BMP/Wnt antagonists are upregulated by dexamethasone in osteoblasts and reversed by alendronate and PTH: Potential therapeutic targets for glucocorticoid-induced osteoporosis

We used osteoblastic MC3T3-E1 cells to clarify the mechanisms by which dexamethasone (Dex) suppresses osteoblast function, or alendronate or parathyroid hormone (PTH) alleviate it. Dex (10 (7) M) increased mRNA expression of bone morphogenetic protein (BMP) antagonists, follistatin and Dan, and of a Wilt antagonist, secreted frizzled-related protein-1 (sFRP-1) and a Wilt signal inhibitor, axin-2, while concomitantly decreased the expression of downstream Molecules, Runx2 mRNA and beta-catenin protein. Pretreatments with alendronate (10 (8) M) or human PTH-(1-34)(10 (8) M) totally or partially antagonized not only the Dex-induced enhancement in mRNA expression of follistatin/Dan and sFRP-1/axin-2 but also the Dex-induced reduction in Runx2 mRNA expression and mineralization. These findings Suggest that Dex suppresses the Writ and BNIP pathways as well as osteoblast function by enhancing the expression of BMP and Wilt antagonists, and bisphosphonate and PTH exert pharmacologic effects by canceling these processes. (C) 2008 Elsevier Inc. All rights reserved.