Myeloid Deletion of Nemo Causes Osteopetrosis in Mice Owing to Upregulation of Transcriptional Repressors
Identifieur interne : 008594 ( Ncbi/Checkpoint ); précédent : 008593; suivant : 008595Myeloid Deletion of Nemo Causes Osteopetrosis in Mice Owing to Upregulation of Transcriptional Repressors
Auteurs : Gaurav Swarnkar [États-Unis] ; Kyuhwan Shim [États-Unis] ; Amjad M. Nasir [États-Unis] ; Kuljeet Seehra [États-Unis] ; Hung-Po Tim Chen [États-Unis] ; Gabriel Mbalaviele [États-Unis] ; Yousef Abu-Amer [États-Unis]Source :
- Scientific Reports [ 2045-2322 ] ; 2016.
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.
Url:
DOI: 10.1038/srep29896
PubMed: 27435916
PubMed Central: 4951754
Affiliations:
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Myeloid Deletion of Nemo Causes Osteopetrosis in Mice Owing to Upregulation of Transcriptional Repressors</title>
<author><name sortKey="Swarnkar, Gaurav" sort="Swarnkar, Gaurav" uniqKey="Swarnkar G" first="Gaurav" last="Swarnkar">Gaurav Swarnkar</name>
<affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Orthopaedic Surgery, Washington University School of Medicine</institution>
, 660 South Euclid Avenue, St Louis, MO 63110,<country>USA</country>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author><name sortKey="Shim, Kyuhwan" sort="Shim, Kyuhwan" uniqKey="Shim K" first="Kyuhwan" last="Shim">Kyuhwan Shim</name>
<affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Orthopaedic Surgery, Washington University School of Medicine</institution>
, 660 South Euclid Avenue, St Louis, MO 63110,<country>USA</country>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author><name sortKey="Nasir, Amjad M" sort="Nasir, Amjad M" uniqKey="Nasir A" first="Amjad M." last="Nasir">Amjad M. Nasir</name>
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, 660 South Euclid Avenue, St Louis, MO 63110,<country>USA</country>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author><name sortKey="Seehra, Kuljeet" sort="Seehra, Kuljeet" uniqKey="Seehra K" first="Kuljeet" last="Seehra">Kuljeet Seehra</name>
<affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Orthopaedic Surgery, Washington University School of Medicine</institution>
, 660 South Euclid Avenue, St Louis, MO 63110,<country>USA</country>
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<country xml:lang="fr">États-Unis</country>
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<author><name sortKey="Chen, Hung Po Tim" sort="Chen, Hung Po Tim" uniqKey="Chen H" first="Hung-Po Tim" last="Chen">Hung-Po Tim Chen</name>
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, 660 South Euclid Avenue, St Louis, MO 63110,<country>USA</country>
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<country xml:lang="fr">États-Unis</country>
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<author><name sortKey="Mbalaviele, Gabriel" sort="Mbalaviele, Gabriel" uniqKey="Mbalaviele G" first="Gabriel" last="Mbalaviele">Gabriel Mbalaviele</name>
<affiliation wicri:level="1"><nlm:aff id="a2"><institution>Division of Bone and Mineral Diseases, Washington University School of Medicine</institution>
, 660 South Euclid Avenue, St Louis, MO 63110,<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author><name sortKey="Abu Amer, Yousef" sort="Abu Amer, Yousef" uniqKey="Abu Amer Y" first="Yousef" last="Abu-Amer">Yousef Abu-Amer</name>
<affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Orthopaedic Surgery, Washington University School of Medicine</institution>
, 660 South Euclid Avenue, St Louis, MO 63110,<country>USA</country>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<series><title level="j">Scientific Reports</title>
<idno type="eISSN">2045-2322</idno>
<imprint><date when="2016">2016</date>
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<front><div type="abstract" xml:lang="en"><p>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. <italic>NEMO</italic>
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 <italic>NEMO</italic>
(<italic>IKBKG)</italic>
human gene manifest skeletal defects implicating NEMO in the regulation of bone homeostasis. To specifically investigate such role, we conditionally deleted <italic>Nemo</italic>
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.</p>
</div>
</front>
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<affiliations><list><country><li>États-Unis</li>
</country>
</list>
<tree><country name="États-Unis"><noRegion><name sortKey="Swarnkar, Gaurav" sort="Swarnkar, Gaurav" uniqKey="Swarnkar G" first="Gaurav" last="Swarnkar">Gaurav Swarnkar</name>
</noRegion>
<name sortKey="Abu Amer, Yousef" sort="Abu Amer, Yousef" uniqKey="Abu Amer Y" first="Yousef" last="Abu-Amer">Yousef Abu-Amer</name>
<name sortKey="Chen, Hung Po Tim" sort="Chen, Hung Po Tim" uniqKey="Chen H" first="Hung-Po Tim" last="Chen">Hung-Po Tim Chen</name>
<name sortKey="Mbalaviele, Gabriel" sort="Mbalaviele, Gabriel" uniqKey="Mbalaviele G" first="Gabriel" last="Mbalaviele">Gabriel Mbalaviele</name>
<name sortKey="Nasir, Amjad M" sort="Nasir, Amjad M" uniqKey="Nasir A" first="Amjad M." last="Nasir">Amjad M. Nasir</name>
<name sortKey="Seehra, Kuljeet" sort="Seehra, Kuljeet" uniqKey="Seehra K" first="Kuljeet" last="Seehra">Kuljeet Seehra</name>
<name sortKey="Shim, Kyuhwan" sort="Shim, Kyuhwan" uniqKey="Shim K" first="Kyuhwan" last="Shim">Kyuhwan Shim</name>
</country>
</tree>
</affiliations>
</record>
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