title: RelB is the NF-kappaB subunit downstream of NIK responsible for osteoclast differentiation.
abstract: NF-kappaB inducing kinase (NIK) is required for osteoclastogenesis in response to pathologic stimuli, and its loss leads to functional blockade of both alternative and classical NF-kappaB caused by cytoplasmic retention by p100. We now show that deletion of p100 restores the capacity of NIK-deficient osteoclast (OC) precursors to differentiate and normalizes RelB and p65 signaling. Differentiation of NIK-/- precursors is also restored by overexpression of RelB, but not p65. Additionally, RelB-/- precursors fail to form OCs in culture, and this defect is rescued by re-expression of RelB, but not by overexpression of p65. To further support the role of RelB in OCs, we challenged RelB-/- mice with TNF-alpha in vivo and found a diminished osteoclastogenic response. We then examined tumor-induced osteolysis in both RelB-/- and NIK-/- mice by using the B16 melanoma model. Growth of tumor cells in the bone marrow was similar to WT controls, but the absence of either RelB or NIK completely blocked the tumor-induced loss of trabecular bone. Thus, the alternative NF-kappaB pathway, culminating in activation of RelB, has a key and specific role in the differentiation of OCs that cannot be compensated for by p65.
authors.affiliation: Division of Bone and Mineral Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Sergio
authors.initials: S
authors.lastname: Vaira
authors.forename: Trevor
authors.initials: T
authors.lastname: Johnson
authors.forename: Angela C
authors.initials: AC
authors.lastname: Hirbe
authors.forename: Muhammad
authors.initials: M
authors.lastname: Alhawagri
authors.forename: Imani
authors.initials: I
authors.lastname: Anwisye
authors.forename: Benedicte
authors.initials: B
authors.lastname: Sammut
authors.forename: Julie
authors.initials: J
authors.lastname: O'Neal
authors.forename: Wei
authors.initials: W
authors.lastname: Zou
authors.forename: Katherine N
authors.initials: KN
authors.lastname: Weilbaecher
authors.forename: Roberta
authors.initials: R
authors.lastname: Faccio
authors.forename: Deborah Veis
authors.initials: DV
authors.lastname: Novack
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D017353:Gene Deletion; D007113:Immunity, Innate / Q000187:drug effects; D007249:Inflammation; D051379:Mice; D008810:Mice, Inbred C57BL; D052003:NF-kappa B p52 Subunit / Q000378:metabolism; D009369:Neoplasms / Q000473:pathology; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D010012:Osteogenesis / Q000187:drug effects; D010014:Osteolysis / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism*; D021122:Protein Subunits / Q000378:metabolism*; D053245:RANK Ligand / Q000494:pharmacology; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects; D051996:Transcription Factor RelA / Q000378:metabolism; D051841:Transcription Factor RelB / Q000172:deficiency / Q000378:metabolism*; D048069:Tumor Necrosis Factors / Q000494:pharmacology; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D052003:NF-kappa B p52 Subunit; D017346:Protein Serine-Threonine Kinases; D021122:Protein Subunits; D053245:RANK Ligand; D051996:Transcription Factor RelA; D051841:Transcription Factor RelB; D048069:Tumor Necrosis Factors; D000097782:NF-kappaB-Inducing Kinase