Notch signaling inhibition protects against LPS mediated osteolysis

Goel, Peeyush N.; Egol, Alexander J.; Moharrer, Yasaman; Brandfield-Harvey, Beatrix; Ahn, Jaimo; Ashley, Jason W.

doi:10.1016/j.bbrc.2019.05.166

Cited by 7 publications

(5 citation statements)

References 34 publications

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“…It has been reported that LPS can stimulate osteoblasts and osteoclasts to secrete various inflammatory factors leading to an inflammatory response [ 7 ]. LPS can also stimulate osteoblast production and secretion of inflammatory cytokines to activate osteoclasts and promote osteoclast maturation [ 8 , 9 ]. Although the destructive effect of LPS on bone tissue has been widely recognized, the specific pathogenic mechanism remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of circular RNA circ_0138959 alleviates pyroptosis of human gingival fibroblasts via the microRNA-527/caspase-5 axis

et al. 2022

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Circular RNA (circRNA) plays a regulatory role in periodontitis. This study explored whether circ_0138959 affected lipopolysaccharide (LPS)-induced pyroptosis in human gingival fibroblasts (HGFs). The periodontal ligament (PDL) tissues and HGFs were derived from patients with periodontitis and healthy volunteers. HGFs treated with LPS were considered to mimic periodontitis in vitro . Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to evaluate the mRNA expression levels of circRNAs, miR-527, and caspase-5 (CASP5), and Western blotting assay was used to measure protein expression levels of caspase-1, caspase-4, and cleaved N-terminal gasdermin D (GSDMD-N). Cell viability was evaluated by cell counting kit-8 (CCK-8) assay. The concentration of lactate dehydrogenase (LDH), interleukin (IL)-1β, and IL-18 and the pyroptosis rate were determined to evaluate pyroptosis. The interaction between miR-527 and circ_0138959 or CASP5 was verified by dual-luciferase reporter and RNA pull-down assays. Circ_0138959 expression was higher in the PDL tissues of patients with periodontitis than in the healthy group; likewise, circ_0138959 was also upregulated in LPS-treated HGFs. Suppressed circ_0138959 increased cell viability and decreased pyroptosis of HGFs induced by LPS. miR-527 was a target of circ_0138959, and inhibition of miR-527 contributed to the dysfunction of LPS-treated HGFs and reversed the protective effects of downregulated circ_0138959. Additionally, miR-527 targeted CASP5. Increased CASP5 abrogated the effects of overexpressed miR-527 on cell viability and pyroptosis of LPS-treated HGFs. Inhibition of circ_0138959 promoted cell viability and suppressed pyroptosis of HGFs via the miR-527/CASP5 axis. Therefore, knockdown of circ_0138959 may be a promising therapy for periodontitis.

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Section: Introductionmentioning

confidence: 99%

Inhibition of circular RNA circ_0138959 alleviates pyroptosis of human gingival fibroblasts via the microRNA-527/caspase-5 axis

et al. 2022

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“…For example, it has been previously shown that mice with persistent high levels of circulating LPS have a significantly lower bone mass than mice with low levels of LPS. ( 9–12 ) Furthermore, focal LPS administration to joints has been shown to induce synovitis in horses and has been used as a model to evaluate potential treatments for acute synovitis. ( 13–17 ) Studies have been conducted on the differences between LPS levels in serum of germ‐free mice and specific pathogen‐free mice; this experiment had LPS assay inhibitors, therefore they did not show any difference between circulating LPS levels in germ‐free mice and specific pathogen‐free mice.…”

Section: Introductionmentioning

confidence: 99%

LPS-Induced Inflammation Prior to Injury Exacerbates the Development of Post-Traumatic Osteoarthritis in Mice

Mendez

Sebastian

Murugesh

et al. 2020

Journal of Bone and Mineral Research

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Osteoarthritis (OA) is a debilitating and painful disease characterized by the progressive loss of articular cartilage. Post-traumatic osteoarthritis (PTOA) is an injury-induced type of OA that persists in an asymptomatic phase for years before it becomes diagnosed in~50% of injured individuals. Although PTOA is not classified as an inflammatory disease, it has been suggested that inflammation could be a major driver of PTOA development. Here we examined whether a state of systemic inflammation induced by lipopolysaccharide (LPS) administration 5-days before injury would modulate PTOA outcomes. RNA-seq analysis at 1-day post-injury followed by micro-computed tomography (μCT) and histology characterization at 6 weeks post-injury revealed that LPS administration causes more severe PTOA phenotypes. These phenotypes included significantly higher loss of cartilage and subchondral bone volume. Gene expression analysis showed that LPS alone induced a large cohort of inflammatory genes previously shown to be elevated in synovial M1 macrophages of rheumatoid arthritis (RA) patients, suggesting that systemic LPS produces synovitis. This synovitis was sufficient to promote PTOA in MRL/MpJ mice, a strain previously shown to be resistant to PTOA. The synovium of LPS-treated injured joints displayed an increase in cellularity, and immunohistological examination confirmed that this increase was in part attributable to an elevation in type 1 macrophages. LPS induced the expression of Tlr7 and Tlr8 in both injured and uninjured joints, genes known to be elevated in RA. We conclude that inflammation before injury is an important risk factor for the development of PTOA and that correlating patient serum endotoxin levels or their state of systemic inflammation with PTOA progression may help develop new, effective treatments to lower the rate of PTOA in injured individuals.

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“…It has been confirmed that LPS can induce inflammatory bone loss [ 47 ], and LPS is recognized as a bacterial polysaccharide that can induce macrophages to differentiate into M1 phenotype and secrete pro-inflammatory factors [ 48 ]. In this study, LPS was used to induce the differentiation of macrophages into the M1 phenotype.…”

Section: Discussionmentioning

confidence: 99%

Study on Optimizing Novel Antimicrobial Peptides with Bifunctional Activity to Prevent and Treat Peri-Implant Disease

Zhang

et al. 2022

Antibiotics

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The bacterial invasions and inflammatory responses after implant placement often affect osseointegration; the increased secretion of pro-inflammatory cytokines can lead to poor formation of bone and bone absorption. Previous research has shown that the antimicrobial peptide 6K-F17 has antibacterial and immunomodulatory properties. The objective of this study was to optimize KR−1 and KR−2, based on 6K-F17, to apply to the tissue around the oral implant. Our first objective is to study its antibacterial properties, and then we intend to further study its osteogenic ability to osteoblasts by modulating the immune response of macrophages. In this research, KR−1 and KR−2 can inhibit the formation of bacterial biofilm, and further kill bacteria S. gordonii and F. nucleatum by destroying the cell wall and cell membrane of bacteria. The novel peptides restrained the activation of the NF-κB signaling pathway by reducing the phosphorylation levels of IκBα and p65, inhibiting the degradation of IκBα and the nuclear translocation of p65, and increasing the percentage of M2 phenotype in macrophages. This suppressed the inflammatory response induced by lipopolysaccharides and enhanced the osteogenic activity of osteoblasts; this, in turn, promoted osteogenesis. The antimicrobial peptide KR−1 showed better performance. Our results demonstrate that KR−1 and KR−2 have antibacterial and bone immunomodulatory effects, and further promote osteogenesis by modulating the immune microenvironment, which provides the possibility for the adjuvant treatment of peri-implant diseases.

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Notch signaling inhibition protects against LPS mediated osteolysis

Cited by 7 publications

References 34 publications

Inhibition of circular RNA circ_0138959 alleviates pyroptosis of human gingival fibroblasts via the microRNA-527/caspase-5 axis

Inhibition of circular RNA circ_0138959 alleviates pyroptosis of human gingival fibroblasts via the microRNA-527/caspase-5 axis

LPS-Induced Inflammation Prior to Injury Exacerbates the Development of Post-Traumatic Osteoarthritis in Mice

Study on Optimizing Novel Antimicrobial Peptides with Bifunctional Activity to Prevent and Treat Peri-Implant Disease

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