Page 791 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 42 Agents That Affect Bone Mineral Homeostasis 777

TABLE 42–1 Vitamin D and its major metabolites an RXXR site (amino acids 176–179). Mutations in this site lead
and analogs. to excess FGF23, the underlying problem in autosomal dominant
hypophosphatemic rickets. A similar disease, X-linked hypophos-
Chemical and Generic Names Abbreviation phatemic rickets, is due to mutations in PHEX, an endopeptidase,
Vitamin D 3 ; cholecalciferol D 3 which initially was thought to cleave FGF23. However, this concept
has been shown to be invalid, and the mechanism by which PHEX
Vitamin D 2 ; ergocalciferol D 2
mutations lead to increased FGF23 levels remains obscure. FGF23
25-Hydroxyvitamin D 3 ; calcifediol
binds to FGF receptors (FGFR) 1 and 3c in the presence of the
25(OH)D 3
1,25-Dihydroxyvitamin D 3 ; calcitriol 1,25(OH) 2 D 3 accessory receptor Klotho-α. Both Klotho and the FGFR must
24,25-Dihydroxyvitamin D 3 ; secalciferol 24,25(OH) 2 D 3 be present for signaling in most tissues, although high levels of
Dihydrotachysterol DHT FGF23 appear to affect cardiomyocytes lacking Klotho. Mutations
Calcipotriene (calcipotriol) None in Klotho disrupt FGF23 signaling, resulting in elevated phosphate
and 1,25(OH) D levels, a phenotype quite similar to inactivating
1α-Hydroxyvitamin D 2 ; doxercalciferol 1α(OH)D 2 2
mutations in FGF23 or GALNT3. FGF23 production is stimulated
19-nor-1,25-Dihydroxyvitamin D 2 ; paricalcitol 19-nor-1,25(OH)D 2
by 1,25(OH) D and phosphate and directly or indirectly inhibited
2
by the dentin matrix protein DMP1 found in osteocytes. Mutations
in DMP1 lead to increased FGF23 levels and osteomalacia.
brush border and basolateral membranes by processes that do
not all require new protein synthesis. The molecular action of
1,25(OH) D on bone is more complex and controversial as it is INTERACTION OF PTH, FGF23, &
2
both direct and indirect. Much of the skeletal effect is attributed VITAMIN D
to the provision of adequate calcium and phosphate from the
diet by stimulation of their intestinal absorption. However,
like PTH, 1,25(OH) D can induce RANKL in osteoblasts to A summary of the principal actions of PTH, FGF23, and vitamin
2
regulate osteoclast activity and proteins such as osteocalcin and D on the three main target tissues—intestine, kidney, and bone—
alkaline phosphatase, which may regulate the mineralization pro- is presented in Table 42–2. The net effect of PTH is to raise
cess by osteoblasts. The metabolites 25(OH)D and 24,25(OH) D serum calcium and reduce serum phosphate; the net effect of
2
are far less potent stimulators of intestinal calcium and phosphate FGF23 is to decrease serum phosphate; the net effect of vitamin D
transport or bone resorption. is to raise both. Regulation of calcium and phosphate homeostasis
Specific receptors for 1,25(OH) D (VDR) exist in nearly all is achieved through important feedback loops. Calcium is one
2
tissues, not just intestine, bone, and kidney. As a result much of two principal regulators of PTH secretion. It binds to a novel
q
effort has been made to develop analogs of 1,25(OH) D that will ion recognition site that is part of a G protein–coupled recep-
2
target these non-classic target tissues without increasing serum tor called the calcium-sensing receptor (CaSR) that employs the
calcium. These non-classic actions include regulation of the secre- phosphoinositide second messenger system to link changes in the
tion of PTH, insulin, and renin; regulation of innate and adaptive extracellular calcium concentration to changes in the intracellular
immune function through actions on dendritic cell and T-cell free calcium. As serum calcium levels rise and activate this recep-
differentiation; enhanced muscle function; and proliferation and tor, intracellular calcium levels increase and inhibit PTH secretion.
differentiation of a number of cancer cells. Thus, the potential This inhibition by calcium of PTH secretion, along with inhibi-
clinical utility of 1,25(OH) D and its analogs is expanding. tion of renin and atrial natriuretic peptide secretion, is the opposite
2
of the effect in other tissues such as the beta cell of the pancreas,
in which calcium stimulates secretion. Phosphate regulates PTH
FIBROBLAST GROWTH FACTOR 23 secretion directly and indirectly. Its indirect actions are the result
of forming complexes with calcium in the serum. Because it is the
Fibroblast growth factor 23 (FGF23) is a single-chain protein with ionized free concentration of extracellular calcium that is detected
251 amino acids, including a 24-amino-acid leader sequence. It by the parathyroid gland, increases in serum phosphate levels
inhibits 1,25(OH) D production and phosphate reabsorption reduce the ionized calcium levels, leading to enhanced PTH secre-
2
(via the sodium phosphate co-transporters NaPi 2a and 2c) in the tion. Whether the parathyroid gland expresses phosphate receptors
kidney and can lead to both hypophosphatemia and inappropri- that mediate the direct action of phosphate on PTH secretion
ately low levels of circulating 1,25(OH) D. Whereas FGF23 was remains unclear. Such feedback regulation is appropriate to the net
2
originally identified in certain mesenchymal tumors, osteoblasts effect of PTH to raise serum calcium and reduce serum phosphate
and osteocytes in bone appear to be its primary site of production. levels. Likewise, both calcium and phosphate at high levels reduce
Other tissues can also produce FGF23, though at lower levels. the amount of 1,25(OH) D produced by the kidney and increase
2
FGF23 requires O-glycosylation for its secretion, a glycosylation the amount of 24,25(OH) D produced.
2
mediated by the glycosyl transferase GALNT3. Mutations in High serum calcium works directly and indirectly by reducing
GALNT3 result in abnormal deposition of calcium phosphate in PTH secretion. High serum phosphate works directly and indirectly
periarticular tissues (tumoral calcinosis) with elevated phosphate by increasing FGF23 levels. Since 1,25(OH) 2 D raises serum calcium
and 1,25(OH) D. FGF23 is normally inactivated by cleavage at and phosphate, whereas 24,25(OH) D has less effect, such feedback
2
2