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
Osteoclasts (OCs) function to reabsorb bone and are responsible for the bone loss associated with inflammatory arthritis and osteoporosis. OC numbers are elevated in most disorders of accelerated bone destruction, reflecting altered rates of precursor differentiation and apoptosis. Both of these processes are regulated by the JNK family of MAP kinases. In this study, we have demonstrated that the NF-κB subunit RelA/p65 inhibits JNKmediated apoptosis during a critical period of commitment to the OC phenotype in response to the cytokine RANKL. This RelA/p65-mediated arrest of cell death led to enhanced OC differentiation. Hence, Rela -/-OC precursors displayed prolonged JNK activation in response to RANKL, and this was accompanied by an increase in cell death that prevented efficient differentiation. Although complete blockade of JNK activity inhibits osteoclastogenesis, both short-term blockade in RelA-deficient cultures and suppression of the downstream mediator, Bid rescued apoptosis and differentiation. These antiapoptotic effects were RelA specific, as overexpression of RelA, but not RelB, blocked apoptosis and rescued differentiation in Rela -/-precursors. Thus, RelA blocks a RANKL-induced, apoptotic JNK-Bid pathway, thereby promoting OC differentiation. Consistent with this, mice lacking RelA/p65 in the hematopoietic compartment were shown to have a deficient osteoclastogenic response to RANKL and were protected from arthritis-induced osteolysis. IntroductionOsteoclasts (OCs) are multinucleated cells derived from myeloid bone marrow progenitors that express RANK, the receptor for the key osteoclastogenic cytokine RANKL (1). Increased OC formation and activity is observed in many osteopenic disorders, including postmenopausal osteoporosis, lytic bone metastasis, and rheumatoid arthritis, and leads to pain and structural instability. Osteoblast lineage cells express a membrane-bound form of RANKL, a member of the TNF cytokine family. Like other members of the TNF receptor superfamily, RANK strongly activates the NF-κB pathway.In mammals, the NF-κB family has 5 members: RelA/p65, RelB, c-Rel, NF-κB1/p50, and NF-κB2/p52 (2). In the canonical NF-κB pathway, ligation of RANK activates the inhibitor of IκB kinase (IKK) complex, which phosphorylates NF-κB-associated IκBα, leading to its ubiquitination and proteosomal degradation. These events release NF-κB dimers containing RelA and c-Rel in the cytosol, allowing them to translocate into the nucleus where they enhance transcription of target genes. In the alternative NF-κB pathway, NF-κB-inducing kinase (NIK) and IKKα target p100 for ubiquitination and processing, thereby allowing nuclear translocation of predominantly RelB-containing dimers.The importance of NF-κB in osteoclastogenesis has been highlighted by several mouse models. Mice lacking both NF-κB1 and NF-κB2 have severe osteopetrosis with complete absence of OCs
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