Effects of Osteoporosis-Inducing Drugs on Vitamin D-Related Gene Transcription and Mineralization in MG-63 and Saos-2 Cells.
Vitamin D3is important for calcium and phosphate homeostasis. To exert its effects, vitamin D3has to be enzymatically activated into 1,25D3(1,25-dihydroxyvitamin D3). Regulation by endogenous vitamin D metabolites of the activation and inactivation of 1,25D3is important to maintain adequate amounts of active vitamin D3. Vitamin D deficiency and low bone mineral density have been linked to treatments with antiretroviral drugs and glucocorticoids. However, the causes of drug-induced osteoporosis remain unclear. The antiretroviral drugs efavirenz and ritonavir as well as the glucocorticoid dexamethasone were included in this study. Their effects on transcription of vitamin D-regulating enzymes in MG-63 cells were investigated. Ritonavir and dexamethasone both induced transcription of CYP27B1, the enzyme responsible for the formation of 1,25D3. Efavirenz, however, suppressed CYP27B1 expression. When administered together with endogenous vitamin D metabolites, dexamethasone and efavirenz counteracted the 1,25D3-mediated up-regulation of CYP24A1, which inactivates 1,25D3. This suggests that the drugs may interfere with local regulation of the vitamin D metabolizing system in osteoblasts. Studies on mineralization were performed in MG-63 cells and Saos-2 cells by measuring calcium concentrations accumulated over time. The effects of efavirenz, ritonavir and dexamethasone and/or vitamin D metabolites were examined. 1,25D3induced mineralization in both cell lines. Efavirenz administered alone did not affect mineralization but suppressed the inducing effects of 1,25D3on mineralization in both MG-63 cells and Saos-2 cells. In summary, the results suggest that antiretroviral drugs and glucocorticoids may adversely affect bone by interference with the vitamin D system in osteoblasts.
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
Christine
C
Wegler
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
Kjell
K
Wikvall
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden. maria.norlin@farmbio.uu.se.
Maria
M
Norlin
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000378:metabolism; D000480:Alkynes; D044966:Anti-Retroviral Agents / Q000009:adverse effects*; D048588:Benzoxazines / Q000009:adverse effects; D015519:Bone Density / Q000187:drug effects*; D002117:Calcitriol / Q000378:metabolism; D045744:Cell Line, Tumor; D003521:Cyclopropanes; D003907:Dexamethasone / Q000009:adverse effects; D005938:Glucocorticoids / Q000009:adverse effects*; D006801:Humans; D010006:Osteoblasts / Q000378:metabolism; D010024:Osteoporosis / Q000139:chemically induced*; D019438:Ritonavir / Q000009:adverse effects; D014158:Transcription, Genetic / Q000187:drug effects*; D015854:Up-Regulation; D065668:Vitamin D3 24-Hydroxylase / Q000378:metabolism; D014815:Vitamins
D000480:Alkynes; D044966:Anti-Retroviral Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D005938:Glucocorticoids; D014815:Vitamins; D003907:Dexamethasone; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; C000600378:CYP27B1 protein, human; D002117:Calcitriol; C098320:efavirenz; D019438:Ritonavir