RelB is the NF-κB subunit downstream of NIK responsible for osteoclast differentiation

Abstract

NF-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-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-␣ 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-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.bone ͉ metastasis ͉ receptor activator of NF-B ligand

TNF activates calcium–nuclear factor of activated T cells (NFAT)c1 signaling pathways in human macrophages

“…In contrast to TNF, RANKL does not induce sustained canonical NF-κB activation (21,28), and thus noncanonical NF-κB signaling typically mediated by NIK/IKKα has been implicated in RANKL-induced osteoclastogenesis (29,30). Consistent with these reports that used murine cells, RANKL-induced multinuclear cell formation was decreased in human macrophages when the noncanonical NF-κB pathway was inhibited by RNA interference (RNAi)-mediated knockdown of IKKα expression (Fig.…”

The Src family kinase, Lyn, suppresses osteoclastogenesis in vitro and in vivo

“…A similar scenario holds in the context of other proteins such as FHL2, which dampens OC formation in response to stress situations (42). Similarly, the absence of NF-kB molecules including NIK, p65, or RelB modulate in vivo osteoclastogenesis exclusively in the presence of elevated RANKL or TNF (43)(44)(45). Our data, therefore, establish Lyn as the second functionally significant SFK in the OC, exerting its effects in a manner antithetically different from c-Src.…”

A single NFκB system for both canonical and non-canonical signaling

“…RelB:p52 activation was proposed to rescue the delay in the early mammary gland development observed in transgenic mice overexpressing the IκBα super-repressor [83]. Defective osteoclastogenesis observed in nik −/− mice can be restored by overexpressing RelB, but not RelA, indicating a specific function of RelB in osteoclast differentiation [84]. Further, specific expression of relb transcripts was found in antigen-presenting cells, and requirement of RelB for CD4 + CD8α − dendritic cell development was reported [85][86][87].…”