title: Myeloid Deletion of Nemo Causes Osteopetrosis in Mice Owing to Upregulation of Transcriptional Repressors.
abstract: The transcription factor NF-κB is central to numerous physiologic processes including bone development, and its activation is controlled by IKKγ (also called NEMO), the regulatory subunit of IKK complex. NEMO is X-linked, and mutations in this gene result in Incontinentia Pigmenti in human hemizygous females. In mice, global deficiency causes embryonic lethality. In addition, certain point mutations in the NEMO (IKBKG) human gene manifest skeletal defects implicating NEMO in the regulation of bone homeostasis. To specifically investigate such role, we conditionally deleted Nemo from osteoclast and myeloid progenitors. Morphometric, histologic, and molecular analyses demonstrate that myeloid NEMO deletion causes osteopetrosis in mice. Mechanistically, NEMO deficiency hampered activation of IKK complex in osteoclast precursors, causing arrest of osteoclastogenesis and apoptosis. Interestingly, inhibiting apoptosis by genetic ablation of TNFr1 significantly increased cell survival, but failed to rescue osteoclastogenesis or reverse osteopetrosis. Based on this observation, we analyzed the expression of different regulators of osteoclastogenesis and discovered that NEMO deletion leads to increased RBPJ expression, resulting in a decrease of Blimp1 expression. Consequently, expression of IRF8 and Bcl6 which are targets of Blimp1 and potent osteoclastogenic transcriptional repressors, is increased. Thus, NEMO governs survival and osteoclast differentiation programs through serial regulation of multiple transcription factors.
authors.affiliation: Department of Orthopaedic Surgery, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Swarnkar
authors.affiliation: Department of Orthopaedic Surgery, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA.
authors.forename: Kyuhwan
authors.initials: K
authors.lastname: Shim
authors.affiliation: Department of Orthopaedic Surgery, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA.
authors.forename: Amjad M
authors.initials: AM
authors.lastname: Nasir
authors.affiliation: Department of Orthopaedic Surgery, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA.
authors.forename: Kuljeet
authors.initials: K
authors.lastname: Seehra
authors.affiliation: Department of Orthopaedic Surgery, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA.
authors.forename: Hung-Po Tim
authors.initials: HP
authors.lastname: Chen
authors.affiliation: Division of Bone and Mineral Diseases, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Mbalaviele
authors.affiliation: Department of Orthopaedic Surgery, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA.
authors.forename: Yousef
authors.initials: Y
authors.lastname: Abu-Amer
mesh_terms: D000818:Animals; D001846:Bone Development / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D051379:Mice; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D010022:Osteopetrosis / Q000235:genetics* / Q000503:physiopathology; D017354:Point Mutation; D000074462:Positive Regulatory Domain I-Binding Factor 1 / Q000235:genetics; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D047908:Intracellular Signaling Peptides and Proteins; C514981:NEMO protein, mouse; D016328:NF-kappa B; C513258:Prdm1 protein, mouse; C497571:Rbpj protein, mouse; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D000074462:Positive Regulatory Domain I-Binding Factor 1