The IκB Function of NF-κB2 p100 Controls Stimulated Osteoclastogenesis

Abstract

The prototranscription factor p100 represents an intersection of the NF-B and I B families, potentially serving as both the precursor for the active NF-B subunit p52 and as an I B capable of retaining NF-B in the cytoplasm. NF-B-inducing kinase (NIK) controls processing of p100 to generate p52, and thus NIK-deficient mice can be used to examine the biological effects of a failure in such processing. We demonstrate that treatment of wild-type osteoclast precursors with the osteoclastogenic cytokine receptor activator of NF-B ligand (RANKL) increases both expression of p100 and its conversion to p52, resulting in unchanged net levels of p100. In the absence of NIK, p100 expression is increased by RANKL, but its conversion to p52 is blocked, leading to cytosolic accumulation of p100, which, acting as an I B protein, binds NF-B complexes and prevents their nuclear translocation. High levels of unprocessed p100 in osteoclast precursors from NIK Ϫ / Ϫ mice or a nonprocessable form of the protein in wild-type cells impair RANKL-mediated osteoclastogenesis. Conversely, p100-deficient osteoclast precursors show enhanced sensitivity to RANKL. These data demonstrate a novel, biologically relevant means of regulating NF-B signaling, with upstream control and kinetics distinct from the classical I B ␣ pathway.

NF-κB and the regulation of hematopoiesis

“…NIK-deficient bone marrow cells are unable to differentiate into mature osteoclasts upon RANK stimulation. 16 However, no osteopetrotic phenotype has been observed in NIK-deficient or mutant (aly/aly mice expressing a mutant NIK protein) mouse models under basal conditions. 16 However, after RANKL delivery, the number of osteoclasts is reduced in NIK-deficient mice compared to wildtype animals.…”

“…16 However, no osteopetrotic phenotype has been observed in NIK-deficient or mutant (aly/aly mice expressing a mutant NIK protein) mouse models under basal conditions. 16 However, after RANKL delivery, the number of osteoclasts is reduced in NIK-deficient mice compared to wildtype animals. 16 The importance of NIK in osteoclast development has been confirmed in a serum transferred arthritis (STA) model.…”

“…16 However, after RANKL delivery, the number of osteoclasts is reduced in NIK-deficient mice compared to wildtype animals. 16 The importance of NIK in osteoclast development has been confirmed in a serum transferred arthritis (STA) model. While inflammation was shown to induce RANKL secretion and osteoclast differentiation in wild-type animals, it was demonstrated that NIK-deficient mice show a reduction of bone erosion.…”

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

“…Mice expressing a mutant form of p100 that does not allow for processing show defective activation of RelAcontaining dimers, impaired development of secondary lymphoid organs and B cells, and impaired osteoclastogenesis [97]. Cytosolic accumulation of p100 in nik −/− osteoclast precursors leads to enhanced association of RelA with p100 and defective RANKL-induced osteoclastogenesis [98]. Sequestration of RelA:p50 by p100 mediates a immunosuppressive phenotype observed in nik −/− mice through regulating the activation of naïve T cells [99].…”

Non-canonical NF-κB signaling pathway

“…Indeed, the NF-κB-inducing kinase (NIK) induces p100 processing in transfected cells and is required for in vivo p100 processing in splenocytes [5]. Moreover, endogenous p100 processing can be induced by various receptor signals in a NIK-dependent manner [7,[11][12][13][14].…”