Human bladder as a novel target for vitamin D receptor ligands.
Human prostate is now considered a target for vitamin D receptor (VDR) ligands, such as BXL-628. Because BXL-628 inhibited prostate growth without interfering with androgen signaling, it represents a new option for benign prostate hyperplasia (BPH) therapy. However, BPH symptoms are related not only to prostate size, but also to compensatory bladder hypertrophy and eventual overactivity. We now report that human bladder expresses VDR (determined by real-time PCR immunohistochemistry and Western blot) and responds to VDR agonists, such as the natural ligand, calcitriol, and its synthetic and less hypercalcemic derivative, BXL-628. Experiments were conducted with stromal cells derived from human bladder neck obtained at surgery from BPH patients. BXL-628 counteracted keratinocyte growth factor (KGF) and androgen-induced cell proliferation and stimulated apoptosis with a parallel reduced expression of the survival oncoprotein Bcl-2. Prolonged serum starvation time-dependently pushed bladder stromal cells to express activated myofibroblast markers, such as desmin and smoothelin, without changing other contractile-related proteins and intermediate filaments, such as vimentin. Chronic exposure to BXL-628 prevented starvation-induced cell phenotype modification. Because hypertrophy and starvation-induced bladder remodeling are supposed to underlie bladder overactivity, it is possible that BXL-628 might be helpful in reducing not only cumbersome symptoms related to prostate overgrowth, but also those related to bladder irritation.
Crescioli
Clara
C
Department of Clinical Pathophysiology, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.
Morelli
Annamaria
A
Adorini
Luciano
L
Ferruzzi
Pietro
P
Luconi
Michaela
M
Vannelli
Gabriella Barbara
GB
Marini
Mirca
M
Gelmini
Stefania
S
Fibbi
Benedetta
B
Donati
Silvia
S
Villari
Donata
D
Forti
Gianni
G
Colli
Enrico
E
Andersson
Karl-Erik
KE
Maggi
Mario
M
D001842:Bone and Bones / Q000187:drug effects / Q000196:embryology; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D006801:Humans; D008024:Ligands; D008297:Male; D011470:Prostatic Hyperplasia / Q000188:drug therapy / Q000601:surgery; D051497:Receptor, Fibroblast Growth Factor, Type 2; D018167:Receptors, Calcitriol / Q000502:physiology*; D017468:Receptors, Fibroblast Growth Factor / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D001743:Urinary Bladder / Q000187:drug effects / Q000502:physiology*
C487049:BXL628; D008024:Ligands; D018167:Receptors, Calcitriol; D017468:Receptors, Fibroblast Growth Factor; D051497:Receptor, Fibroblast Growth Factor, Type 2; C065104:keratinocyte growth factor receptor; D002117:Calcitriol