Inhibition of osteoblastic bone formation by nuclear factor-κB

Abstract

An imbalance in bone formation relative to bone resorption results in the net bone loss in osteoporosis and inflammatory bone diseases. While it is well known how bone resorption is stimulated, the molecular mechanisms that mediate impaired bone formation are poorly understood. Here we show that the time- and stage-specific inhibition of endogenous IκB kinase (IKK)/nuclear factor-kappa B (NF-κB) NF-κB in differentiated osteoblasts significantly increases trabecular bone mass and bone mineral density without affecting osteoclast activities in young mice. Moreover, the inhibition of IKK/NF-κB in differentiated osteoblasts maintains bone formation, thereby preventing osteoporotic bone loss induced by ovariectomy (OVX) in adult mice. The inhibition of IKK/NF-κB enhances the expression of Fra-1, an essential factor for bone matrix formation in vitro and in vivo. Taken together, our results suggest that targeting IKK/NF-κB may help to promote bone formation in the treatment of osteoporosis and other bone diseases.

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

“…Moreover, we used the Col1a1 promoter to specifically drive Cre recombinase in the osteoblast lineage much like how they used it to drive IKKγ-DN, so the inconsistency is not because of differences in the stage of the osteoblast at which IKK was inactivated. The most plausible reason then for the inconsistency is that they overexpressed the IKKγ-DN, whereas we conditionally The C417R mutant of human IKKγ (equivalent to C410R mutant of mouse), which Chang et al 35 used in their study, has been shown to serve as a dominant-negative mutant for cytokine-induced NF-κB activation in human T cells, 36 whereas NF-κB activation by lipopolysaccharide is normal when this mutant is expressed in mouse B cells. 37 In addition, IKKγ has been shown to control the activation of JNK and p38 MAPK by cooperating with Ubc13 E2 ubiqutin-conjugating enzyme.…”

“…38 JNK and p38 MAPK are well-known cytokineresponsive MAPKs and are coordinatively activated with NF-κB in response to a wide range of stimuli. Of note, JNK and p38 MAPK are also known to regulate Fra-1, which Chang et al 35 have shown is dysregulated in IKKγ-DN-expressing cells.…”

“…35 In addition, they reported that osteobast lineage-specific expression of IKKγ-DN in mice prevented the osteoporotic bone loss induced by ovariectomy. 35 Our different observations cannot be attributed to different genetic backgrounds of the mice, as they too used C57BL/6 mice. Moreover, we used the Col1a1 promoter to specifically drive Cre recombinase in the osteoblast lineage much like how they used it to drive IKKγ-DN, so the inconsistency is not because of differences in the stage of the osteoblast at which IKK was inactivated.…”

“…Contrary to expectations based on the well-known importance of cytokine signaling in the regulation of bone homeostasis, 22,34 we found that IKKβ is dispensable in the osteoblast lineage during normal development and also for osteoprotection during postmenopausal osteoporosis. Chang et al 35 have reported that the inhibition of IKK in the osteoblast lineage by a dominant-negative form of the regulatory subunit IKKγ (also known as NEMO), IKKγ-DN, expressed from the promoter of bone γ-carboxyglutamate protein-2 (Bglap2) or Col1a1 resulted in a substantial increase of trabecular bone mass and bone mineral density without affecting the activities of osteoclasts in young mice. 35 In addition, they reported that osteobast lineage-specific expression of IKKγ-DN in mice prevented the osteoporotic bone loss induced by ovariectomy.…”

“…Chang et al 35 have reported that the inhibition of IKK in the osteoblast lineage by a dominant-negative form of the regulatory subunit IKKγ (also known as NEMO), IKKγ-DN, expressed from the promoter of bone γ-carboxyglutamate protein-2 (Bglap2) or Col1a1 resulted in a substantial increase of trabecular bone mass and bone mineral density without affecting the activities of osteoclasts in young mice. 35 In addition, they reported that osteobast lineage-specific expression of IKKγ-DN in mice prevented the osteoporotic bone loss induced by ovariectomy. 35 Our different observations cannot be attributed to different genetic backgrounds of the mice, as they too used C57BL/6 mice.…”