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TAK1 is essential for osteoclast differentiation and an important modulator of cell death by apoptosis and necroptosis

dr.qinan 添加于 2012-12-9 11:30 | 2282 次阅读 | 0 个评论

作者
Lamothe B, Lai Y, Xie M, Schneider MD, Darnay BG
摘要
TGFbeta-activated kinase 1 (TAK1), a MAP3 kinase, plays an essential role in inflammation by activating the IKK/NF-kappaB and stress kinase (p38 and JNK) pathways in response to many stimuli. The TNF superfamily member RANKL regulates osteoclastogenesis through its receptor, RANK, and the signaling adaptor TRAF6. Because TAK1 activation is mediated through TRAF6 in the IL1R and TLR pathways, we sought to investigate the consequence of TAK1 deletion in RANKL-mediated osteoclastogenesis. We generated M-CSF-derived monocytes from the bone marrow of mice with TAK1 deletion in the myeloid lineage. Unexpectedly, TAK1-deficient monocytes in culture died rapidly but could be rescued by retroviral expression of TAK1, inhibition of RIP1 kinase activity with necrostatin-1, or simultaneous genetic deletion of TNFR1. Further investigation using TAK1-deficient mouse embryonic fibroblasts revealed that TNFalpha-induced cell death was abrogated by the simultaneous inhibition of caspases and knockdown of RIP3, suggesting that TAK1 is an important modulator of both apoptosis and necroptosis. Moreover, TAK1-deficient monocytes rescued from programmed cell death did not form mature osteoclasts in response to RANKL, indicating that TAK1 is indispensable to RANKL-induced osteoclastogenesis. To our knowledge, we are the first to report that mice in which TAK1 has been conditionally deleted in osteoclasts develop osteopetrosis.
详细资料
- 文献种类:期刊
- 期刊名称: Molecular and Cellular Biology
- 期刊缩写: Mol Cell Biol
- 期卷页: 2012年
- 地址: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- ISBN: 0270-7306
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