Lipopolysaccharide of Aggregatibacter actinomycetemcomitans up‐regulates inflammatory cytokines, prostaglandin E₂ synthesis and osteoclast formation in interleukin‐1 receptor antagonist‐deficient mice

Abstract

IL-1Ra regulates IL-1 activity and appears to reduce the levels of other inflammatory cytokines, including TNF-α and IL-6, while it also reduces expression of the EP4 receptor related to prostanoid sensitivity and osteoclast formation. These results suggest that IL-1Ra is an important molecule for inhibition of inflammatory periodontal bone resorption.

Inflammatory Bone Loss in Experimental Periodontitis Induced by Aggregatibacter actinomycetemcomitans in Interleukin-1 Receptor Antagonist Knockout Mice

“…Histo- pathological analysis has revealed marked synovial and periarticular inflammation, accompanied by articular erosion, caused by invasion of granulation tissue in those mice (25,52). Mizutani et al reported that stimulation of supernatant fluids from IL-1Ra KO mouse peritoneal macrophages with A. actinomycetemcomitans LPS induced severe calvarial bone resorption, in contrast to the findings for WT mice (22). Accordingly, we reasoned that IL-1Ra KO mice might be a suitable model animal for studies of experimental periodontitis.…”

“…RANK is expressed at very high levels on osteoclast precursors and is required for osteoclast differentiation and activation (55). RANK mRNA expression is elevated in IL-1Ra KO mouse bone marrow cells (22). RANKL binds to RANK, to induce bone resorption (56,57).…”

“…Previous studies of proinflammatory cytokine production, osteoclast formation, and bone resorption in IL-1Ra knockout (KO) and wild-type (WT) mice in response to A. actinomycetemcomitans LPS have demonstrated that IL-1Ra regulates IL-1 activity, and it appears to reduce the levels of other proinflammatory cytokines, including tumor necrosis factor alpha (TNF-␣) and IL-6, while reducing the expression of the EP4 receptor, which is related to prostanoid sensitivity and osteoclast formation in vitro (22). IL-1Ra inhibited osteoclast formation (23), and it decreased bone resorption in ovariectomized rats (24).…”

Puerarin Prevents LPS-Induced Osteoclast Formation and Bone Loss <i>via</i> Inhibition of Akt Activation

“…Our data and previous study showed that LPS could trigger osteoclast precursor RAW264.7 cells to release pro-inflammatory cytokines TNF-α, IL-1β and PGE 2 , that directly stimulate osteoclast differentiation, and increase excessive bone resorption. 4,5) Furthermore, we demonstrated that LPS dramatically increased mRNA expression of osteoclast-specific genes such as TRAP, cathepsin K and MMP-9 (Table 3), involved in degrading the bone matrix during bone resorption by initiating the bone resorptive process, or by removing the collageous layer from the bone surface before demineralization begins. Combining these previous reports and our results, we conclude that LPS can directly induce osteoclastogenesis independent of RANKL, and afterwards cause bone resorption in inflammatory bone destruction diseases like osteomyelitis, septic arthritis, periodontitis.…”

“…3) LPS induces the production of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, prostaglandin E 2 (PGE 2 ) and IL-6, that are able to directly stimulate osteoclast differentiation and ultimately lead to the destructive bone loss via increasing the expression of receptor activator for nuclear factor-κB ligand (RANKL). [4][5][6] RANKL is the key cytokine that stimulates entire processes for the development of bone-resorbing osteoclasts. 5,7) The binding of RANKL to its receptor RANK triggers the activation of signaling molecules such as Akt that subsequently induce the activation of transcription factors to regulate the expression of genes required for osteoclast differentiation and survival.…”