Nijenhuis Tom, van der Eerden Bram C J, Zügel Ulrich, Steinmeyer Andreas, Weinans Harrie, Hoenderop Joost G J, van Leeuwen Johannes P T M, Bindels René J M
Department of Physiology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, P.O. Box 9101, Nijmegen, NL-6500 HB, The Netherlands.
FASEB J. 2006 Oct;20(12):2171-3. doi: 10.1096/fj.05-5515fje.
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.
维生素D[1,25(OH)₂D₃]通过刺激钙（再）吸收和骨转换在钙稳态中发挥关键作用。1,25(OH)₂D₃类似物ZK191784最近被开发出来，以将治疗性免疫调节活性与1,25(OH)₂D₃的高钙血症副作用分离，并且含有一个结构修饰的侧链，其特征为22,23-双键、24R-羟基、25-环丙基环和5-丁基恶唑单元。我们研究了ZK191784对野生型（WT）小鼠和缺乏肾上皮钙通道TRPV5（TRPV5⁻/⁻）的小鼠钙稳态的影响以及钙转运蛋白的调节。后者表现出高钙尿症、维生素D过多症、上皮钙通道TRPV6、钙结合蛋白钙结合蛋白-D(9K)的肠道表达增加以及肠道钙过度吸收。ZK191784使TRPV5⁻/⁻小鼠的钙过度吸收和肠道钙转运蛋白的表达正常化。此外，该化合物降低了WT小鼠的肠道钙吸收，并减少了Caco-2细胞对1,25(OH)₂D₃依赖性的⁴⁵Ca²⁺摄取，证实了ZK191784在肠道中的1,25(OH)₂D₃拮抗作用。ZK191784增加了WT小鼠肾TRPV5和钙结合蛋白-D(₂₈K)的表达，并减少了尿钙排泄。1,25(OH)₂D₃和ZK191784均增强了兔连接小管和皮质集合管原代培养物中的跨细胞钙转运，表明在肾脏中具有1,25(OH)₂D₃激动作用。ZK191784增强了骨TRPV6 mRNA水平，并且1,25(OH)₂D₃以及ZK191784在大鼠骨肉瘤细胞中刺激了骨形成标志物骨钙素的分泌，尽管程度不同。总之，ZK191784是一种合成的1,25(OH)₂D₃配体，在体内给药时表现出独特的组织特异性特征。由于ZK191784作为一种肠道特异性的1,25(OH)₂D₃拮抗剂，与目前临床实践中使用的1,25(OH)₂D₃类似物相比，该化合物的高钙血症副作用将更少。
