IκB kinase (IKK)β, but not IKKα, is a critical mediator of osteoclast survival and is required for inflammation-induced bone loss

Abstract

Transcription factor, nuclear factor κB (NF-κB), is required for osteoclast formation in vivo and mice lacking both of the NF-κB p50 and p52 proteins are osteopetrotic. Here we address the relative roles of the two catalytic subunits of the IκB kinase (IKK) complex that mediate NF-κB activation, IKKα and IKKβ, in osteoclast formation and inflammation-induced bone loss. Our findings point out the importance of the IKKβ subunit as a transducer of signals from receptor activator of NF-κB (RANK) to NF-κB. Although IKKα is required for RANK ligand-induced osteoclast formation in vitro, it is not needed in vivo. However, IKKβ is required for osteoclastogenesis in vitro and in vivo. IKKβ also protects osteoclasts and their progenitors from tumor necrosis factor α–induced apoptosis, and its loss in hematopoietic cells prevents inflammation-induced bone loss.

NLRP2, an Inhibitor of the NF-κB Pathway, Is Transcriptionally Activated by NF-κB and Exhibits a Nonfunctional Allelic Variant

“…Based on these data, both positive and negative regulators appear to be less dispensable in mature cells where they may establish a balance that controls the activity of NF-B. NF-B has been shown to protect osteoclast progenitors from apoptosis (26) and to be activated in bone marrow and cord blood progenitor cells (27). Additionally, it has been described that NF-B activation can prevent chondrogenesis and myogenesis from mesenchymal cells (28).…”

Unravelling the complexities of the NF-κB signalling pathway using mouse knockout and transgenic models

“…In keeping with the capacity of NF-kB to inhibit or promote apoptosis, loss of IKKb function has similar outcomes, which depend on the type of stress and the tissue involved (Graham and Gibson, 2005). For example, whereas conditional knockouts have shown that IKKb protects macrophages , osteoclasts (Ruocco et al, 2005) and gut epithelium (Chen et al, 2003) from apoptosis triggered by TLR signals, IKKb is required for neuronal apoptosis induced by ischemic brain injury (Herrmann et al, 2005). While a detailed account of the role played by IKKb in cell survival is dealt with elsewhere in this edition (Ge´linas, 2006), the specific ablation of IKKb in hepatocytes helps illustrate the nuances of NF-kB antiapoptotic function in adult mice.…”

“…For example, IKKb is crucial for the production of various inflammatory cytokines by macrophages , it is involved in inflammation-induced bone loss (Ruocco et al, 2005) and it has been implicated in the inflammatory component of obesityinduced insulin resistance (Arkan et al, 2005). In the case of the link between inflammation and obesityinduced diabetes, conditional deletion of IKKb in different mouse tissues reveals the importance of NF-kBdependent myeloid inflammatory responses in this disease (Arkan et al, 2005).…”

IKKβ in postnatal perichondrium remotely controls endochondral ossification of the growth plate through downregulation of MCP-5

“…Bone remodeling depends on the orchestrated balance between bone formation and bone resorption. The role for IKK-NF-κB signaling in osteoclastogenesis is well established, 16 but far less is known about role for IKKβ in bone formation. We therefore crossed Ikkβ F/F mice 10 with mice expressing Cre recombinase under the control of type I collagen promoter elements.…”

“…The development and activation of osteoclasts are well characterized at the genetic and molecular levels, 14,15 and the role of IKK signaling in these processes has been established. 16 In contrast, less is known about the role of IKK in osteoblast development.…”