TY - JOUR
T1 - RelB is the NF-κB subunit downstream of NIK responsible for osteoclast differentiation
AU - Vaira, Sergio
AU - Johnson, Trevor
AU - Hirbe, Angela C.
AU - Alhawagri, Muhammad
AU - Anwisye, Imani
AU - Sammut, Benedicte
AU - O'Neal, Julie
AU - Zou, Wei
AU - Weilbaecher, Katherine N.
AU - Faccio, Roberta
AU - Novack, Deborah Veis
PY - 2008/3/25
Y1 - 2008/3/25
N2 - NF-κB 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-κB 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-α 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-κB pathway, culminating in activation of RelB, has a key and specific role in the differentiation of OCs that cannot be compensated for by p65.
AB - NF-κB 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-κB 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-α 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-κB pathway, culminating in activation of RelB, has a key and specific role in the differentiation of OCs that cannot be compensated for by p65.
KW - Bone
KW - Metastasis
KW - Receptor activator of NF-κB ligand
UR - http://www.scopus.com/inward/record.url?scp=41649089360&partnerID=8YFLogxK
U2 - 10.1073/pnas.0708576105
DO - 10.1073/pnas.0708576105
M3 - Article
C2 - 18322009
AN - SCOPUS:41649089360
SN - 0027-8424
VL - 105
SP - 3897
EP - 3902
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 10
ER -