title: Vitamin D receptor agonist VS-105 directly modulates parathyroid hormone expression in human parathyroid cells and in 5/6 nephrectomized rats.
abstract: Vitamin D receptor (VDR) agonists (VDRAs) are commonly used to treat secondary hyperparathyroidism (SHPT) associated with chronic kidney disease (CKD). Current VDRA therapy often causes hypercalcemia, which is a critical risk for vascular calcification. Previously we have shown that a novel VDRA, VS-105, effectively suppresses serum parathyroid hormone (PTH) without affecting serum calcium levels in 5/6 nephrectomized (NX) uremic rats. However, it is not known whether VS-105 directly regulates PTH gene expression. To study the direct effect of VS-105 on modulating PTH, we tested VS-105 and paricalcitol in the spheroid culture of parathyroid cells from human SHPT patients, and examined the time-dependent effect of the compounds on regulating serum PTH in 5/6 NX uremic rats (i.p. 3x/week for 14days). In human parathyroid cells, VS-105 (100nM) down-regulated PTH mRNA expression (to 3.6% of control) and reduced secreted PTH (to 43.9% of control); paricalcitol was less effective. VS-105 effectively up-regulated the expression of VDR (1.9-fold of control) and CaSR (1.8-fold of control) in spheroids; paricalcitol was also less effective. In 5/6 NX rats, one single dose of 0.05-0.2μg/kg of VS-105 or 0.02-0.04μg/kg of paricalcitol effectively reduced serum PTH by >40% on Day 2. Serum PTH remained suppressed during the dosing period, but tended to rebound in the paricalcitol groups. These data indicate that VS-105 exerts a rapid effect on suppressing serum PTH, directly down-regulates the PTH gene, and modulates PTH, VDR and CaSR gene expression more effectively than paricalcitol.
authors.affiliation: Tokai University School of Medicine, Kanagawa, Japan.
authors.forename: Kaichiro
authors.initials: K
authors.lastname: Sawada
authors.affiliation: Vidasym, Chicago, IL, USA. Electronic address: ruth.wuwong@prodigy.net.
authors.forename: J Ruth
authors.initials: JR
authors.lastname: Wu-Wong
authors.affiliation: Vidasym, Chicago, IL, USA.
authors.forename: Yung-Wu
authors.initials: YW
authors.lastname: Chen
authors.affiliation: Vidasym, Chicago, IL, USA.
authors.forename: Jerry L
authors.initials: JL
authors.lastname: Wessale
authors.affiliation: Tokai University School of Medicine, Kanagawa, Japan.
authors.forename: Genta
authors.initials: G
authors.lastname: Kanai
authors.affiliation: Tokai University School of Medicine, Kanagawa, Japan.
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Kakuta
authors.affiliation: Tokai University School of Medicine, Kanagawa, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Fukagawa
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000737:chemistry; D015536:Down-Regulation; D004872:Ergocalciferols / Q000737:chemistry; D007668:Kidney / Q000378:metabolism*; D008297:Male; D009392:Nephrectomy; D010280:Parathyroid Glands / Q000166:cytology / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000097:blood*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018167:Receptors, Calcitriol / Q000819:agonists* / Q000378:metabolism*; D018874:Spheroids, Cellular / Q000378:metabolism
chemical_list: C570781:5-(2-(1-(1-(3-hydroxy-2,3-dimethylbutoxy)ethyl)-7alpha-methyldihydro-1H-inden-4(2H,5H,6H,7H,7alphaH)-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol; D004872:Ergocalciferols; D010281:Parathyroid Hormone; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; C084656:paricalcitol; D002117:Calcitriol
keywords: Calcium-sensing receptor; Chronic kidney disease; PTH; Secondary hyperparathyroidism; Vitamin D receptor; Vitamin D receptor activator