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 Wnt antagonist, secreted frizzled-related protein-1 (sFRP-1) and a Wnt 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 Wnt and BMP pathways as well as osteoblast function by enhancing the expression of BMP and Wnt antagonists, and bisphosphonate and PTH exert pharmacologic effects by canceling these processes.
Hayashi
Kumi
K
Department of Internal Medicine 1, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo 693-8501, Japan.
Yamaguchi
Toru
T
Yano
Shozo
S
Kanazawa
Ippei
I
Yamauchi
Mika
M
Yamamoto
Masahiro
M
Sugimoto
Toshitsugu
T
D019386:Alendronate / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D060466:Axin Protein; D050071:Bone Density Conservation Agents / Q000494:pharmacology* / Q000627:therapeutic use; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors*; D002113:Calcification, Physiologic / Q000187:drug effects; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D003907:Dexamethasone / Q000378:metabolism / Q000494:pharmacology*; D005938:Glucocorticoids / Q000378:metabolism / Q000494:pharmacology*; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism; D010024:Osteoporosis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D010281:Parathyroid Hormone / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000096:biosynthesis; D015854:Up-Regulation; D051153:Wnt Proteins / Q000037:antagonists & inhibitors*; D000099274:Frizzled-Related Proteins
D019386:Alendronate; D060466:Axin Protein; D050071:Bone Density Conservation Agents; D019485:Bone Morphogenetic Proteins; D003598:Cytoskeletal Proteins; D003907:Dexamethasone; D005938:Glucocorticoids; D006023:Glycoproteins; D047908:Intracellular Signaling Peptides and Proteins; D010281:Parathyroid Hormone; D012333:RNA, Messenger; D051153:Wnt Proteins; D000099274:Frizzled-Related Proteins; C111729:Axin2 protein, mouse