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Vitamin D refers to a group of molecules known as calciferols which are all chemically related and posses antirachitic activity(Zempleni et al., 2014). Two important forms of Vitamin D exist in humans; Vitamin D3 (cholecalciferol) obtained from meats and oils and produced in the skin upon exposure to sunlight and, Vitamin D2 (ergocalciferol) obtained from plant based foods. Both these forms of Vitamin D can be obtained through the diet from foods such as oily fish and foods fortified with vitamin D (either D3 or D2) such as cereals and milk (Combs, 1998). Both vitamin D3 and vitamin D2 are biologically inactive and a series of reactions must be undertaken to produce the biologically active for of vitamin D. As the body is capable of generating vitamin D itself in the skin Vitamin D does not meet the normal definition of a vitamin it is more like a hormone. Vitamin D is also unique in the fact it has a dual source.
Vitamin D is traditionally known for its role in bone maintenance via calcium and phosphate homeostasis within the body. However, further investigation into Vitamin D is revealing other, non-traditional roles of the Vitamin such as fighting infections, muscle function and possible anti-cancer affects (Gilbert et al., 2016).
Phosphorus and calcium are required for many biological processes in the body. Calcium is utilised in muscle contraction, in blood clotting, as an enzyme cofactor and in bone mineralization. Similarly phosphorous is utilized in bones and is also used by cells to store energy in the form of ATP.
Vitamin D works in conjugation with parathyroid hormone to excerpt a positive effect on calcium and phosphate serum levels. Another hormone, calc+++++++++++++itonin has a negative effect on calcium serum levels as it inhibits the production of 1,25(OH)2D (Porth and Matfin, 2008).
When calcium serum levels are low calcium receptors in the parathyroid gland detect this and secretion of parathyroid hormone (PTH) begins. PTH in turn stimulates 1-α-hydroxylase in the kidneys to produce 1,25(OH)2D which increase the absorption of calcium form the intestine and as a result increase serum calcium levels (Organization and Nations, 2004). The Vitamin D Receptor (VDR), which binds vitamin D and enables it to carry out its action in a tissue, is expressed in all parts of the small and large intestine. 1,25(OH)2D is reported to influence calcium entry, calcium binding and basolateral extrusion of calcium and as a result regulates each step of calcium’s transport in the intestine (Veldurthy et al., 2016).
Vitamin D metabolism
Vitamin D is generated in the skin when exposed to sunlight which contains UV.B radiation within the wavelengths of 290-315nm (Bendik et al., 2014). 7-dehydrocholestrol in the basal and stratum spinosum of the epidermis is converted to pre-vitamin D3 when exposed to sunlight of the above criteria. A non-enzymatic thermal isomerisation process then converts the pre-vitamin D3 into Vitamin D3 which is also called cholecalciferol. Vitamin D3 is released into circulation for 3 days after exposure to sunlight (Holick, 1981).
Once Vitamin D3 is in the blood it binds to Vitamin D Binding Protein which transports it in the blood to the liver. In the liver Vitamin D3 is hydorxylated to form 25-hydroxycholecalciferol (25(OH)D), which is a pre-hormone. This reaction is carried out by an enzyme called cholecalciferol 25-hydroxylase which is encoded by the gene CYP2R1 and has been crystallised to study its structure when in complex with vitamin D3 (Strushkevich et al., 2008). Mutations within the CYP2R1 gene have been linked with selective deficiencies in 25-hydroxyvitamin D.
25(OH)D is then transported to the kidneys where it is hydroxylated again, this time at position 1 by the enzyme 1-α-hydroxylase. Activity of this enzyme is stimulated by parathyroid hormone. 1-α-hydroxylase is encoded by the CYP27B1 gene, mutations in this gene have been associated with vitamin D-dependent rickets (Yan et al., 2011). The reaction carried out by 1-α-hydroxylase forms 1,25-dihydroxycholecalciferol (1,25(OH)2D), which is the active form of vitamin D in the body.
Synthesis of 1,25(OH)2D occurs almost exclusively in the kidney however, other tissues posses the 1-α-hydroxylase enzyme and therefore have to ability to produce 1,25-(OH)2D. Examples of these tissues include epithelial cells in the intestine and lungs as well as endocrine glands such as the parathyroid gland (Bikle, 2014).
Vitamin D levels are monitored in the body by measuring the serum 25(OH)D levels. Vitamin D deficiency is defined as a serum 25(OH)D level bellow 20ng/ml (50nmol/L) while Vitamin D insufficiency is defined as a serum 25(OH)D level between 21-29ng/ml (525-725nmol/L) (Holick et al., 2011). A deficiency in vitamin D can lead to improper bone mineralisation, bone weakness and muscle weakness or pain.
Vitamin D deficiency can be prevented using three principle methods; exposure to sunlight, supplementation of vitamin D where necessary and, food fortification. The recommended daily intake of vitamin D based upon age is show in table 1.
|Age group (years)||Recommended daily intake (IU/d)|
Table 1 the recommended daily intake of vitamin D based on age as recommended by the IOM and Endocrine Practice Guidelines Committee. 1IU=25ng (Institute of Medicine Committee to Review Dietary Reference Intakes for Vitamin, 2011).
A common condition caused by vitamin D deficiency is Rickets. Rickets is a disease which occurs in growing children, before epiphyseal closure in the bones. Rickets is caused by inadequate mineralization of bones which can cause the bone to soften. As a result deformities in the bone may arise. Deformations that may occur include bowed legs, bent forearms in crawling infants, frontal bossing of the skull and, Harrison’s sulcus caused by the diaphragm pulling on the softened rib cage (Porth and Matfin, 2008).
Most commonly Rickets results from conditions, such as vitamin D deficiency, which cause low calcium or phosphate serum levels and as a result is referred to as ‘nutritional rickets’. Treatment of nutritional rickets is commonly a daily dose of between 1000-10000IU of either vitamin D3 or vitamin D2 for a period of 8-12 weeks depending upon the age of the child (Shaw, 2016).
As well as nutritional Rickets two rare autosomal recessive disorders can also cause Rickets (Malloy and Feldman, 2010). The first of these disorders is Vitamin D dependent rickets type-1, which is caused by an inactivating mutation in the CYP27B1 gene which impairs or inactivates the 1-α-hydroxylase enzyme. This inborn error of metabolism results in failure to convert 25(OH)D to 1,25(OH)2D. Individuals usually experience muscle weakness, joint pain and growth failure. Treatment with calcitriol is usually effective.
The second of these genetic disorders is Hereditary Vitamin D-resistance Rickets. This disorder results from a mutation in the VDR receptor causing the individual to have a partial or complete resistance to 1,25(OH)2D. Infants with this disorder usually develop severe Rickets within months of being born (Malloy et al., 2011). Treatment with large doses of 1,25(OH)2D has been successful in certain cases however, in others high doses of calcium are required.
In adults rickets does not occur as the epiphyseal closure has already occurred. However, adults can develop osteomalacia, a disorder of bone metabolism which can lead to inadequate mineralization of bones. Osteomalacia can cause softening of the bones similar to rickets however, adults do not develop obvious skeletal deformities. Typical symptoms of osteomalacia include bone pain and tenderness, difficulty walking and muscle weakness (Bhan et al., 2010). As these symptoms are vague and unspecific measures of alkaline phosphatase, 25 (OH) vitamin D 3as well as phosphate in the serum can be used for diagnosis. Diagnosis of osteomalacia can be confirmed with a bone biopsy from the pelvis this isn’t usually necessary but is helpful in unusual cases. Treatment involves supplementation of 5000-10000IU of vitamin D and supplementation of 1000-1500mg of calcium daily (Reuss-Borst, 2014).
Vitamin D has also been recognised in literature for its role in the immune response to infections. Among these infections are Mycobacterium tuberculosis and influenza.
Vitamin D was used prior to the discovery of antibiotics in the treatment of M. tuberculosis. In 1849 Williams observed the effects of fish liver oil on 34 patients with M.tuberculosis and witnessed improvements in the 203 of the 234 individuals within a few days (Williams, 1849). Further studies into vitamin D have found that the metabolite 1,25(OH2)D has antimycobacterial actions. Among these is the ability to bind to nuclear VDR and upregulate the production of antimicrobial agents such as nirtic oxide and cathelicidin (Martineau et al., 2007). It has also been observed that low levels of Vitamin D is usually present in M. tuberculosis patients and decreased vitamin D levels has been associated with an increased risk of developing M. tuberculosis. A meta-analysis concluded that vitamin D is likely a risk factor of M. tuberculosis and not a consequence however, further studies would be required to establish whether or not vitamin D supplementation is beneficial to prevention and treatment (Huang et al., 2017).
Levels of vitamin D in the body are known to vary seasonally with the greatest levels in the summer (July) and the lowest in the winter (February) (Klingberg et al., 2015). This variation has been referred to as a ‘seasonal stimulus’ for infections of the respiratory tract. Studies have found a 7% decrease in risk of developing an infection for every 10nmol/L increase in 25(OH)D (Berry et al., 2011). A randomized control trial carried out on school children found that supplements of vitamin D3 reduced the incidents of influenza to a statistically significant level (Urashima et al., 2010), suggesting that vitamin D supplementation during the winter months may help prevent incidents of influenza.
Both Mycobacterium tuberculosis and influenza highlight vitamin D’s vast role in human health and the vast number of actions vitamin D posses.
Mechanism of Action:
1,25(OH)2D acts on tissues by binding with the VDR which is a typical nuclear receptor. VDR in turn regulates gene expression. VDR activation causes calcium absorption in the kideny, calcium resporption in the intestine and mobilization of calium from the bones.
VDR is expressed in almost every tissue.
1,25(OH)2D binds with VDR causing a conformational change allowing it to interact with retinoid X receptor (RXR). This complex (1,25(OH)2D-VDR-RXR) binds to the VDRE (Vitamin D response element) located on the DNA and as a result regulates gene expression.
Expression of VDR regulated by external factors in a tissue specific manner. Mechanism of tissue specificity still unclear.
VDR experiments carried out in vitro so results are limited.
- Polymorphism of VDR and it’s effectts – mice with defects displayed functional weaknesses.
- Heterodimer formed
- Traditional sites of VDR receptors
Why skeletal mass/ strenght important to human health:
- Uses in human health
- Stucture etc….
- Skeletal muslces responde to a range of hormones
- Skeletal muscle responsible for 85% of whole bodies insulin mediated glucose uptake.
Vit D, skeletal muscle mass/stregnth and human health:
- Cross sectional studies in relation to vit D deficency
- Vit D and falls – vit D suplementation decreases the risk of falls in institutionalised and elderly patients.
- Evdeince shows muscle defect caused by Vit D deficency in part but also in part due to calcium deficency
- Skeletal muscles a store for vit D
- Human health can be linked with the effects on immune response.
- VDRKO mice- how they vary vs. wild type mice in development etc…
- Cyp27b1 null-mice
VDR Expressed in Muscle Cells: (explore after)
Grigis et al. found C2C12 cells expressed VDR mRNA and the mRNA of vitamin D assocaited enzymes; CYP27B1, CYP24A1 and 1 α-hydroxylase. Results from this experiment also showed that expression was induciable and increased 48 hours after treatment with 1,25(OH)2D. Expression of VDR was also seen to decrease significantly during differentiation. Levels of VDR transcript in the muscle of wild type mice was lower than that of typical sites of VDR action such as the duodenum however, this does not rule out an active role as it may be functionally active at low levels in muscle. This study proves that VDR is present in skeletal muscle cells.
The levels of VDR expression varry significatly in whole muscle and in vitro models. As the C2C12 myotubes express higher levels of VDR mRNA than whole muscle cells it suggests that expression is activated after isolation and immortalization. This experient was carried out on murine muscle and not human muscle and as a result has its limitations.
- Antibodies previously used faulty – are these experients valid? Antibodies that should be used.
- Look at recent studies to see if present
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