Dexamethasone-induced apoptosis of osteocytic and osteoblastic cells is mediated by TAK1 activation
Dexamethasone-induced apoptosis of osteocytic and osteoblastic cells is mediated by TAK1 activation
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DOI：
10.1016/j.bbrc.2015.02.161
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发表时间：
2015-05-01
影响因子：
3.1
通讯作者：
Li, Yiming
中科院分区：
文献类型：
--
作者：
Ding, Heyuan;Wang, Tao;Li, Yiming
成骨细胞和骨细胞凋亡增加是糖皮质激素（GC）诱导骨坏死的主要机制。在目前的研究中，我们研究了地塞米松（Dex）诱导的成骨细胞和骨细胞凋亡是否是通过激活转化生长因子-β（TGF-β）激活的激酶1（TAK 1）介导的，以及TAK 1抑制是否可以促进生存对抗Dex的有害影响。我们发现TAK 1在成骨细胞MLO-Y 4和成骨细胞OB-6中被Dex激活，这被两种已知的抗氧化剂N-乙酰半胱氨酸（NAC）和依布硒啉阻止。TAK 1抑制剂LYTAK 1和5 Z-7-oxozeaenol（57-OZ）可抑制Dex诱导的MLO-Y 4和OB-6细胞凋亡。同时，shRNA介导的TAM 1的敲低也抑制了Dex对MLO-Y 4和OB-6细胞的损伤。另一方面，外源性过表达TAK 1可增强Dex诱导的MLO-Y 4和OB-6细胞凋亡。在分子水平上，我们发现TAKI介导Dex诱导的促凋亡Pyk 2-JNK激活。TAK 1的抑制或沉默几乎消除了Dex在MLO-Y 4和OB-6细胞中的Pyk 2-JNK磷酸化。另一方面，TAK 1过表达增加了Dex对上述细胞中Pyk 2-JNK磷酸化的活性。我们的结论是，部分的促凋亡作用的地塞米松对成骨细胞和骨细胞介导的TAK 1激活，和TAK 1的抑制可能会保护从GC诱导的损伤成骨细胞和骨细胞。(C)2015 Elsevier Inc. All rights reserved.
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-beta (TGF-beta)-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 TAM1 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 TAKI mediated Dex-induced proapoptotic 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. (C) 2015 Elsevier Inc. All rights reserved.