Figure 1 summarizes that portion of the vitamin D endocrine system concerned with calcium homeostasis. The steroid hormone 1α,25(OH)2D3 is produced only in accord with strict physiological signals dictated by the calcium “demand” of the organism; a bimodal mode of regulation has been suggested. On a time scale of minutes, changes in the ionic environment of the kidney mitochondria resulting from the accumulation and release of calcium and/or inorganic phosphate may alter the enzymatic activity of the 25(OH)D3-1α hydroxylase. In addition, parathyroid hormone has been shown, on a time scale of hours, to be capable of stimulating the production of 1α,25(OH)2D3, possibly by stimulating the biosynthesis of the 1α-hydroxylase. It is also intriguing that 1α,25(OH)2D3 is a stimulant for the renal mitochondrial production of 24,25(OH) D3 (see following paragraph). Thus, under normal physiological circumstances, both renal dihydroxylated metabolites are secreted and are circulating in the plasma. There is also evidence of a “short feedback loop” for 1α,25(OH)2D3 to modulate and/or reduce the secretion of PTH (see Figure2). The half-life of both 1α,25(OH)2D3 and 24R,25(OH)2D3 is 6–8 hours. Thus, the kidney is clearly an endocrine gland, in the classic sense, in that it has the responsibility, in a physiologically regulated manner, to produce appropriate amounts of the steroid hormone, 1α,25(OH)2D3.
Fig1. A schematic of the vitamin D endocrine system governing calcium homeostasis. The process of calcium homeostasis describes the mechanisms by which the serum Ca2+ concentration is maintained ~constant at 9.5–10.5 mg/100 mL of serum via the integrated actions of the intestine, bone, and kidney; all three of these organs can contribute Ca2+ to the serum compartment based on the actions of three hormones, namely parathyroid hormone (PTH), 1α,25(OH)2D3 and fibroblast growth factor 23 (FGF23). 1α,25(OH)2D3 is responsible for stimulating intestinal Ca2+ absorption in accordance with the circulating level of 1α,25(OH)2D3. If the dietary intake of Ca2+ is inappropriately low, then Ca2+ contribution from the intestine is not adequate and PTH will therefore stimulate the bone to solubilize Ca2+ and HPO4−. At the same time PTH will interact with its kidney receptor and increase the renal tubular reabsorption of Ca2+ and at the same time diminish the renal tubular reabsorption of phosphate (i.e., increase the urinary concentration of phosphate). Also the kidney functions as an endocrine gland in that it enzymatically produces the steroid hormone 1α,25(OH)2D3 according to the stimulatory actions of PTH on the kidney proximal tubule’s 25(OH)2D3-1α-hydroxylase in accordance with the magnitude of the need to elevate the prevailing level of serum Ca2+. The secretion of PTH is governed by the Ca2+receptor of the parathyroid gland which monitors the serum Ca2+ concentration (see Figure2). Finally bone osteocytes secrete the hormone FGF23 when serum Ca2+ is inappropriately low. The FGF23 binds to its receptor in the kidney and inhibits the renal tubular reabsorption of phosphate (i.e., increases the urinary concentration of phosphate).
Fig2. Regulation of PTH secretion via changes in stability of the PTH messenger RNA. The plasma membrane Ca2+ receptor of the PTH secreting cell senses changes in the serum Ca2+ level through a seven-transmembrane G protein linked to phospholipases that sends a second messenger to the cellular site of the regulation of the PTH mRNA concentration (see the two gold stars). Changes in the rate of secretion of PTH PTh secreting cells are mediated by changing the stability of the PTH mRNA. In the inset below the cell, there are two schematic diagrams of the PTH mRNA from 5′-UTR to 3′-UTR. The More stable mRNA schematic illustrates the circumstance of hypocalcemia, resulting in an increase in the stability of PTH mRNA and ultimately greater PTH secretion. The Less stable mRNA schematic illustrates the circumstance of hypercalcemia (with associated low serum phosphate) resulting in reduction of PTH mRNA stability and ultimately lower PTH secretion. Two key regulatory proteins (UNR and AUF1) bind to the 3′ untranslated region (3′UTR) of the PTH mRNA stabilizing PTH mRNA levels necessary to increase PTH secretion. In contrast, the K homology-type Splicing Regulatory Protein (KSRP) also binds to the PTH mRNA 3′-UTR, specifically to the ARE (Adenine- and uridine-Rich Elements) which is a conserved 26 nucleotide sequence that decreases PTH mRNA stability and as a consequence reduces PTH secretion. When KSRP is phosphorylated on serine-181 it cannot bind to the 3′-UTR ARE region (More stable mRNA) and there is no reduction of PTH mRNA stability and accordingly PTH secretion is increased. But when KSRP is not phosphorylated, it can bind (Less stable mRNA) to the PTH mRNA 3′-UTR ARE region, thus decreasing PTH mRNA stability and thereby reducing the secretion of PTH. Pin1 is a peptidyl- cis-trans isomerase that specifically binds to the unphosphorylated Ser/Thr-Pro protein motif of KSRP. This catalyzes the cis/trans isomerization of the KSRP proline peptide bonds, thus causing a conformational change in KSRP and increasing the biological activity of KSRP so that it can bind to the ARE nucleotide sequence of the PTH mRNA, which then results in a decrease in both the stability of the PTH mRNA and the secretion of PTH. The PTH secreting cell also has receptors for both 1α,25(OH)2D3 (produced by the kidney) and FGF-23 (produced by bone). Both hormones downregulate PTH gene transcription, thus lowering PTH production and secretion.
The biological role of 24R,25(OH)2D3 is still under discussion. There is evidence that 24R,25(OH)2D3 can play a role in fracture healing, and there is preliminary evidence of a receptor for 24R,25(OH)2D3. The enzyme that converts 25(OH)D3 to 24R,25(OH)2D3, namely the cytochrome P450-24A1 hydroxy lase (CYP24A1) also converts 1α,25(OH)2D3 to 1α,24R,25(OH)3D3 which represents the first step of catabolism of 1α,25(OH)2D3. Most target cells for 1α,25(OH)2D3 which possess the VDR also have low concentrations of CYP24A1; this ensures a short half life for 1α,25(OH)2D3.
The plasma compartment contains the vitamin D-binding protein (DBP) that is utilized to transport vitamin D secosterols. DBP is similar in function to the corticosteroid-binding globulin (CBG), which carries glucocorticoids (see Chapter 10), and the steroid hormone-binding globulin (SHBG), which transports estrogens or androgens (see Chapter 12). DBP is a slightly acidic (pH = 5.2) monomeric glycoprotein of 53,000 Da, which is synthesized and secreted by the liver as a major plasma constituent.
DBP is a multifunctional protein in that it binds both vitamin D and its metabolites and also monomers of the protein actin, thereby preventing their polymerization in the blood compartment. One molecule of DBP has only one ligand-binding domain-binding site for secosterols of the vitamin D family. Thus, while a single DBP can carry only one ligand, the relatively high concentration of DBP molecules present in the blood compartment permits the DBP population as a whole to bind the hydrophobic parent, vitamin D3, as well as the hydrophobic daughter metabolites, 25(OH) D3, 1α,25(OH)2D3, and 24,25(OH)D3. Since the total plasma concentration of vitamin D sterols is only ~0.2 μM, while DBP circulates at 9–13 μM, under normal circumstances only a very small proportion of the sterol-binding sites on DBP are occupied.
