期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 105, 期 10, 页码 3897-3902出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0708576105
关键词
bone; metastasis; receptor activator of NF-kappa B ligand
资金
- NCI NIH HHS [R01 CA097250, R56 CA097250, CA097250, P50 CA094056, CA94056, CA103035] Funding Source: Medline
- NHLBI NIH HHS [T32 HL007088] Funding Source: Medline
- NIAMS NIH HHS [R01 AR052705, AR52921, K08 AR047846, AR52705, AR47846] Funding Source: Medline
NF-kappa B 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-kappa B 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 INK completely blocked the tumor-induced loss of trabecular bone. Thus, the alternative NF-kappa B pathway, culminating in activation of RelB, has a key and specific role in the differentiation of OCs that cannot be compensated for by p65.
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