Abstract
Physiologic osteoclastogenesis entails activation of multiple signal transduction pathways distal to the cell membrane receptor RANK. However, atypical osteoclastogenesis driven by pro-inflammatory stimuli has been described. We have reported recently a novel mechanism whereby endogenous mutational activation of the classical NF-κB pathway is sufficient to induce RANKL/RANK-independent osteoclastogenesis. Here we investigate the physiologic relevance of this phenomenon in vivo. Using a knock-in approach, the active form of IKK2, namely IKK2SSEE, was introduced into the myeloid lineage with the aid of CD11b-cre mice. Phenotypic assessment revealed that expression of IKK2SSEE in the myeloid compartment induced significant bone loss in vivo. This observation was supported by a dramatic increase in the number and size of osteoclasts in trabecular regions, elevated levels of circulating TRACP-5b, and reduced bone volume. Mechanistically, we observed that IKK2SSEE induced high expression of not only p65 but also p52 and RelB; the latter two molecules are considered exclusive members of the alternative NF-κB pathway. Intriguingly, RelB and P52 were both required to mediate the osteoclastogenic effect of IKK2SSEE and co-expression of these two proteins was sufficient to recapitulate osteoclastogenesis in the absence of RANKL or IKK2SSEE. Furthermore, we found that NF-κB2/p100 is a potent inhibitor of IKK2SSEE-induced osteoclastogenesis. Deletion of p52 enabled more robust osteoclast formation by the active kinase. In summary, molecular activation of IKK2 may play a role in conditions of pathologic bone destruction, which may be refractory to therapeutic interventions targeting the proximal RANKL/RANK signal.
Highlights
Bone metabolism is tightly regulated by the actions of osteoblasts and osteoclasts throughout life [1]
This ubiquitous pathway controls physiologic and pathologic responses in various tissues and encompasses several critical kinases and signaling molecules with varying degrees of contribution to tissue health and disease [7,8]. These proteins have been classified into canonical and non-canonical NF-kB pathways. The former pathway which is activated by RANK ligand as well as by inflammatory stimuli such as TNF and IL-1b, is regulated by the IKK complex dominated by IKK2 and IKKc/NEMO leading to phosphorylation of IkB and activation of p50, p65, cRel transcriptional complexes
We have established that deletion of the IKK2 gene in the myeloid compartment impedes osteoclastogenesis [11]
Summary
Bone metabolism is tightly regulated by the actions of osteoblasts and osteoclasts throughout life [1]. The critical role of NF-kB in osteoclast differentiation and bone homeostasis has been widely investigated [5,6] This ubiquitous pathway controls physiologic and pathologic responses in various tissues and encompasses several critical kinases and signaling molecules with varying degrees of contribution to tissue health and disease [7,8]. Genetic studies have shown that all members of canonical and non-canonical NF-kB pathway are crucial for normal skeletal development and bone health In this regard, deletion of IKK1 [10], IKK2 [11,12], NEMO (unpublished data and [13]), NIK, p52/p50, p65, RelB, and cRel resulted with impaired osteoclast differentiation and/or function and abnormal skeletal development [14,15,16]
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