title: Dexamethasone-induced apoptosis of osteocytic and osteoblastic cells is mediated by TAK1 activation.
abstract: Increased apoptosis of osteoblasts and osteocytes is the main mechanism of glucocorticoid (GC)-induced osteonecrosis. In the current study, we investigated whether dexamethasone (Dex)-induced osteoblastic and osteocytic cell apoptosis is mediated through activation of transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1), and whether TAK1 inhibition could promote survival opposing the deleterious effects of Dex. We found that TAK1 was activated by Dex in both osteocytic MLO-Y4 and osteoblastic OB-6 cells, which was prevented by two known anti-oxidants N-acetylcysteine (NAC) and ebselen. TAK1 inhibitors, including LYTAK1 and 5Z-7-oxozeaenol (57-OZ), inhibited Dex-induced apoptosis of MLO-Y4 and OB-6 cells. Meanwhile shRNA-mediated knockdown of TAK1 also suppressed Dex-induced damages to MLO-Y4 and OB-6 cells. On the other hand, exogenously over-expressing TAK1 enhanced Dex-induced MLO-Y4 and OB-6 cell apoptosis. At the molecular level, we found that TAK1 mediated Dex-induced pro-apoptotic Pyk2-JNK activation. Inhibition or silencing of TAK1 almost abolished Pyk2-JNK phosphorylations by Dex in MLO-Y4 and OB-6 cells. TAK1 over-expression, on the other hand, increased Dex's activity on Pyk2-JNK phosphorylations in above cells. We conclude that part of the pro-apoptotic actions of Dex on osteoblastic and osteocytic cells are mediated through TAK1 activation, and that inhibition of TAK1 might protect from GC-induced damages to osteoblasts and osteocytes.
authors.affiliation: Department of Endocrinology, Huashan Hospital, Fudan University, Shanghai, China; Department of Endocrinology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China.
authors.forename: Heyuan
authors.initials: H
authors.lastname: Ding
authors.affiliation: Department of Neurosurgery, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Endocrinology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China.
authors.forename: Dongli
authors.initials: D
authors.lastname: Xu
authors.affiliation: Department of Endocrinology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China.
authors.forename: Bingbing
authors.initials: B
authors.lastname: Cha
authors.affiliation: Department of Endocrinology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China. Electronic address: junliumda163@163.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Endocrinology, Huashan Hospital, Fudan University, Shanghai, China. Electronic address: yiminglishanghai8@163.com.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Li
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology*; D004789:Enzyme Activation; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects*; D010011:Osteocytes / Q000166:cytology / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D003907:Dexamethasone; D020930:MAP Kinase Kinase Kinases; D047428:Protein Kinase Inhibitors; D000099151:MAP Kinase Kinase Kinase 7
keywords: Apoptosis; Dexamethasone; Osteonecrosis; Pyk2-JNK signaling; TAK1