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Dexamethasone enhances vitamin D-24-hydroxylase expression in osteoblastic (UMR-106) and renal (LLC-PK1) cells treated with 1α,25-dihydroxyvitamin D3

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Abstract

Chronic glucocorticoid therapy causes rapid bone loss and clinical osteoporosis. We previously found that dexamethasone, a potent glucocorticoid, increased renal expression of vitamin D-24-hydroxylase, which degrades such vitamin D metabolites as 25-hydroxyvitamin D3 and 1α,25-dihydroxyvitamin D3 (1,25[OH]2D3). We therefore investigated the mechanisms of this increase in UMR-106 osteoblast-like cells and LLC-PK1 kidney cells. To induce 24-hydroxylase expression, 1,25(OH)2D3 (10−7 M) and dexamethasone were added simultaneously to the medium of LLC-PK1 cells, and 24 h before dexamethasone treatment, 1,25(OH)2D3 was added to the medium of UMR-106 cells. Dexamethasone dose dependently increased 24-hydroxylase mRNA and enzymatic activity in 1,25(OH)2D3-treated LLC-PK1 and UMR-106 cells. Maximal stimulation was observed with 10−6 M dexamethasone in both cell lines. The addition of 10−6 M dexamethasone significantly increased the abundance of 24-hydroxylase mRNA by 24 and 8 h in 1,25(OH)2D3-treated LLC-PK1 and UMR-106 cells, respectively. Stimulation for dexamethasone in UMR-106 cells persisted for up to 48 h. Dexamethasone stimulation of 24-hydroxylase mRNA expression in UMR-106 cells was abolished by pretreatment with cycloheximide, an inhibitor of protein synthesis. Northern and Western analyses indicated that 10−6 M dexamethasone markedly increased the abundance of c-fos mRNA at 20 min and c-fos protein concentration at 60 min in 1,25(OH)2D3-treated UMR-106 cells but only slightly induced the abundance of c-jun mRNA. The addition of phorbol 12-myristate 13-acetate increased mRNA expression for both c-fos and 24-hydroxylase in 1,25(OH)2D3-treated UMR-106 cells. The effect of dexamethasone on 24-hydroxylase mRNA expression was blocked by RO31-8220, a specific inhibitor of protein kinase C. Thus, dexamethasone in the presence of 1,25(OH)2D3 enhances expression of 24-hydroxylase in UMR-106 osteoblastic cells via new protein synthesis. The mechanism of this effect appears to involve activation of the AP-1 site by increased c-fos protein.

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Authors and Affiliations

  1. Department of Oral Surgery, Ohu University School of Dentistry, Koriyama, Japan

    Izuru Kurahashi

  2. Department of Biochemistry, Ohu University School of Dentistry, 963-8611, Koriyama, Japan

    Izuru Kurahashi, Ayako Matsunuma, Tetsuya Kawane, Masatoshi Abe &  Noboru Horiuchi

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  1. Izuru Kurahashi
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  2. Ayako Matsunuma
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  3. Tetsuya Kawane
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  4. Masatoshi Abe
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  5. Noboru Horiuchi
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Correspondence to Noboru Horiuchi.

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Kurahashi, I., Matsunuma, A., Kawane, T. et al. Dexamethasone enhances vitamin D-24-hydroxylase expression in osteoblastic (UMR-106) and renal (LLC-PK1) cells treated with 1α,25-dihydroxyvitamin D3 . Endocr 17, 109–118 (2002). https://doi.org/10.1385/ENDO:17:2:109

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