Selective inhibition of NF-κB blocks osteoclastogenesis and prevents inflammatory bone destruction in vivo

Abstract

Bone destruction is a pathological hallmark of several chronic inflammatory diseases, including rheumatoid arthritis and periodontitis. Inflammation-induced bone loss of this sort results from elevated numbers of bone-resorbing osteoclasts. Gene targeting studies have shown that the transcription factor nuclear factor-kappa B (NF-kappa B) has a crucial role in osteoclast differentiation, and blocking NF-kappa B is a potential strategy for preventing inflammatory bone resorption. We tested this approach using a cell-permeable peptide inhibitor of the I kappa B-kinase complex, a crucial component of signal transduction pathways to NF-kappa B. The peptide inhibited RANKL-stimulated NF-kappa B activation and osteoclastogenesis both in vitro and in vivo. In addition, this peptide significantly reduced the severity of collagen-induced arthritis in mice by reducing levels of tumor necrosis factor-alpha and interleukin-1 beta, abrogating joint swelling and reducing destruction of bone and cartilage. Therefore, selective inhibition of NF-kappa B activation offers an effective therapeutic approach for inhibiting chronic inflammatory diseases involving bone resorption.

Amelioration of acute inflammation by systemic administration of a cell‐permeable peptide inhibitor of NF‐κB activation

“…In contrast, the mutant NBD peptide, even at a dose of 500 g/mouse, did not show any effect on carrageenan-induced NF-B DNA binding activity (Figure 2D). It was found previously that the NBD peptide at the same doses did not affect the DNA binding of the NF-Y or Oct-1 transcription factors (12,14).…”

“…The housekeeping gene ␤-actin was used as an internal control. Total RNA (7 g) was reverse-transcribed into complementary DNA by using oligo(dT) [12][13][14][15][16][17][18] primer (Invitrogen) and Superscript II reverse transcriptase (Invitrogen). Complementary DNA (1 l) was amplified by PCR using Taq polymerase (Promega, Madison, WI) according to the manufacturer's instructions.…”

“…Notably, however, the NBD peptide did not affect the basal activity of the IKK, but only suppressed the induction of activity in response to proinflammatory cytokines. More recent studies have shown that continuous administration of the NBD peptide effectively ameliorates inflammatory responses in animal models of inflammation without overt signs of toxicity (14).…”

NF-κB and the regulation of hematopoiesis

“…66 In mouse models of arthritis, this NDB peptide inhibited osteoclastogenesis but also prevented the inflammatory bone destruction. 67 Finally, curcumin has been shown to inhibit in vitro NF-kB activation and consequently inhibits both RANKL-and TNFainduced osteoclast differentiations. 68 …”

Tectorigenin inhibits RANKL‐induced osteoclastogenesis via suppression of NF‐κB signalling and decreases bone loss in ovariectomized C57BL/6

“…Considering the importance of NF‐κB signalling in osteoclast differentiation,20 we investigated the effect of tectorigenin on RANKL‐induce activation of NF‐κB signalling on BMM cells in vitro. In Western blot assay, phosphorylation and protein levels of NF‐κB p65 and IκBα were measured in the present study.…”