RelB is the NF-kappaB subunit downstream of NIK responsible for osteoclast differentiation.
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.
Vaira
Sergio
S
Division of Bone and Mineral Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Johnson
Trevor
T
Hirbe
Angela C
AC
Alhawagri
Muhammad
M
Anwisye
Imani
I
Sammut
Benedicte
B
O'Neal
Julie
J
Zou
Wei
W
Weilbaecher
Katherine N
KN
Faccio
Roberta
R
Novack
Deborah Veis
DV
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
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