Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/41626
Type: Conference paper
Title: Vitamin D metabolism in human osteoblasts
Author: Atkins, G.
Anderson, P.
Welldon, K.
Zannettino, A.
Morris, H.
Findlay, D.
Citation: Journal of Bone and Mineral Research, 2004; 19 (suppl.1):SA-587
Part of: Abstracts of the 26th Annual Meeting of the American Society for Bone and Mineral Research
Publisher: American Society for Bone and Mineral Research
Issue Date: 2004
ISSN: 0884-0431
Conference Name: Annual Meeting of the American Society for Bone and Mineral Research (26th : 2004 : Seattle, Washington)
Abstract: Circulating 1 α ,25-dihydroxyvitamin D₃ (1,25D) derives from conversion of 25-hydroxyvitamin D₃ (25D) by the kidney 1 α -hydroxylase (CYP27B1). 1,25D exerts a number of effects on human osteoblasts, including inhibition of proliferation and differentiation, and effects on gene expression, including stimulation of RANKL, osteocalcin (OCN) and bone sialoprotein (BSP). We have examined vitamin D₃ metabolism in human osteoblastic cells, and found that primary normal human osteoblasts (NHBC) and human osteosarcoma cell lines, including MG-63, SaOS-2, HOS, G-292, all up-regulate the negative regulator of 1,25D, the 24-hydroxylase (CYP24), in response to 1,25D exposure. Additionally, all of these cell types expressed CYP27B1 mRNA, implying that human osteoblasts are capable of metabolising 25D into 1,25D. We have investigated this possibility and found that NHBC exposed to physiological concentrations of 25D (10 - 100 nM) in the absence of serum, exhibit up-regulated transcription of the downstream genes RANKL and OCN. Unlike 1,25D, 25D did not elicit a vigorous CYP24 response except at high concentrations (10⁻⁷ - 10⁻⁶ M). Consistent with this, NHBC treated with high concentrations of 25D secreted detectable 1,25D into the culture supernatant. We also found that NHBC express the 25-hydroxylase, and treatment with 1-hydroxyvitamin D₃ (1D), resulted in a gene expression response qualitatively similar to 25D. Inhibition of CYP activity using ketoconazole (10 μ M) resulted in an elevated response to 1,25D, probably due to inhibition of the catabolic activity of CYP24. Results to date indicate that the activity of 1D is CYP-dependent, since ketoconazole abolished its effects. However, 25D effects at low concentrations were unaffected by ketoconazole, indicating that 25D may have direct effects in osteoblasts independent of its conversion to 1,25D. Our results suggest that vitamin D₃ metabolism represents an intrinsic autocrine/paracrine pathway in these cells. Thus, vitamin D metabolites may regulate key functions in human osteoblasts independently of circulating levels of 1,25D.
RMID: 0030001781
Published version: http://www.abstractsonline.com/viewer/viewAbstract.asp?CKey=%7BF31A05B1-077A-4C52-9117-6FB73ACD5CDE%7D&MKey=%7B96915C07-D110-439D-BF0C-C23CD3392D2D%7D&AKey=%7BD0C01D4F-E23B-45E2-ACD4-0AF8AC866B8B%7D&SKey=%7B87F99664-71A6-4493-A6FE-A288D562AC11%7D
Appears in Collections:Orthopaedics and Trauma publications

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