title: TAK1 is essential for osteoclast differentiation and is an important modulator of cell death by apoptosis and necroptosis.
abstract: 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.
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Betty
authors.initials: B
authors.lastname: Lamothe
authors.forename: YunJu
authors.initials: Y
authors.lastname: Lai
authors.forename: Min
authors.initials: M
authors.lastname: Xie
authors.forename: Michael D
authors.initials: MD
authors.lastname: Schneider
authors.forename: Bryant G
authors.initials: BG
authors.lastname: Darnay
mesh_terms: D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D002470:Cell Survival; D002478:Cells, Cultured; D017353:Gene Deletion; D055786:Gene Knockout Techniques; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009000:Monocytes / Q000166:cytology* / Q000378:metabolism; D009336:Necrosis; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism; D010012:Osteogenesis; D053245:RANK Ligand / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D020930:MAP Kinase Kinase Kinases; D053245:RANK Ligand; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D000099151:MAP Kinase Kinase Kinase 7; C506236:Tnfrsf1a protein, mouse; C505689:Tnfsf11 protein, mouse; C485615:Ripk3 protein, mouse