300.PubMedGoogle Scholar
  71. Holick MF, Chen TC: Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr. 2008, 87: 1080S-1086S.PubMedGoogle Scholar
  72. Nagpal S, Na S, Rathnachalam R: Noncalcemic actions of vitamin D receptor ligands. Endocr Rev. 2005, 26: 662-687.PubMedGoogle Scholar
  73. Krishnan AV, Feldman D: Mechanisms of the anti-cancer and anti-inflammatory actions of vitamin D. Annu Rev Pharmacol Toxicol. 2011, 51: 311-336.PubMedGoogle Scholar
  74. Bartley J: Post herpetic neuralgia, schwann cell activation and vitamin D. Med Hypotheses. 2009, 73: 927-929.PubMedGoogle Scholar
  75. Singman EL, Poon D, Jun AS: Putative Corneal Neuralgia Responding to Vitamin D Supplementation. Case Rep Ophthalmol. 2013, 4: 105-108.PubMedPubMed CentralGoogle Scholar
  76. Hughes DA, Norton R: Vitamin D and respiratory health. Clin Exp Immunol. 2009, 158: 20-25.PubMedPubMed CentralGoogle Scholar
  77. Rance K: The emerging role of Vitamin D in asthma management. J Am Assoc Nurse Pract. 2014, 26: 263-267.PubMedGoogle Scholar
  78. Adams JS, Hewison M: Unexpected actions of vitamin D: new perspectives on the regulation of innate and adaptive immunity. Nat Clin Pract Endocrinol Metab. 2008, 4: 80-90.PubMedPubMed CentralGoogle Scholar
  79. Hewison M: Vitamin D and the immune system: new perspectives on an old theme. Endocrinol Metab Clin North Am. 2010, 39: 365-379.PubMedPubMed CentralGoogle Scholar
  80. Haugen M, Brantsaeter AL, Trogstad L, Alexander J, Roth C, Magnus P, Meltzer HM: Vitamin D supplementation and reduced risk of preeclampsia in nulliparous women. Epidemiology (Cambridge, Mass). 2009, 20: 720-726.Google Scholar
  81. Shand AW, Nassar N, Von Dadelszen P, Innis SM, Green TJ: Maternal vitamin D status in pregnancy and adverse pregnancy outcomes in a group at high risk for pre-eclampsia. BJOG. 2010, 117: 1593-1598.PubMedGoogle Scholar
  82. Robinson CJ, Alanis MC, Wagner CL, Hollis BW, Johnson DD: Plasma 25-hydroxyvitamin D levels in early-onset severe preeclampsia. Am J Obstet Gynecol. 2010, 203: 366-e361-366PubMedPubMed CentralGoogle Scholar
  83. Pérez-López FR: Vitamin D: The secosteroid hormone and human reproduction. Gynecol Endocrinol. 2007, 23: 13-24.PubMedGoogle Scholar
  84. Grundmann M, von Versen-Hoynck F: Vitamin D - roles in women's reproductive health?. Reprod Biol Endocrinol. 2011, 9: 146.PubMedPubMed CentralGoogle Scholar
  85. Luk J, Torrealday S, Neal Perry G, Pal L: Relevance of vitamin D in reproduction. Hum Reprod. 2012, 27: 3015-3027.PubMedPubMed CentralGoogle Scholar
  86. Thys-Jacobs S: Vitamin D and calcium in menstrual migraine. Headache. 1994, 34: 544-546.PubMedGoogle Scholar
  87. Al Faraj S, Al Mutairi K: Vitamin D deficiency and chronic low back pain in Saudi Arabia. Spine. 2003, 28: 177-179.PubMedGoogle Scholar
  88. Lotfi A, Abdel-Nasser AM, Hamdy A, Omran AA, El-Rehany MA: Hypovitaminosis D in female patients with chronic low back pain. Clin Rheumatol. 2007, 26: 1895-1901.PubMedGoogle Scholar
  89. Jesus CA, Feder D, Peres MF: The role of vitamin D in pathophysiology and treatment of fibromyalgia. Curr Pain Headache Rep. 2013, 17: 355.PubMedGoogle Scholar
  90. Turner MK, Hooten WM, Schmidt JE, Kerkvliet JL, Townsend CO, Bruce BK: Prevalence and clinical correlates of vitamin D inadequacy among patients with chronic pain. Pain Med. 2008, 9: 979-984.PubMedGoogle Scholar
  91. Soderstrom LH, Johnson SP, Diaz VA, Mainous AG: Association between vitamin D and diabetic neuropathy in a nationally representative sample: results from 2001-2004 NHANES. Diabet Med. 2012, 29: 50-55.PubMedPubMed CentralGoogle Scholar
  92. Bell DS: Reversal of the Symptoms of Diabetic Neuropathy through Correction of Vitamin D Deficiency in a Type 1 Diabetic Patient. Case Rep Endocrinol. 2012, 2012: 165056.PubMedPubMed CentralGoogle Scholar
  93. Lee P, Chen R: Vitamin D as an analgesic for patients with type 2 diabetes and neuropathic pain. Arch Intern Med. 2008, 168: 771-772.PubMedGoogle Scholar
  94. Kalueff AV, Minasyan A, Keisala T, Kuuslahti M, Miettinen S, Tuohimaa P: The vitamin D neuroendocrine system as a target for novel neurotropic drugs. CNS Neurol Disord Drug Targets. 2006, 5: 363-371.PubMedGoogle Scholar
  95. Eyles DW, Smith S, Kinobe R, Hewison M, McGrath JJ: Distribution of the vitamin D receptor and 1 alpha-hydroxylase in human brain. J Chem Neuroanat. 2005, 29: 21-30.PubMedGoogle Scholar
  96. Garcion E, Wion-Barbot N, Montero-Menei CN, Berger F, Wion D: New clues about vitamin D functions in the nervous system. Trends Endocrinol Metab. 2002, 13: 100-105.PubMedGoogle Scholar
  97. Malcok U, Sengul G, Kadioglu H, Aydin I: Therapeutic Effect of Vitamin D3 in a Rat Diffuse Axonal Injury Model. J Int Med Res. 2005, 33: 90-95.PubMedGoogle Scholar
  98. Wang JY, Wu JN, Cherng TL, Hoffer BJ, Chen HH, Borlongan CV, Wang Y: Vitamin D(3) attenuates 6-hydroxydopamine-induced neurotoxicity in rats. Brain Res. 2001, 904: 67-75.PubMedGoogle Scholar
  99. Chen KB, Lin AM, Chiu TH: Systemic vitamin D3 attenuated oxidative injuries in the locus coeruleus of rat brain. Ann N Y Acad Sci. 2003, 993: 313-324. discussion 345-319PubMedGoogle Scholar
  100. Cass WA, Smith MP, Peters LE: Calcitriol protects against the dopamine- and serotonin-depleting effects of neurotoxic doses of methamphetamine. Ann N Y Acad Sci. 2006, 1074: 261-271.PubMedGoogle Scholar
  101. Ibi M, Sawada H, Nakanishi M, Kume T, Katsuki H, Kaneko S, Shimohama S, Akaike A: Protective effects of 1α, 25-(OH) < sub > 2</sub > D < sub > 3</sub > against the neurotoxicity of glutamate and reactive oxygen species in mesencephalic culture. Neuropharmacology. 2001, 40: 761-771.PubMedGoogle Scholar
  102. Kalueff AV, Eremin KO, Tuohimaa P: Mechanisms of neuroprotective action of vitamin D(3). Biochemistry (Mosc). 2004, 69: 738-741.Google Scholar
  103. Garcion E, Sindji L, Leblondel G, Brachet P, Darcy F: 1,25-dihydroxyvitamin D3 regulates the synthesis of gamma-glutamyl transpeptidase and glutathione levels in rat primary astrocytes. J Neurochem. 1999, 73: 859-866.PubMedGoogle Scholar
  104. Eyles DW, Feron F, Cui X, Kesby JP, Harms LH, Ko P, McGrath JJ, Burne TH: Developmental vitamin D deficiency causes abnormal brain development. Psychoneuroendocrinology. 2009, 34 (Suppl 1): S247-S257.PubMedGoogle Scholar
  105. Brewer LD, Thibault V, Chen KC, Langub MC, Landfield PW, Porter NM: Vitamin D hormone confers neuroprotection in parallel with downregulation of L-type calcium channel expression in hippocampal neurons. J Neurosci. 2001, 21: 98-108.PubMedGoogle Scholar
  106. Kiraly SJ, Kiraly MA, Hawe RD, Makhani N: Vitamin D as a neuroactive substance: review. ScientificWorldJournal. 2006, 6: 125-139.PubMedGoogle Scholar
  107. Cekic M, Sayeed I, Stein DG: Combination treatment with progesterone and vitamin D hormone may be more effective than monotherapy for nervous system injury and disease. Front Neuroendocrinol. 2009, 30: 158-172.PubMedPubMed CentralGoogle Scholar
  108. Harms LR, Burne TH, Eyles DW, McGrath JJ: Vitamin D and the brain. Best Pract Res Clin Endocrinol Metab. 2011, 25: 657-669.PubMedGoogle Scholar
  109. Brown J, Bianco JI, McGrath JJ, Eyles DW: 1,25-Dihydroxyvitamin D3 induces nerve growth factor, promotes neurite outgrowth and inhibits mitosis in embryonic rat hippocampal neurons. Neurosci Lett. 2003, 343: 139-143.PubMedGoogle Scholar
  110. Eyles D, Brown J, Mackay-Sim A, McGrath J, Feron F: Vitamin d3 and brain development. Neuroscience. 2003, 118: 641-653.PubMedGoogle Scholar
  111. Musiol IM, Stumpf WE, Bidmon HJ, Heiss C, Mayerhofer A, Bartke A: Vitamin D nuclear binding to neurons of the septal, substriatal and amygdaloid area in the Siberian hamster (Phodopus sungorus) brain. Neuroscience. 1992, 48: 841-848.PubMedGoogle Scholar
  112. Prufer K, Veenstra TD, Jirikowski GF, Kumar R: Distribution of 1,25-dihydroxyvitamin D3 receptor immunoreactivity in the rat brain and spinal cord. J Chem Neuroanat. 1999, 16: 135-145.PubMedGoogle Scholar
  113. Smolders J, Moen SM, Damoiseaux J, Huitinga I, Holmoy T: Vitamin D in the healthy and inflamed central nervous system: access and function. J Neurol Sci. 2011, 311: 37-43.PubMedGoogle Scholar
  114. Stumpf WE, O'Brien LP: 1,25 (OH)2 vitamin D3 sites of action in the brain. An autoradiographic study. Histochemistry. 1987, 87: 393-406.PubMedGoogle Scholar
  115. Tague SE, Smith PG: Vitamin D receptor and enzyme expression in dorsal root ganglia of adult female rats: modulation by ovarian hormones. J Chem Neuroanat. 2011, 41: 1-12.PubMedGoogle Scholar
  116. Haussler MR, Whitfield GK, Haussler CA, Hsieh JC, Thompson PD, Selznick SH, Dominguez CE, Jurutka PW: The nuclear vitamin D receptor: biological and molecular regulatory properties revealed. J Bone Miner Res. 1998, 13: 325-349.PubMedGoogle Scholar
  117. Veenstra TD, Prufer K, Koenigsberger C, Brimijoin SW, Grande JP, Kumar R: 1,25-Dihydroxyvitamin D3 receptors in the central nervous system of the rat embryo. Brain Res. 1998, 804: 193-205.PubMedGoogle Scholar
  118. Stumpf WE, Clark SA, O'Brien LP, Reid FA: 1,25(OH)2 vitamin D3 sites of action in spinal cord and sensory ganglion. Anat Embryol (Berl). 1988, 177: 307-310.Google Scholar
  119. Videman T, Leppavuori J, Kaprio J, Battie MC, Gibbons LE, Peltonen L, Koskenvuo M: Intragenic polymorphisms of the vitamin D receptor gene associated with intervertebral disc degeneration. Spine. 1998, 23: 2477-2485.PubMedGoogle Scholar
  120. Kawaguchi Y, Kanamori M, Ishihara H, Ohmori K, Matsui H, Kimura T: The association of lumbar disc disease with vitamin-D receptor gene polymorphism. J Bone Joint Surg Am. 2002, 84-A: 2022-2028.PubMedGoogle Scholar
  121. Eser B, Cora T, Eser O, Kalkan E, Haktanir A, Erdogan MO, Solak M: Association of the polymorphisms of vitamin D receptor and aggrecan genes with degenerative disc disease. Genet Test Mol Biomarkers. 2010, 14: 313-317.PubMedGoogle Scholar
  122. Yuan H-Y, Tang Y, Liang Y-X, Lei L, Xiao G-B, Wang S, Xia Z-L: Matrix metalloproteinase-3 and vitamin d receptor genetic polymorphisms, and their interactions with occupational exposure in lumbar disc degeneration. J Occup Health. 2010, 52: 23-30.PubMedGoogle Scholar
  123. Cheung KM, Chan D, Karppinen J, Chen Y, Jim JJ, Yip SP, Ott J, Wong KK, Sham P, Luk KD, Cheah KS, Leong JC, Song YQ: Association of the Taq I allele in vitamin D receptor with degenerative disc disease and disc bulge in a Chinese population. Spine. 2006, 31: 1143-1148.PubMedGoogle Scholar
  124. Paesold G, Nerlich AG, Boos N: Biological treatment strategies for disc degeneration: potentials and shortcomings. Eur Spine J. 2007, 16: 447-468.PubMedGoogle Scholar
  125. Shankar H, Scarlett JA, Abram SE: Anatomy and pathophysiology of intervertebral disc disease. Tech Reg Anesthesia Pain Manage. 2009, 13: 67-75.Google Scholar
  126. Anderson DG, Tannoury C: Molecular pathogenic factors in symptomatic disc degeneration. Spine J. 2005, 5: 260S-266S.PubMedGoogle Scholar
  127. Horner HA, Urban JP: Volvo Award Winner in Basic Science Studies: Effect of nutrient supply on the viability of cells from the nucleus pulposus of the intervertebral disc. Spine. 2001, 2001 (26): 2543-2549.Google Scholar
  128. Colombini A, Lanteri P, Lombardi G, Grasso D, Recordati C, Lovi A, Banfi G, Bassani R, Brayda-Bruno M: Metabolic effects of vitamin D active metabolites in monolayer and micromass cultures of nucleus pulposus and annulus fibrosus cells isolated from human intervertebral disc. Int J Biochem Cell Biol. 2012, 44: 1019-1030.PubMedGoogle Scholar
  129. Gruber HE, Hoelscher G, Ingram JA, Chow Y, Loeffler B, Hanley EN: 1,25(OH)2-vitamin D3 inhibits proliferation and decreases production of monocyte chemoattractant protein-1, thrombopoietin, VEGF, and angiogenin by human annulus cells in vitro. Spine. 2008, 33: 755-765.PubMedGoogle Scholar
  130. Griffin MD, Xing N, Kumar R: Vitamin D and its analogs as regulators of immune activation and antigen presentation. Annu Rev Nutr. 2003, 23: 117-145.PubMedGoogle Scholar
  131. van Etten E, Mathieu C: Immunoregulation by 1,25-dihydroxyvitamin D3: basic concepts. J Steroid Biochem Mol Biol. 2005, 97: 93-101.PubMedGoogle Scholar
  132. Bikle DD: Vitamin D: newly discovered actions require reconsideration of physiologic requirements. Trends Endocrinol Metab. 2010, 21: 375-384.PubMedPubMed CentralGoogle Scholar
  133. Hewison M: Antibacterial effects of vitamin D. Nat Rev Endocrinol. 2011, 7: 337-345.PubMedGoogle Scholar
  134. Bikle D: Nonclassic actions of vitamin D. J Clin Endocrinol Metab. 2009, 94: 26-34.PubMedGoogle Scholar
  135. Baeke F, Takiishi T, Korf H, Gysemans C, Mathieu C: Vitamin D: modulator of the immune system. Curr Opin Pharmacol. 2010, 10: 482-496.PubMedGoogle Scholar
  136. Lefebvre d'Hellencourt C, Montero-Menei CN, Bernard R, Couez D: Vitamin D3 inhibits proinflammatory cytokines and nitric oxide production by the EOC13 microglial cell line. J Neurosci Res. 2003, 71: 575-582.PubMedGoogle Scholar
  137. Michel G, Gailis A, Jarzebska-Deussen B, Muschen A, Mirmohammadsadegh A, Ruzicka T: 1,25-(OH)2-vitamin D3 and calcipotriol induce IL-10 receptor gene expression in human epidermal cells. Inflamm Res. 1997, 46: 32-34.PubMedGoogle Scholar
  138. Dickie LJ, Church LD, Coulthard LR, Mathews RJ, Emery P, McDermott MF: Vitamin D3 down-regulates intracellular Toll-like receptor 9 expression and Toll-like receptor 9-induced IL-6 production in human monocytes. Rheumatology (Oxford, England). 2010, 49: 1466-1471.Google Scholar
  139. D'Ambrosio D, Cippitelli M, Cocciolo MG, Mazzeo D, Di Lucia P, Lang R, Sinigaglia F, Panina-Bordignon P: Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3. Involvement of NF-kappaB downregulation in transcriptional repression of the p40 gene. J Clin Invest. 1998, 101: 252-262.PubMedPubMed CentralGoogle Scholar
  140. Griffin MD, Lutz W, Phan VA, Bachman LA, McKean DJ, Kumar R: Dendritic cell modulation by 1alpha,25 dihydroxyvitamin D3 and its analogs: a vitamin D receptor-dependent pathway that promotes a persistent state of immaturity in vitro and in vivo. Proc Natl Acad Sci U S A. 2001, 98: 6800-6805.PubMedPubMed CentralGoogle Scholar
  141. Bemiss CJ, Mahon BD, Henry A, Weaver V, Cantorna MT: Interleukin-2 is one of the targets of 1,25-dihydroxyvitamin D3 in the immune system. Arch Biochem Biophys. 2002, 402: 249-254.PubMedGoogle Scholar
  142. Canning MO, Grotenhuis K, de Wit H, Ruwhof C, Drexhage HA: 1-alpha,25-Dihydroxyvitamin D3 (1,25(OH)(2)D(3)) hampers the maturation of fully active immature dendritic cells from monocytes. Eur J Endocrinol. 2001, 145: 351-357.PubMedGoogle Scholar
  143. Zhang Y, Leung DY, Richers BN, Liu Y, Remigio LK, Riches DW, Goleva E: Vitamin D inhibits monocyte/macrophage proinflammatory cytokine production by targeting MAPK phosphatase-1. J Immunol. 2012, 188: 2127-2135.PubMedPubMed CentralGoogle Scholar
  144. Schleithoff SS, Zittermann A, Tenderich G, Berthold HK, Stehle P, Koerfer R: Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial. Am J Clin Nutr. 2006, 83: 754-759.PubMedGoogle Scholar
  145. Kuo YT, Kuo CH, Lam KP, Chu YT, Wang WL, Huang CH, Hung CH: Effects of vitamin D3 on expression of tumor necrosis factor-alpha and chemokines by monocytes. J Food Sci. 2010, 75: H200-H204.PubMedGoogle Scholar
  146. Cippitelli M, Santoni A: Vitamin D3: a transcriptional modulator of the interferon-gamma gene. Eur J Immunol. 1998, 28: 3017-3030.PubMedGoogle Scholar
  147. Taniura H, Ito M, Sanada N, Kuramoto N, Ohno Y, Nakamichi N, Yoneda Y: Chronic vitamin D3 treatment protects against neurotoxicity by glutamate in association with upregulation of vitamin D receptor mRNA expression in cultured rat cortical neurons. J Neurosci Res. 2006, 83: 1179-1189.PubMedGoogle Scholar
  148. Staud R: Vitamin D: more than just affecting calcium and bone. Curr Rheumatol Rep. 2005, 7: 356-364.PubMedGoogle Scholar
  149. Garcion E, Nataf S, Berod A, Darcy F, Brachet P: 1,25-Dihydroxyvitamin D3 inhibits the expression of inducible nitric oxide synthase in rat central nervous system during experimental allergic encephalomyelitis. Brain Res Mol Brain Res. 1997, 45: 255-267.PubMedGoogle Scholar
  150. Bazzani C, Arletti R, Bertolini A: Pain threshold and morphine activity in vitamin D-deficient rats. Life Sci. 1984, 34: 461-466.PubMedGoogle Scholar
  151. Bischoff HA, Borchers M, Gudat F, Duermueller U, Theiler R, Stahelin HB, Dick W: In situ detection of 1,25-dihydroxyvitamin D3 receptor in human skeletal muscle tissue. Histochem J. 2001, 33: 19-24.PubMedGoogle Scholar
  152. Boland R, Norman A, Ritz E, Hasselbach W: Presence of a 1,25-dihydroxy-vitamin D3 receptor in chick skeletal muscle myoblasts. Biochem Biophys Res Commun. 1985, 128: 305-311.PubMedGoogle Scholar
  153. Costa EM, Blau HM, Feldman D: 1,25-dihydroxyvitamin D3 receptors and hormonal responses in cloned human skeletal muscle cells. Endocrinology. 1986, 119: 2214-2220.PubMedGoogle Scholar
  154. Ceglia L, da Silva MM, Park LK, Morris E, Harris SS, Bischoff-Ferrari HA, Fielding RA, Dawson-Hughes B: Multi-step immunofluorescent analysis of vitamin D receptor loci and myosin heavy chain isoforms in human skeletal muscle. J Mol Histol. 2010, 41: 137-142.PubMedPubMed CentralGoogle Scholar
  155. Garcia LA, Ferrini MG, Norris KC, Artaza JN: 1,25(OH)(2)vitamin D(3) enhances myogenic differentiation by modulating the expression of key angiogenic growth factors and angiogenic inhibitors in C(2)C(12) skeletal muscle cells. J Steroid Biochem Mol Biol. 2013, 133: 1-11.PubMedGoogle Scholar
  156. Montero-Odasso M, Duque G: Vitamin D in the aging musculoskeletal system: an authentic strength preserving hormone. Mol Aspects Med. 2005, 26: 203-219.PubMedGoogle Scholar
  157. Ceglia L, Niramitmahapanya S, da Silva Morais M, Rivas DA, Harris SS, Bischoff-Ferrari H, Fielding RA, Dawson-Hughes B: A randomized study on the effect of vitamin d3 supplementation on skeletal muscle morphology and vitamin d receptor concentration in older women. J Clin Endocrinol Metab. 2013, 98: E1927-E1935.PubMedPubMed CentralGoogle Scholar
  158. Barker T, Henriksen VT, Martins TB, Hill HR, Kjeldsberg CR, Schneider ED, Dixon BM, Weaver LK: Higher serum 25-hydroxyvitamin D concentrations associate with a faster recovery of skeletal muscle strength after muscular injury. Nutrients. 2013, 5: 1253-1275.PubMedPubMed CentralGoogle Scholar
  159. Stockton KA, Mengersen K, Paratz JD, Kandiah D, Bennell KL: Effect of vitamin D supplementation on muscle strength: a systematic review and meta-analysis. Osteoporos Int. 2011, 22: 859-871.PubMedGoogle Scholar
  160. Rand N, Reichert F, Floman Y, Rotshenker S: Murine nucleus pulposus-derived cells secrete interleukins-1-beta, -6, and -10 and granulocyte-macrophage colony-stimulating factor in cell culture. Spine. 1997, 22: 2598-2601. discussion 2602PubMedGoogle Scholar
  161. Omarker K, Myers RR: Pathogenesis of sciatic pain: role of herniated nucleus pulposus and deformation of spinal nerve root and dorsal root ganglion. Pain. 1998, 78: 99-105.PubMedGoogle Scholar
  162. Mulleman D, Mammou S, Griffoul I, Watier H, Goupille P: Pathophysiology of disk-related sciatica. I.–Evidence supporting a chemical component. Joint Bone Spine. 2006, 73: 151-158.PubMedGoogle Scholar
  163. Xu JT, Xin WJ, Zang Y, Wu CY, Liu XG: The role of tumor necrosis factor-alpha in the neuropathic pain induced by Lumbar 5 ventral root transection in rat. Pain. 2006, 123: 306-321.PubMedGoogle Scholar
  164. Burke JG, Watson RW, McCormack D, Dowling FE, Walsh MG, Fitzpatrick JM: Spontaneous production of monocyte chemoattractant protein-1 and interleukin-8 by the human lumbar intervertebral disc. Spine. 2002, 27: 1402-1407.PubMedGoogle Scholar
  165. Specchia N, Pagnotta A, Toesca A, Greco F: Cytokines and growth factors in the protruded intervertebral disc of the lumbar spine. Eur Spine J. 2002, 11: 145-151.PubMedPubMed CentralGoogle Scholar
  166. Doita M, Kanatani T, Harada T, Mizuno K: Immunohistologic study of the ruptured intervertebral disc of the lumbar spine. Spine. 1996, 21: 235-241.PubMedGoogle Scholar
  167. Grönblad M, Virri J, Tolonen J, Seitsalo S, Kääpä E, Kankare J, Myllynen P, Karaharju EO: A controlled immunohistochemical study of inflammatory cells in disc herniation tissue. Spine. 1994, 19: 2744-2751.PubMedGoogle Scholar
  168. Takahashi H, Suguro T, Okazima Y, Motegi M, Okada Y, Kakiuchi T: Inflammatory cytokines in the herniated disc of the lumbar spine. Spine. 1996, 21: 218-224.PubMedGoogle Scholar
  169. Kobayashi S, Yoshizawa H, Yamada S: Pathology of lumbar nerve root compression Part 1: Intraradicular inflammatory changes induced by mechanical compression. J Orthop Res. 2004, 22: 170-179.PubMedGoogle Scholar
  170. Burke JG, Watson RW, McCormack D, Dowling FE, Walsh MG, Fitzpatrick JM: Intervertebral discs which cause low back pain secrete high levels of proinflammatory mediators. J Bone Joint Surgery British Volume. 2002, 84: 196-201.Google Scholar
  171. Olmarker K, Blomquist J, Stromberg J, Nannmark U, Thomsen P, Rydevik B: Inflammatogenic properties of nucleus pulposus. Spine. 1995, 20: 665-669.PubMedGoogle Scholar
  172. Saal JS: The role of inflammation in lumbar pain. Spine. 1995, 20: 1821-1827.PubMedGoogle Scholar
  173. Cuellar JM, Montesano PX, Carstens E: Role of TNF-alpha in sensitization of nociceptive dorsal horn neurons induced by application of nucleus pulposus to L5 dorsal root ganglion in rats. Pain. 2004, 110: 578-587.PubMedGoogle Scholar
  174. Anzai H, Hamba M, Onda A, Konno S, Kikuchi S: Epidural application of nucleus pulposus enhances nociresponses of rat dorsal horn neurons. Spine. 2002, 27: E50-E55.PubMedGoogle Scholar
  175. Yoshida M, Nakamura T, Sei A, Kikuchi T, Takagi K, Matsukawa A: Intervertebral disc cells produce tumor necrosis factor alpha, interleukin-1beta, and monocyte chemoattractant protein-1 immediately after herniation: an experimental study using a new hernia model. Spine. 2005, 30: 55-61.PubMedGoogle Scholar
  176. Omoigui S: The biochemical origin of pain: the origin of all pain is inflammation and the inflammatory response. Part 2 of 3 - inflammatory profile of pain syndromes. Med Hypotheses. 2007, 69: 1169-1178.PubMedPubMed CentralGoogle Scholar
  177. Murai K, Sakai D, Nakamura Y, Nakai T, Igarashi T, Seo N, Murakami T, Kobayashi E, Mochida J: Primary immune system responders to nucleus pulposus cells: evidence for immune response in disc herniation. Eur Cell Mater. 2010, 19: 13-21.PubMedGoogle Scholar
  178. Rothman SM, Huang Z, Lee KE, Weisshaar CL, Winkelstein BA: Cytokine mRNA expression in painful radiculopathy. J Pain. 2009, 10: 90-99.PubMedGoogle Scholar
  179. Olmarker K, Larsson K: Tumor necrosis factor alpha and nucleus-pulposus-induced nerve root injury. Spine. 1998, 23: 2538-2544.PubMedGoogle Scholar
  180. Onda A, Hamba M, Yabuki S, Kikuchi S: Exogenous tumor necrosis factor-alpha induces abnormal discharges in rat dorsal horn neurons. Spine. 2002, 27: 1618-1624. discussion 1624PubMedGoogle Scholar
  181. Shamji MF, Setton LA, Jarvis W, So S, Chen J, Jing L, Bullock R, Isaacs RE, Brown C, Richardson WJ: Proinflammatory cytokine expression profile in degenerated and herniated human intervertebral disc tissues. Arthritis Rheum. 2010, 62: 1974-1982.PubMedPubMed CentralGoogle Scholar
  182. Park JB, Chang H, Kim YS: The pattern of interleukin-12 and T-helper types 1 and 2 cytokine expression in herniated lumbar disc tissue. Spine. 2002, 27: 2125-2128.PubMedGoogle Scholar
  183. Olmarker K, Rydevik B: Selective inhibition of tumor necrosis factor-alpha prevents nucleus pulposus-induced thrombus formation, intraneural edema, and reduction of nerve conduction velocity: possible implications for future pharmacologic treatment strategies of sciatica. Spine. 2001, 26: 863-869.PubMedGoogle Scholar
  184. Ohtori S, Inoue G, Eguchi Y, Orita S, Takaso M, Ochiai N, Kishida S, Kuniyoshi K, Aoki Y, Nakamura J, Ishikawa T, Arai G, Miyagi M, Kamoda H, Suzuki M, Sakuma Y, Oikawa Y, Kubota G, Inage K, Sainoh T, Toyone T, Yamauchi K, Kotani T, Akazawa T, Minami S, Takahashi K: Tumor necrosis factor-alpha-immunoreactive cells in nucleus pulposus in adolescent patients with lumbar disc herniation. Spine. 2013, 38: 459-462.PubMedGoogle Scholar
  185. De Leo JA, Tawfik VL, LaCroix-Fralish ML: The tetrapartite synapse: path to CNS sensitization and chronic pain. Pain. 2006, 122: 17-21.PubMedGoogle Scholar
  186. Watkins LR, Milligan ED, Maier SF: Spinal cord glia: new players in pain. Pain. 2001, 93: 201-205.PubMedGoogle Scholar
  187. Yajima Y, Narita M, Usui A, Kaneko C, Miyatake M, Narita M, Yamaguchi T, Tamaki H, Wachi H, Seyama Y, Suzuki T: Direct evidence for the involvement of brain-derived neurotrophic factor in the development of a neuropathic pain-like state in mice. J Neurochem. 2005, 93: 584-594.PubMedGoogle Scholar
  188. Moalem G, Tracey DJ: Immune and inflammatory mechanisms in neuropathic pain. Brain Res Rev. 2006, 51: 240-264.PubMedGoogle Scholar
  189. Myers RR, Campana WM, Shubayev VI: The role of neuroinflammation in neuropathic pain: mechanisms and therapeutic targets. Drug Discov Today. 2006, 11: 8-20.PubMedGoogle Scholar
  190. Watkins LR, Maier SF: Beyond neurons: evidence that immune and glial cells contribute to pathological pain states. Physiol Rev. 2002, 82: 981-1011.PubMedGoogle Scholar
  191. Watkins LR, Maier SF: Glia: a novel drug discovery target for clinical pain. Nat Rev Drug Discov. 2003, 2: 973-985.PubMedGoogle Scholar
  192. Thompson SW, Bennett DL, Kerr BJ, Bradbury EJ, McMahon SB: Brain-derived neurotrophic factor is an endogenous modulator of nociceptive responses in the spinal cord. Proc Natl Acad Sci U S A. 1999, 96: 7714-7718.PubMedPubMed CentralGoogle Scholar
  193. Kerr BJ, Bradbury EJ, Bennett DL, Trivedi PM, Dassan P, French J, Shelton DB, McMahon SB, Thompson SW: Brain-derived neurotrophic factor modulates nociceptive sensory inputs and NMDA-evoked responses in the rat spinal cord. J Neurosci. 1999, 19: 5138-5148.PubMedGoogle Scholar
  194. Mannion RJ, Costigan M, Decosterd I, Amaya F, Ma QP, Holstege JC, Ji RR, Acheson A, Lindsay RM, Wilkinson GA, Woolf CJ: Neurotrophins: peripherally and centrally acting modulators of tactile stimulus-induced inflammatory pain hypersensitivity. Proc Natl Acad Sci U S A. 1999, 96: 9385-9390.PubMedPubMed CentralGoogle Scholar
  195. Ha SO, Kim JK, Hong HS, Kim DS, Cho HJ: Expression of brain-derived neurotrophic factor in rat dorsal root ganglia, spinal cord and gracile nuclei in experimental models of neuropathic pain. Neuroscience. 2001, 107: 301-309.PubMedGoogle Scholar
  196. Ohtori S, Takahashi K, Moriya H: Existence of brain-derived neurotrophic factor and vanilloid receptor subtype 1 immunoreactive sensory DRG neurons innervating L5/6 intervertebral discs in rats. J Orthop Sci. 2003, 8: 84-87.PubMedGoogle Scholar
  197. Cho HJ, Kim JK, Zhou XF, Rush RA: Increased brain-derived neurotrophic factor immunoreactivity in rat dorsal root ganglia and spinal cord following peripheral inflammation. Brain Res. 1997, 764: 269-272.PubMedGoogle Scholar
  198. Obata K, Tsujino H, Yamanaka H, Yi D, Fukuoka T, Hashimoto N, Yonenobu K, Yoshikawa H, Noguchi K: Expression of neurotrophic factors in the dorsal root ganglion in a rat model of lumbar disc herniation. Pain. 2002, 99: 121-132.PubMedGoogle Scholar
  199. Costigan M, Woolf CJ: Pain: Molecular mechanisms. J Pain. 2000, 1: 35-44.PubMedGoogle Scholar
  200. Marcol W, Kotulska K, Larysz-Brysz M, Kowalik JL: BDNF contributes to animal model neuropathic pain after peripheral nerve transection. Neurosurg Rev. 2007, 30: 235-243. discussion 243PubMedGoogle Scholar
  201. Fukuoka T, Kondo E, Dai Y, Hashimoto N, Noguchi K: Brain-derived neurotrophic factor increases in the uninjured dorsal root ganglion neurons in selective spinal nerve ligation model. J Neurosci. 2001, 21: 4891-4900.PubMedGoogle Scholar
  202. Gruber HE, Ingram JA, Hoelscher G, Zinchenko N, Norton HJ, Hanley EN: Brain-derived neurotrophic factor and its receptor in the human and the sand rat intervertebral disc. Arthritis Res Ther. 2008, 10: R82.PubMedPubMed CentralGoogle Scholar
  203. Zhou XF, Chie ET, Deng YS, Zhong JH, Xue Q, Rush RA, Xian CJ: Injured primary sensory neurons switch phenotype for brain-derived neurotrophic factor in the rat. Neuroscience. 1999, 92: 841-853.PubMedGoogle Scholar
  204. Onda A, Murata Y, Rydevik B, Larsson K, Kikuchi S, Olmarker K: Immunoreactivity of brain-derived neurotrophic factor in rat dorsal root ganglion and spinal cord dorsal horn following exposure to herniated nucleus pulposus. Neurosci Lett. 2003, 352: 49-52.PubMedGoogle Scholar
  205. Nagano M, Sakai A, Takahashi N, Umino M, Yoshioka K, Suzuki H: Decreased expression of glial cell line-derived neurotrophic factor signaling in rat models of neuropathic pain. Br J Pharmacol. 2003, 140: 1252-1260.PubMedPubMed CentralGoogle Scholar
  206. Boucher TJ, Okuse K, Bennett DL, Munson JB, Wood JN, McMahon SB: Potent analgesic effects of GDNF in neuropathic pain states. Science. 2000, 290: 124-127.PubMedGoogle Scholar
  207. Wang R, Guo W, Ossipov MH, Vanderah TW, Porreca F, Lai J: Glial cell line-derived neurotrophic factor normalizes neurochemical changes in injured dorsal root ganglion neurons and prevents the expression of experimental neuropathic pain. Neuroscience. 2003, 121: 815-824.PubMedGoogle Scholar
  208. Gardell LR, Wang R, Ehrenfels C, Ossipov MH, Rossomando AJ, Miller S, Buckley C, Cai AK, Tse A, Foley SF, Gong B, Walus L, Carmillo P, Worley D, Huang C, Engber T, Pepinsky B, Cate RL, Vanderah TW, Lai J, Sah DW, Porreca F: Multiple actions of systemic artemin in experimental neuropathy. Nat Med. 2003, 9: 1383-1389.PubMedGoogle Scholar
  209. Scholz J, Woolf CJ: The neuropathic pain triad: neurons, immune cells and glia. Nat Neurosci. 2007, 10: 1361-1368.PubMedGoogle Scholar
  210. Costigan M, Scholz J, Woolf CJ: Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci. 2009, 32: 1-32.PubMedPubMed CentralGoogle Scholar
  211. Sommer C, Kress M: Recent findings on how proinflammatory cytokines cause pain: peripheral mechanisms in inflammatory and neuropathic hyperalgesia. Neurosci Lett. 2004, 361: 184-187.PubMedGoogle Scholar
  212. Czeschik JC, Hagenacker T, Schafers M, Busselberg D: TNF-alpha differentially modulates ion channels of nociceptive neurons. Neurosci Lett. 2008, 434: 293-298.PubMedGoogle Scholar
  213. Sacerdote P, Franchi S, Trovato AE, Valsecchi AE, Panerai AE, Colleoni M: Transient early expression of TNF-alpha in sciatic nerve and dorsal root ganglia in a mouse model of painful peripheral neuropathy. Neurosci Lett. 2008, 436: 210-213.PubMedGoogle Scholar
  214. Tsuda M, Inoue K, Salter MW: Neuropathic pain and spinal microglia: a big problem from molecules in "small" glia. Trends Neurosci. 2005, 28: 101-107.PubMedGoogle Scholar
  215. Hanisch UK: Microglia as a source and target of cytokines. Glia. 2002, 40: 140-155.PubMedGoogle Scholar
  216. Wang Y, Chiang YH, Su TP, Hayashi T, Morales M, Hoffer BJ, Lin SZ: Vitamin D(3) attenuates cortical infarction induced by middle cerebral arterial ligation in rats. Neuropharmacology. 2000, 39: 873-880.PubMedGoogle Scholar
  217. Naveilhan P, Neveu I, Wion D, Brachet P: 1,25-Dihydroxyvitamin D3, an inducer of glial cell line-derived neurotrophic factor. Neuroreport. 1996, 7: 2171-2175.PubMedGoogle Scholar
  218. Kawakami M, Matsumoto T, Kuribayashi K, Tamaki T: mRNA expression of interleukins, phospholipase A2, and nitric oxide synthase in the nerve root and dorsal root ganglion induced by autologous nucleus pulposus in the rat. J Orthop Res. 1999, 17: 941-946.PubMedGoogle Scholar
  219. Levy D, Zochodne DW: NO pain: potential roles of nitric oxide in neuropathic pain. Pain Pract. 2004, 4: 11-18.PubMedGoogle Scholar
  220. Harrington JF, Messier AA, Bereiter D, Barnes B, Epstein MH: Herniated lumbar disc material as a source of free glutamate available to affect pain signals through the dorsal root ganglion. Spine. 2000, 25: 929-936.PubMedGoogle Scholar
  221. Harrington JF, Messier AA, Hoffman L, Yu E, Dykhuizen M, Barker K: Physiological and behavioral evidence for focal nociception induced by epidural glutamate infusion in rats. Spine. 2005, 30: 606-612.PubMedGoogle Scholar
  222. Persson JK, Lindh B, Elde R, Robertson B, Rivero-Melian C, Eriksson NP, Hokfelt T, Aldskogius H: The expression of different cytochemical markers in normal and axotomised dorsal root ganglion cells projecting to the nucleus gracilis in the adult rat. Exp Brain Res. 1995, 105: 331-344.PubMedGoogle Scholar
  223. Wilding TJ, Huettner JE: Differential antagonism of alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid-preferring and kainate-preferring receptors by 2,3-benzodiazepines. Mol Pharmacol. 1995, 47: 582-587.PubMedGoogle Scholar
  224. Wong LA, Mayer ML: Differential modulation by cyclothiazide and concanavalin A of desensitization at native alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid- and kainate-preferring glutamate receptors. Mol Pharmacol. 1993, 44: 504-510.PubMedGoogle Scholar
  225. Ahn SH, Cho YW, Ahn MW, Jang SH, Sohn YK, Kim HS: mRNA expression of cytokines and chemokines in herniated lumbar intervertebral discs. Spine. 2002, 27: 911-917.PubMedGoogle Scholar
  226. Xystrakis E, Kusumakar S, Boswell S, Peek E, Urry Z, Richards DF, Adikibi T, Pridgeon C, Dallman M, Loke TK, Robinson DS, Barrat FJ, O'Garra A, Lavender P, Lee TH, Corrigan C, Hawrylowicz CM: Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients. J Clin Invest. 2006, 116: 146-155.PubMedGoogle Scholar
  227. Almerighi C, Sinistro A, Cavazza A, Ciaprini C, Rocchi G, Bergamini A: 1Alpha,25-dihydroxyvitamin D3 inhibits CD40L-induced pro-inflammatory and immunomodulatory activity in human monocytes. Cytokine. 2009, 45: 190-197.PubMedGoogle Scholar
  228. Kang JD, Georgescu HI, McIntyre-Larkin L, Stefanovic-Racic M, Donaldson WF, Evans CH: Herniated lumbar intervertebral discs spontaneously produce matrix metalloproteinases, nitric oxide, interleukin-6, and prostaglandin E2. Spine. 1996, 21: 271-277.PubMedGoogle Scholar
  229. Kang JD, Georgescu HI, McIntyre-Larkin L, Stefanovic-Racic M, Evans CH: Herniated cervical intervertebral discs spontaneously produce matrix metalloproteinases, nitric oxide, interleukin-6, and prostaglandin E2. Spine. 1995, 20: 2373-2378.PubMedGoogle Scholar
  230. Winkelstein BA, Rutkowski MD, Weinstein JN, DeLeo JA: Quantification of neural tissue injury in a rat radiculopathy model: comparison of local deformation, behavioral outcomes, and spinal cytokine mRNA for two surgeons. J Neurosci Methods. 2001, 111: 49-57.PubMedGoogle Scholar
  231. Kim SJ, Park SM, Cho YW, Jung YJ, Lee DG, Jang SH, Park HW, Hwang SJ, Ahn SH: Changes in expression of mRNA for interleukin-8 and effects of interleukin-8 receptor inhibitor in the spinal dorsal horn in a rat model of lumbar disc herniation. Spine. 2011, 36: 2139-2146.PubMedGoogle Scholar
  232. Bahar-Shany K, Ravid A, Koren R: Upregulation of MMP-9 production by TNFalpha in keratinocytes and its attenuation by vitamin D. J Cell Physiol. 2010, 222: 729-737.PubMedGoogle Scholar
  233. Maeda S, Dean DD, Sylvia VL, Boyan BD, Schwartz Z: Metalloproteinase activity in growth plate chondrocyte cultures is regulated by 1,25-(OH)(2)D(3) and 24,25-(OH)(2)D(3) and mediated through protein kinase C. Matrix Biol. 2001, 20: 87-97.PubMedGoogle Scholar
  234. Tetlow LC, Woolley DE: Expression of vitamin D receptors and matrix metalloproteinases in osteoarthritic cartilage and human articular chondrocytes in vitro. Osteoarthritis Cartilage. 2001, 9: 423-431.PubMedGoogle Scholar
  235. Schmitz JP, Schwartz Z, Sylvia VL, Dean DD, Calderon F, Boyan BD: Vitamin D3 regulation of stromelysin-1 (MMP-3) in chondrocyte cultures is mediated by protein kinase C. J Cell Physiol. 1996, 168: 570-579.PubMedGoogle Scholar
  236. Dean DD, Schwartz Z, Schmitz J, Muniz OE, Lu Y, Calderon F, Howell DS, Boyan BD: Vitamin D regulation of metalloproteinase activity in matrix vesicles. Connect Tissue Res. 1996, 35: 331-336.PubMedGoogle Scholar
  237. Boyan BD, Schwartz Z: 1,25-Dihydroxy vitamin D3 is an autocrine regulator of extracellular matrix turnover and growth factor release via ERp60-activated matrix vesicle matrix metalloproteinases. Cells Tissues Organs. 2009, 189: 70-74.PubMedGoogle Scholar
  238. Long K, Nguyen LT: Roles of vitamin D in amyotrophic lateral sclerosis: possible genetic and cellular signaling mechanisms. Mol Brain. 2013, 6: 16.PubMedGoogle Scholar
  239. Halder SK, Osteen KG, Al-Hendy A: Vitamin D3 inhibits expression and activities of matrix metalloproteinase-2 and -9 in human uterine fibroid cells. Hum Reprod. 2013, 28: 2407-2416.PubMedPubMed CentralGoogle Scholar
  240. Finklea JD, Grossmann RE, Tangpricha V: Vitamin D and chronic lung disease: a review of molecular mechanisms and clinical studies. Adv Nutr. 2011, 2: 244-253.PubMedPubMed CentralGoogle Scholar
  241. Kanemoto M, Hukuda S, Komiya Y, Katsuura A, Nishioka J: Immunohistochemical study of matrix metalloproteinase-3 and tissue inhibitor of metalloproteinase-1 human intervertebral discs. Spine. 1996, 21: 1-8.PubMedGoogle Scholar
  242. Bachmeier BE, Nerlich A, Mittermaier N, Weiler C, Lumenta C, Wuertz K, Boos N: Matrix metalloproteinase expression levels suggest distinct enzyme roles during lumbar disc herniation and degeneration. Eur Spine J. 2009, 18: 1573-1586.PubMedPubMed CentralGoogle Scholar
  243. Benoist M: The natural history of lumbar disc herniation and radiculopathy. Joint Bone Spine. 2002, 69: 155-160.PubMedGoogle Scholar
  244. Kim HK, Park SK, Zhou JL, Taglialatela G, Chung K, Coggeshall RE, Chung JM: Reactive oxygen species (ROS) play an important role in a rat model of neuropathic pain. Pain. 2004, 111: 116-124.PubMedGoogle Scholar
  245. Furusawa N, Baba H, Miyoshi N, Maezawa Y, Uchida K, Kokubo Y, Fukuda M: Herniation of cervical intervertebral disc: immunohistochemical examination and measurement of nitric oxide production. Spine. 2001, 26: 1110-1116.PubMedGoogle Scholar
  246. Brisby H, Byrod G, Olmarker K, Miller VM, Aoki Y, Rydevik B: Nitric oxide as a mediator of nucleus pulposus-induced effects on spinal nerve roots. J Orthop Res. 2000, 18: 815-820.PubMedGoogle Scholar
  247. Kawakami M, Tamaki T, Hayashi N, Hashizume H, Nishi H: Possible mechanism of painful radiculopathy in lumbar disc herniation. Clin Orthop Relat Res. 1998, 241-251.Google Scholar
  248. Levy D, Hoke A, Zochodne DW: Local expression of inducible nitric oxide synthase in an animal model of neuropathic pain. Neurosci Lett. 1999, 260: 207-209.PubMedGoogle Scholar
  249. Suzuki A, Tokuda H, Kotoyori J, Ito Y, Oiso Y, Kozawa O: Effect of vitamin D3 on prostaglandin E2 synthesis in osteoblast-like cells. Prostaglandins Leukot Essent Fatty Acids. 1994, 51: 27-31.PubMedGoogle Scholar
  250. Takahashi H: A mechanism for sciatic pain caused by lumbar disc herniation–involvement of inflammatory cytokines with sciatic pain. Nihon Seikeigeka Gakkai Zasshi. 1995, 69: 17-29.PubMedGoogle Scholar
  251. O'Donnell JL, O'Donnell AL: Prostaglandin E2 content in herniated lumbar disc disease. Spine. 1996, 21: 1653-1655. discussion 1655-1656PubMedGoogle Scholar
  252. Muramoto T, Atsuta Y, Iwahara T, Sato M, Takemitsu Y: The action of prostaglandin E2 and triamcinolone acetonide on the firing activity of lumbar nerve roots. Int Orthop. 1997, 21: 172-175.PubMedPubMed CentralGoogle Scholar
  253. Lemire JM, Archer DC: 1,25-dihydroxyvitamin D3 prevents the in vivo induction of murine experimental autoimmune encephalomyelitis. J Clin Invest. 1991, 87: 1103-1107.PubMedPubMed CentralGoogle Scholar
  254. Mannion AF, Kaser L, Weber E, Rhyner A, Dvorak J, Muntener M: Influence of age and duration of symptoms on fibre type distribution and size of the back muscles in chronic low back pain patients. Eur Spine J. 2000, 9: 273-281.PubMedPubMed CentralGoogle Scholar
  255. Demoulin C, Crielaard JM, Vanderthommen M: Spinal muscle evaluation in healthy individuals and low-back-pain patients: a literature review. Joint Bone Spine. 2007, 74: 9-13.PubMedGoogle Scholar
  256. Mannion AF: Fibre type characteristics and function of the human paraspinal muscles: normal values and changes in association with low back pain. J Electromyogr Kinesiol. 1999, 9: 363-377.PubMedGoogle Scholar
  257. Kjaer P, Bendix T, Sorensen JS, Korsholm L, Leboeuf-Yde C: Are MRI-defined fat infiltrations in the multifidus muscles associated with low back pain?. BMC Med. 2007, 5: 2.PubMedPubMed CentralGoogle Scholar
  258. Hides JA, Stokes MJ, Saide M, Jull GA, Cooper DH: Evidence of lumbar multifidus muscle wasting ipsilateral to symptoms in patients with acute/subacute low back pain. Spine. 1994, 19: 165-172.PubMedGoogle Scholar
  259. Zhu XZ, Parnianpour M, Nordin M, Kahanovitz N: Histochemistry and morphology of erector spinae muscle in lumbar disc herniation. Spine. 1989, 14: 391-397.PubMedGoogle Scholar
  260. Yoshihara K, Shirai Y, Nakayama Y, Uesaka S: Histochemical changes in the multifidus muscle in patients with lumbar intervertebral disc herniation. Spine. 2001, 26: 622-626.PubMedGoogle Scholar
  261. Zhao WP, Kawaguchi Y, Matsui H, Kanamori M, Kimura T: Histochemistry and morphology of the multifidus muscle in lumbar disc herniation: comparative study between diseased and normal sides. Spine. 2000, 25: 2191-2199.PubMedGoogle Scholar
  262. Franke J, Hesse T, Tournier C, Schuberth W, Mawrin C, LeHuec JC, Grasshoff H: Morphological changes of the multifidus muscle in patients with symptomatic lumbar disc herniation. J Neurosurg Spine. 2009, 11: 710-714.PubMedGoogle Scholar
  263. Mattila M, Hurme M, Alaranta H, Paljarvi L, Kalimo H, Falck B, Lehto M, Einola S, Jarvinen M: The multifidus muscle in patients with lumbar disc herniation. A histochemical and morphometric analysis of intraoperative biopsies. Spine. 1986, 11: 732-738.PubMedGoogle Scholar
  264. Hodges P, Holm AK, Hansson T, Holm S: Rapid atrophy of the lumbar multifidus follows experimental disc or nerve root injury. Spine. 2006, 31: 2926-2933.PubMedGoogle Scholar
  265. Hyun JK, Lee JY, Lee SJ, Jeon JY: Asymmetric atrophy of multifidus muscle in patients with unilateral lumbosacral radiculopathy. Spine. 2007, 32: E598-E602.PubMedGoogle Scholar
  266. Kader DF, Wardlaw D, Smith FW: Correlation between the MRI changes in the lumbar multifidus muscles and leg pain. Clin Radiol. 2000, 55: 145-149.PubMedGoogle Scholar
  267. Boland R: Role of vitamin D in skeletal muscle function. Endocr Rev. 1986, 7: 434-448.PubMedGoogle Scholar
  268. Floyd M, Ayyar DR, Barwick DD, Hudgson P, Weightman D: Myopathy in chronic renal failure. Q J Med. 1974, 43: 509-524.PubMedGoogle Scholar
  269. Lazaro RP, Kirshner HS: Proximal muscle weakness in uremia. Case reports and review of the literature. Arch Neurol. 1980, 37: 555-558.PubMedGoogle Scholar
  270. Snijder MB, van Schoor NM, Pluijm SM, van Dam RM, Visser M, Lips P: Vitamin D status in relation to one-year risk of recurrent falling in older men and women. J Clin Endocrinol Metab. 2006, 91: 2980-2985.PubMedGoogle Scholar
  271. Ceglia L: Vitamin D and skeletal muscle tissue and function. Mol Aspects Med. 2008, 29: 407-414.PubMedGoogle Scholar
  272. Yoshikawa S, Nakamura T, Tanabe H, Imamura T: Osteomalacic myopathy. Endocrinol Jpn. 1979, 26: 65-72.PubMedGoogle Scholar
  273. Oh JH, Kim SH, Kim JH, Shin YH, Yoon JP, Oh CH: The level of vitamin D in the serum correlates with fatty degeneration of the muscles of the rotator cuff. J Bone Joint Surgery British Volume. 2009, 91: 1587-1593.Google Scholar
  274. Tagliafico AS, Ameri P, Bovio M, Puntoni M, Capaccio E, Murialdo G, Martinoli C: Relationship between fatty degeneration of thigh muscles and vitamin D status in the elderly: a preliminary MRI study. AJR Am J Roentgenol. 2010, 194: 728-734.PubMedGoogle Scholar
  275. Tague SE, Clarke GL, Winter MK, McCarson KE, Wright DE, Smith PG: Vitamin D deficiency promotes skeletal muscle hypersensitivity and sensory hyperinnervation. J Neurosci. 2011, 31: 13728-13738.PubMedPubMed CentralGoogle Scholar
  276. Sorensen OH, Lund B, Saltin B, Lund B, Andersen RB, Hjorth L, Melsen F, Mosekilde L: Myopathy in bone loss of ageing: improvement by treatment with 1 alpha-hydroxycholecalciferol and calcium. Clin Sci (Lond). 1979, 56: 157-161.Google Scholar
  277. Ryan KJ, Daniel ZC, Craggs LJ, Parr T, Brameld JM: Dose-dependent effects of vitamin D on transdifferentiation of skeletal muscle cells to adipose cells. J Endocrinol. 2013, 217: 45-58.PubMedPubMed CentralGoogle Scholar
  278. Wu Z, Woodring PJ, Bhakta KS, Tamura K, Wen F, Feramisco JR, Karin M, Wang JY, Puri PL: p38 and extracellular signal-regulated kinases regulate the myogenic program at multiple steps. Mol Cell Biol. 2000, 20: 3951-3964.PubMedPubMed CentralGoogle Scholar
  279. Widmann C, Gibson S, Jarpe MB, Johnson GL: Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human. Physiol Rev. 1999, 79: 143-180.PubMedGoogle Scholar
  280. Buitrago C, Boland R, de Boland AR: The tyrosine kinase c-Src is required for 1,25(OH)2-vitamin D3 signalling to the nucleus in muscle cells. Biochim Biophys Acta. 2001, 1541: 179-187.PubMedGoogle Scholar
  281. Buitrago CG, Pardo VG, de Boland AR, Boland R: Activation of RAF-1 through Ras and protein kinase Calpha mediates 1alpha,25(OH)2-vitamin D3 regulation of the mitogen-activated protein kinase pathway in muscle cells. J Biol Chem. 2003, 278: 2199-2205.PubMedGoogle Scholar
  282. Buitrago C, Gonzalez Pardo V, de Boland AR: Nongenomic action of 1 alpha,25(OH)(2)-vitamin D3. Activation of muscle cell PLC gamma through the tyrosine kinase c-Src and PtdIns 3-kinase. Eur J Biochem. 2002, 269: 2506-2515.PubMedGoogle Scholar


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