In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 105, No. 10 ( 2008-03-11), p. 3897-3902
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.0708576105
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2008
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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