The Expression of Fn14 via Mechanical Stress-activated JNK Contributes to Apoptosis Induction in Osteoblasts
The Expression of Fn14 via Mechanical Stress-activated JNK Contributes to Apoptosis Induction in Osteoblasts
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DOI：
10.1074/jbc.m113.536300
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发表时间：
2014-03-07
影响因子：
4.8
通讯作者：
Tamura, Shinri
中科院分区：
文献类型：
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作者：
Matsui, Hiroyuki;Fukuno, Naoto;Tamura, Shinri
背景：Fn14是肿瘤坏死因子受体家族中具有高度诱导性的成员。结果：大范围机械应力通过JNK诱导成骨细胞表达Fn14。结论：Fn14的表达调控机械应力诱导的成骨细胞凋亡。意义：首次阐明了Fn14介导的过度机械应力诱导细胞凋亡的机制，骨量是由成骨细胞和骨吸收破骨细胞之间的平衡来维持的。众所周知，足够的机械应力对维持骨量是必不可少的，而过高的机械应力会导致骨吸收。然而，成骨细胞如何对不同程度的机械应力做出反应还不是很清楚。在这里，我们报道了大幅度(12%)的循环拉伸诱导钙离子内流，激活了MC3T3-E1成骨细胞中活性氧的产生。然后，活性氧激活了ASK1-JNK/p38通路。激活的JNK导致成纤维细胞生长因子诱导的Fn14(Fn14，肿瘤坏死因子受体超家族成员)基因表达一过性增强。Fn14表达增强的细胞随后对Fn14的配体获得敏感性，Fn14是肿瘤坏死因子相关的弱诱导凋亡因子，并发生凋亡。另一方面，ASK1-p38途径诱导单核细胞趋化蛋白3(MCP-3)基因表达，促进破骨前细胞的趋化。相反，ERK通路被小幅度拉伸(1%)激活，并诱导两个成骨基因-Ia胶原(Col1a)和骨桥蛋白(OPn)的表达。此外，激活的JNK抑制了大范围机械拉伸负荷细胞中COL1a和OPN的诱导。小鼠原代成骨细胞经12%牵张后Fn14和MCP-3表达增强，1%牵张后COL1a和OPN表达增强。这些结果表明，成骨细胞对不同大小的机械应力的反应不同，在骨形成和吸收之间的骨代谢模式转换中起着关键作用。
Background: Fn14 is a highly inducible member of the TNF receptor family. Results: Large-magnitude mechanical stress induced Fn14 expression via JNK in osteoblasts. Conclusion: Expression of Fn14 regulates mechanical stress-induced apoptosis in osteoblasts. Significance: This is the first elucidation of the mechanism of excessive mechanical stress-induced apoptosis mediated by Fn14.Bone mass is maintained by the balance between the activities of bone-forming osteoblasts and bone-resorbing osteoclasts. It is well known that adequate mechanical stress is essential for the maintenance of bone mass, whereas excess mechanical stress induces bone resorption. However, it has not been clarified how osteoblasts respond to different magnitudes of mechanical stress. Here we report that large-magnitude (12%) cyclic stretch induced Ca2+ influx, which activated reactive oxygen species generation in MC3T3-E1 osteoblasts. Reactive oxygen species then activated the ASK1-JNK/p38 pathways. The activated JNK led to transiently enhanced expression of FGF-inducible 14 (Fn14, a member of the TNF receptor superfamily) gene. Cells with enhanced expression of Fn14 subsequently acquired sensitivity to the ligand of Fn14, TNF-related weak inducer of apoptosis, and underwent apoptosis. On the other hand, the ASK1-p38 pathway induced expression of the monocyte chemoattractant protein 3 (MCP-3) gene, which promoted chemotaxis of preosteoclasts. In contrast, the ERK pathway was activated by small-magnitude stretching (1%) and induced expression of two osteogenic genes, collagen Ia (Col1a) and osteopontin (OPN). Moreover, activated JNK suppressed Col1a and OPN induction in large-magnitude mechanical stretch-loaded cells. The enhanced expression of Fn14 and MCP-3 by 12% stretch and the enhanced expression of Col1a and OPN by 1% stretch were also observed in mouse primary osteoblasts. These results suggest that differences in the response of osteoblasts to varying magnitudes of mechanical stress play a key role in switching the mode of bone metabolism between formation and resorption.