Vitamin D3, a fat-soluble steroid hormone known as cholecalciferol, is critical for calcium homeostasis and bone metabolism . Vitamin D3 acts by enhancing calcium absorption and mobilizing calcium from bone, thus helping to build and maintain strong bones and teeth. Endogenous vitamin D is not biologically active, and instead must be metabolized within the body into its active form. Due to its hydrophobicity, active vitamin D3 must be transported in the blood using primarily the vitamin D-binding protein (VDP) in order to reach its target cells containing the vitamin D receptor (VDR) . Similar to other steroid hormone receptors, the VDR has a DNA binding domain and hormone-binding domain. In order to bind DNA, the VDR forms a heterodimer with the retinoid X receptor . Through binding of vitamin D3, VDR acts as a transcription factor for gene expression, resulting in a subsequent increase in calcium levels in order to maintain calcium homeostasis .
Calcium homeostasis, or the regulation of the concentration of calcium, is tightly controlled. Under normal circumstances the plasma calcium concentration remains constant, however, in disease states, the calcium concentration can become too high (hypercalcemia) or too low (hypocalcemia). During the 1950’s in Great Britain, an outbreak in hypercalcemia in infants was proposed to be a consequence of the over fortification of milk with vitamin D for the prevention of rickets . Initially, it was thought that nutritional vitamin D intake was responsible for the pathogenesis of the disorder. However, many of the infants receiving the prophylaxis with vitamin D remained unaffected, and thus it was proposed that there were other contributing intrinsic factors . Following the outbreak, the disorder was determined to be Idiopathic Infantile Hypercalcemia (IIH).
Infants with IIH experience vomiting, increased urination, dehydration, constipation, weight loss, and an inability to grow and gain weight normally . Individuals with IIH may also have high levels of calcium in the urine (hypercalciuria) or deposits of calcium in the urine (nephrocalcinosis).
Overview of Normal Vitamin D Metabolism and Calcium Homeostasis
The primary sources of vitamin D include exposure to sunlight, which is necessary for ultraviolet-B-induced vitamin D production within the skin , along with diet and supplementation. Once in the body, vitamin D3 undergoes activation through several hydroxylation reactions (Fig.1.). First, vitamin D3 is hydroxylated by 25-hydroxylase (CYP2R1) in the liver to produce the primary circulating form, 25-hydroxyvitamin D3 . Next, a second hydroxylation reaction catalyzed by the enzyme 1a-hydroxylase (CYP27B1) in the kidney results in the biologically active form 1,25-dihydroxy vitamin D3 . When levels of 1,25-(OH)2 D3 are high, it is then inactivated through catabolism by 24-hydroxylase (CYP24A1) into 24,25-(OH)2D3 (calcitroic acid) primarily .
Figure 1. Vitamin D Metabolism Under Healthy Conditions. Vitamin D is activated through several subsequent hydroxylation reactions. Once active, vitamin D3 can exert its biological effect through binding to the vitamin D receptor (VDR) and is then catabolized by 24-hydroxylase into products that are more readily excreted.
Calcium homeostasis is regulated through a negative feedback hormone system, the two most important hormones being parathyroid hormone and 1,25(OH)2D3. PTH is the major regulator of extracellular calcium concentration. When serum calcium is low, the calcium-sensing receptor (CaR) in the parathyroid gland becomes inactivated, and as a result, increases PTH secretion from the parathyroid gland . PTH acts on the PTH receptor in the kidney and the bone by stimulating calcium reabsorption and bone resorption respectively. PTH also indirectly stimulates calcium absorption in the gut by triggering the synthesis of 1,25-(OH)2D3 in the kidney . This restores levels of calcium, helping to maintain a baseline extracellular calcium level.
The Power of Animal Models
It is widely known that vitamin D influences bone metabolism indirectly through the maintenance of calcium and phosphate homeostasis. Recent studies have revealed “direct, but non-essential roles for 1,25-(OH)2D in growth plate chondrocytes” . In order to test the hypothesis that 1,25-(OH)2D plays a direct role in chondrocytes, a mouse model was developed allowing for specific inactivation of CYP27B1 genes. The resulting decrease in 1,25-(OH)2D and thus inactivation of the vitamin D receptor (VDR) in chondrocytes was found to result in delayed osteoclastogenesis and thus an increase in bone volume . The inactivated VDR mice also experienced reduced levels of FGF-23 and a resulting elevated serum phosphate concentration. Thus, it was proposed that a “1,25-(OH)2D-induced secreted factor from chondrocytes that affects FGF-23 production of neighboring osteoblasts” .
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