Inhibition of the mevalonate pathway rescues the dexamethasone-induced suppression of the mineralization in osteoblasts via enhancing bone morphogenetic protein-2 signal.
We used dexamethasone (DEX)-treated osteoblastic MC3T3-E1 cells, and investigated the effects of an AMP-activated protein kinase activator, 5-aminoimidazole-4-carboxamide-1-beta- D-ribonucleoside (AICAR), a Rho-associated protein kinase inhibitor, fasudil hydrochrolide, as well as HMG-CoA reductase inhibitors, simvastatin and pitavastatin, all of which inhibit the mevalonate pathway. DEX (10(-8) M) significantly enhanced mRNA expression of bone morphogenetic protein (BMP)-2 antagonists, follistatin and Dan, and addition of each of 10 (-4) M AICAR, 10 (-5) M fasudil, 10(-6) M simvastatin, and 10(-6) M pitavastatin significantly reversed the enhancement in mRNA expression of follistatin and Dan and stimulated that of BMP-2 in the cells (p<0.05). DEX (10(-8) M) also significantly suppressed mineralization in the cells, and addition of each of these agents significantly reversed the suppression of mineralization (p<0.05). These findings suggest that the mevalonate pathway was involved in glucocorticoid-induced osteoblast dysfunction, and that its inhibition might promote bone formation through BMP-2 and alleviate glucocorticoid-induced osteoporosis.
Kanazawa
I
I
Department of Internal Medicine 1, Shimane University Faculty of Medicine, Izumo 693-8501, Japan.
Yamaguchi
T
T
Yano
S
S
Hayashi
K
K
Yamauchi
M
M
Sugimoto
T
T
D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism*; D002113:Calcification, Physiologic / Q000187:drug effects*; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology*; D015536:Down-Regulation; D015870:Gene Expression / Q000187:drug effects; D008798:Mevalonic Acid / Q000378:metabolism*; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*
D055396:Bone Morphogenetic Protein 2; D003907:Dexamethasone; D008798:Mevalonic Acid