Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Mol Cell Biol. 2013 Feb;33(3):582-95. doi: 10.1128/MCB.01225-12. Epub 2012 Nov 19.
Transforming growth factor β (TGF-β)-activated kinase 1 (TAK1), a mitogen-activated protein 3 (MAP3) kinase, plays an essential role in inflammation by activating the IκB kinase (IKK)/nuclear factor κB (NF-κB) and stress kinase (p38 and c-Jun N-terminal kinase [JNK]) pathways in response to many stimuli. The tumor necrosis factor (TNF) superfamily member receptor activator of NF-κB ligand (RANKL) regulates osteoclastogenesis through its receptor, RANK, and the signaling adaptor TRAF6. Because TAK1 activation is mediated through TRAF6 in the interleukin 1 receptor (IL-1R) and toll-like receptor (TLR) pathways, we sought to investigate the consequence of TAK1 deletion in RANKL-mediated osteoclastogenesis. We generated macrophage colony-stimulating factor (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 receptor-interacting protein 1 (RIP1) kinase activity with necrostatin-1, or simultaneous genetic deletion of TNF receptor 1 (TNFR1). Further investigation using TAK1-deficient mouse embryonic fibroblasts revealed that TNF-α-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.
转化生长因子-β（TGF-β）激活激酶 1（TAK1）是一种丝裂原激活的蛋白激酶 3（MAP3）激酶，在炎症中发挥重要作用，通过激活 IκB 激酶（IKK）/核因子 κB（NF-κB）和应激激酶（p38 和 c-Jun N 末端激酶 [JNK]）通路来响应许多刺激。肿瘤坏死因子（TNF）超家族成员核因子 κB 配体（RANKL）受体激活物通过其受体 RANK 和信号适配器 TRAF6 调节破骨细胞的形成。由于 TAK1 的激活是通过白细胞介素 1 受体（IL-1R）和 Toll 样受体（TLR）通路中的 TRAF6 介导的，因此我们试图研究 TAK1 缺失在 RANKL 介导的破骨细胞形成中的后果。我们从骨髓中生成了 TAK1 在髓系中缺失的巨噬细胞集落刺激因子（M-CSF）衍生的单核细胞。出乎意料的是，培养中的 TAK1 缺陷单核细胞迅速死亡，但可以通过逆转录病毒表达 TAK1、用 necrostatin-1 抑制受体相互作用蛋白 1（RIP1）激酶活性或同时遗传缺失肿瘤坏死因子受体 1（TNFR1）来挽救。使用 TAK1 缺陷型鼠胚胎成纤维细胞的进一步研究表明，TNF-α 诱导的细胞死亡被同时抑制半胱天冬酶和敲低 RIP3 所阻断，这表明 TAK1 是细胞凋亡和坏死性凋亡的重要调节剂。此外，从程序性细胞死亡中挽救出来的 TAK1 缺陷型单核细胞在 RANKL 刺激下不能形成成熟的破骨细胞，表明 TAK1 是 RANKL 诱导的破骨细胞形成所必需的。据我们所知，我们是第一个报道 TAK1 在破骨细胞中条件性缺失的小鼠会发生骨质疏松症的人。
