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Human Bladder as a Novel Target for Vitamin D Receptor Ligands

Department of Clinical Physiopathology, Center of Research, Transfer and High Education (C.C., A.M., P.F., M.L., S.G., B.F., S.D., G.F., M.Mag.), Departments of Anatomy, Histology, and Forensic Medicine (G.B.V., M.Mar.) and Surgical and Medical Critical Care (D.V.), Urology Unit, University of Florence, 50139 Florence, Italy; BioXell (L.A., E.C.), Milan, Italy; and Institute of Laboratory Medicine, Department of Clinical Pharmacology, Lund University Hospital (K.-E.A.), 22185 Lund, Sweden

Address all correspondence and requests for reprints to: Dr. Mario Maggi, Department of Clinical Pathophysiology, Unit of Andrology, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy. E-mail: m.maggi{at}dfc.unifi.it.

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.

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