Kdk Luk

Test of linkage and/or association of genes and bone mineral density in Chinese

Prostate Cells Express Vitamin D-25-Hydroxylases and Can Synthesize 1α,25-Dihydroxyvitamin D3 from Vitamin D3. J. N. Flanagan*, M. V. Young*, L. W. Whitlatch*, J. S. Mathieu*, K. S. Persons*, M. F. Holick, T. C. Chen. Department of Medicine, Boston University School of Medicine, Boston, MA, USA. The biologically active form of vitamin D, 1α,25-dihydroxyvitamin D (1,25D), plays essential roles in calcium homeostasis, and regulates proliferation and differentiation of a variety of cells, including prostate cells. Two hydroxylation steps catalyzed by vitamin D25-hydroxylase (25-OHase) in the liver and 25-hydroxyvitamin D (25D)-1α-hydroxylase (1α-OHase) in the kidneys are required for the activation of vitamin D to 1,25D. Previously, we reported that 1α-OHase is also expressed in extra-renal tissues, including prostate cells, suggesting that local production of 1,25D could provide an important cell growth regulatory mechanism. Now, we present evidence that prostate cells also possess 25OHase and are capable of metabolizing vitamin D3 to 1,25D3 in the immortalized PZ-HPV7 cells derived from normal prostate tissue. Three types of 25-OHase, one mitochondrial (CYP27A1) and two microsomal (CYP3A4 and CYP2R1), have been described. Using real-time PCR we found that CYP2R1 was expressed two-fold greater in normal human prostate tissue, 3-fold greater in PZ-HPV-7 cells and 6-fold greater in LNCaP prostate cancer cells than in normal liver tissue, whereas CYP27A1 was expressed 10-fold greater in normal liver tissue than in normal prostate tissue. Very little or no expression of CYP27A1 was found in PZ-HPV-7, LNCaP and PC-3 cells. PC-3 cells also expressed very little or no CYP2R1. The presence of 25-OHase in PZ-HPV-7 cells was further supported by the use of functional assays: (1) the addition of vitamin D3 caused a dose-dependent up-regulation of 24-hydroxylase (CYP24A1) and IGF-BP3 mRNA, two genes known to be sensitive to 1,25D regulation in prostate cells, (2) vitamin D3 at 10 -6 M caused a 40% inhibition of Hthymidine incorporation into DNA. These data suggest that vitamin D3 was converted to 25D3, which in turn was further converted to 1,25D3 before exerting biological actions in prostate cells. The higher expression of CYP2R1 in prostate cells than in liver cells may have chemo-preventive relevance in prostate cancer, since CYP2R1 has been recently identified by a gene mutation analysis of a vitamin D deficient patient as a biologically relevant 25-OHase. Our results suggest that maintaining adequate levels of serum vitamin D or 25D by oral supplementation or sun exposure can be a safe and effective chemo-preventive measure to decrease the risk of prostate cancer.

Test of linkage and association of 14 genetic loci with bone size

Determinants of Bone Mineral Density in Female Adolescents. Z. Harel*1, M. Gold*2, B. Cromer3, A. Bruner*4, M. Stager*3, L. Bachrach5, P. Hertweck*6, A. Nelson*7, D. Nelson8, S. Coupey*9. 1Hasbro Childrens Hospital and Brown University, Providence, RI, USA, 2Childrens Hospital of Pittsburgh, Pittsburgh, PA, USA, 3Metro-Health Medical Center, Cleveland, OH, USA, 4Johns Hopkins University School of Medicine, Baltimore, MD, USA, 5Stanford University School of Medicine, Stanford, CA, USA, 6University of Louisville, Louisville, KY, USA, 7David Geffen School of Medicine at UCLA, Torrance, CA, USA, 8Wayne State University School of Medicine, Detroit, MI, USA, 9Children’s Hospital at Montefiore, New York, NY, USA.