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Effects of Osteoporosis‐Inducing Drugs on Vitamin D‐Related Gene Transcription and Mineralization in MG ‐63 and Saos‐2 Cells
Author(s) -
Wegler Christine,
Wikvall Kjell,
Norlin Maria
Publication year - 2016
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/bcpt.12612
Subject(s) - efavirenz , cyp24a1 , medicine , ritonavir , vitamin d and neurology , endocrinology , chemistry , calcitriol receptor , vitamin , osteomalacia , calcitriol , pharmacology , biology , immunology , human immunodeficiency virus (hiv) , viral load , antiretroviral therapy
Abstract Vitamin D 3 is important for calcium and phosphate homeostasis. To exert its effects, vitamin D 3 has to be enzymatically activated into 1,25D 3 (1,25‐dihydroxyvitamin D 3 ). Regulation by endogenous vitamin D metabolites of the activation and inactivation of 1,25D 3 is important to maintain adequate amounts of active vitamin D 3 . 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 CYP 27B1, the enzyme responsible for the formation of 1,25D 3 . Efavirenz, however, suppressed CYP 27B1 expression. When administered together with endogenous vitamin D metabolites, dexamethasone and efavirenz counteracted the 1,25D 3 ‐mediated up‐regulation of CYP 24A1, which inactivates 1,25D 3 . 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. 1,25D 3 induced mineralization in both cell lines. Efavirenz administered alone did not affect mineralization but suppressed the inducing effects of 1,25D 3 on 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.