A summary of the principal actions of PTH, FGF23, and vitamin D on the three main target tissues—intestine, kidney, and bone— is presented in Table 42–2. The net effect of PTH is to raise serum calcium and reduce serum phosphate; the net effect of FGF23 is to decrease serum phosphate; the net effect of vitamin D is to raise both. Regulation of calcium and phosphate homeostasis is achieved through important feedback loops. Calcium is one of two principal regulators of PTH secretion. It binds to a novel ion recognition site that is part of a Gq protein–coupled receptor called the calcium-sensing receptor (CaSR) that employs the phosphoinositide second messenger system to link changes in the extracellular calcium concentration to changes in the intracellular free calcium. As serum calcium levels rise and activate this receptor, intracellular calcium levels increase and inhibit PTH secretion. This inhibition by calcium of PTH secretion, along with inhibition of renin and atrial natriuretic peptide secretion, is the opposite of the effect in other tissues such as the beta cell of the pancreas, in which calcium stimulates secretion. Phosphate regulates PTH secretion directly and indirectly. Its indirect actions are the result of forming complexes with calcium in the serum. Because it is the ionized free concentration of extracellular calcium that is detected by the parathyroid gland, increases in serum phosphate levels reduce the ionized calcium levels, leading to enhanced PTH secretion. Whether the parathyroid gland expresses phosphate receptors that mediate the direct action of phosphate on PTH secretion remains unclear. Such feedback regulation is appropriate to the net effect of PTH to raise serum calcium and reduce serum phosphate levels. Likewise, both calcium and phosphate at high levels reduce the amount of 1,25(OH)2D produced by the kidney and increase the amount of 24,25(OH)2D produced.
High serum calcium works directly and indirectly by reducing PTH secretion. High serum phosphate works directly and indirectly by increasing FGF23 levels. Since 1,25(OH)2D raises serum calcium and phosphate, whereas 24,25(OH)2D has less effect, such feedback
TABLE 42–2 Actions of parathyroid hormone (PTH), vitamin D, and FGF23 on gut, bone, and kidney.
1Direct effect. Vitamin D also indirectly increases urine calcium owing to increased calcium absorption from the intestine and decreased PTH.