Vitamin D [
1,25(OH)2D3] plays a crucial role in Ca2+ homeostasis by stimulating Ca2+ (re)absorption and bone turnover. The
1,25(OH)2D3 analog
ZK191784 was recently developed to dissociate the therapeutic immunomodulatory activity from the hypercalcemic side effects of
1,25(OH)2D3 and contains a structurally modified side chain characterized by a 22,23-double bond, 24R-hydroxy group, 25-cyclopropyl ring, and 5-butyloxazole unit. We investigated the effect of
ZK191784 on Ca2+ homeostasis and the regulation of Ca2+
transport proteins in wild-type (WT) mice and mice lacking the renal epithelial Ca2+ channel TRPV5 (TRPV5-/-). The latter display
hypercalciuria, hypervitaminosis D, increased intestinal expression of the epithelial Ca2+ channel TRPV6, the Ca2+-
binding protein calbindin-D(9K), and intestinal Ca2+ hyperabsorption.
ZK191784 normalized the Ca2+ hyperabsorption and the expression of intestinal Ca2+
transport proteins in TRPV5-/- mice. Furthermore, the compound decreased intestinal Ca2+ absorption in WT mice and reduced 1,25(OH)2D3-dependent 45Ca2+ uptake by Caco-2 cells, substantiating a 1,25(OH)2D3-antagonistic action of
ZK191784 in the intestine.
ZK191784 increased renal TRPV5 and calbindin-D(28K) expression and decreased urine Ca2+ excretion in WT mice. Both
1,25(OH)2D3 and
ZK191784 enhanced transcellular Ca2+ transport in primary cultures of rabbit connecting tubules and cortical collecting ducts, indicating a 1,25(OH)2D3-agonistic effect in kidney.
ZK191784 enhanced bone TRPV6
mRNA levels and
1,25(OH)2D3 as well as
ZK191784 stimulated secretion of the bone formation marker
osteocalcin in rat
osteosarcoma cells, albeit to a different extent. In conclusion,
ZK191784 is a synthetic
1,25(OH)2D3 ligand displaying a unique tissue-specific profile when administered in vivo. Because
ZK191784 acts as an intestine-specific
1,25(OH)2D3 antagonist, this compound will be associated with less hypercalcemic side effects compared with the
1,25(OH)2D3 analogs currently used in clinical practice.