Overexpression of c‐Fos reverses osteoprotegerin‐mediated suppression of osteoclastogenesis by increasing the Beclin1‐induced autophagy

Tong, Xishuai; Chen, Miaomiao; Song, Ruilong; Zhao, Hongyan; Bian, Jianchun; Gu, Jianhong; Liu, Zongping

doi:10.1111/jcmm.16152

Cited by 10 publications

(8 citation statements)

References 48 publications

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“…A lack of Fos abolishes osteoclastogenesis and induces osteopetrosis in mice, 84 while the overexpression of Fos reverses the OPG-mediated suppression of osteoclastogenesis. 85 In summary, prolonged exposure to inflammatory signals in TLR9 −/− mice may sustain higher expression and transcriptional activity of Fos and Spi1 in progenitors during myelopoiesis and monocyte differentiation. Increased expression and activation of Fos and Spi1 in turn contribute to the increased osteoclast commitment observed in TLR9 −/− mice.…”

Section: Discussionmentioning

confidence: 91%

Toll-like receptor 9 deficiency induces osteoclastic bone loss via gut microbiota-associated systemic chronic inflammation

et al. 2022

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Toll-like receptors (TLRs) play pivotal roles in inflammation and provide important links between the immune and skeletal systems. Although the activation of TLRs may affect osteoclast differentiation and bone metabolism, whether and how TLRs are required for normal bone remodeling remains to be fully explored. In the current study, we show for the first time that TLR9−/− mice exhibit a low bone mass and low-grade systemic chronic inflammation, which is characterized by the expansion of CD4+ T cells and increased levels of inflammatory cytokines, including TNFα, RANKL, and IL1β. The increased levels of these cytokines significantly promote osteoclastogenesis and induce bone loss. Importantly, TLR9 deletion alters the gut microbiota, and this dysbiosis is the basis of the systemic inflammation and bone loss observed in TLR9−/− mice. Furthermore, through single-cell RNA sequencing, we identified myeloid-biased hematopoiesis in the bone marrow of TLR9−/− mice and determined that the increase in myelopoiesis, likely caused by the adaptation of hematopoietic stem cells to systemic inflammation, also contributes to inflammation-induced osteoclastogenesis and subsequent bone loss in TLR9−/− mice. Thus, our study provides novel evidence that TLR9 signaling connects the gut microbiota, immune system, and bone and is critical in maintaining the homeostasis of inflammation, hematopoiesis, and bone metabolism under normal conditions.

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Section: Discussionmentioning

confidence: 91%

Toll-like receptor 9 deficiency induces osteoclastic bone loss via gut microbiota-associated systemic chronic inflammation

et al. 2022

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“… 52–54 Overexpression of c-Fos increased the Beclin1-induced autophagy. 55 Ultimately, Parp1 is a key regulator of cell death. Its inhibition prevented streptozotocin-induced diabetes and attenuated caerulein-induced AP.…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanism analysis of m6A modification-related lncRNA-miRNA-mRNA network in regulating autophagy in acute pancreatitis

Qin

Ali

et al. 2022

Islets

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This study aims to explore the molecular mechanism of N6-methyladenosine (m6A) modification-related long noncoding RNA (lncRNA)–microRNA (miRNA)–messenger RNA (mRNA) network in regulating autophagy and affecting the occurrence and development of acute pancreatitis (AP). RNA-seq datasets related to AP were obtained from Gene Expression Omnibus (GEO) database and merged after batch effect removal. lncRNAs significantly related to m6A in AP, namely candidate lncRNA, were screened by correlation analysis and differential expression analysis. In addition, candidate autophagy genes were screened through the multiple databases. Furthermore, the key pathways for autophagy to play a role in AP were determined by functional enrichment analysis. Finally, we predicted the miRNAs binding to genes and lncRNAs through TargetScan, miRDB and DIANA TOOLS databases and constructed two types of lncRNA-miRNA-mRNA regulatory networks mediated by upregulated and downregulated lncRNAs in AP. Nine lncRNAs related to m6A were differentially expressed in AP, and 21 candidate autophagy genes were obtained. Phosphoinositide 3-kinase (PI3K)-Akt signaling pathway and Forkhead box O (FoxO) signaling pathway might be the key pathways for autophagy to play a role in AP. Finally, we constructed a lncRNA-miRNA-mRNA regulatory network. An upregulated lncRNA competitively binds to 13 miRNAs to regulate 6 autophagy genes, and a lncRNA-miRNA-mRNA regulatory network in which 2 downregulated lncRNAs competitively bind to 7 miRNAs to regulate 2 autophagy genes. m6A modification-related lncRNA Pvt1, lncRNA Meg3 and lncRNA AW112010 may mediate the lncRNA-miRNA-mRNA network, thereby regulating autophagy to affect the development of AP.

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“…Our previous studies showed that AMPK, Akt, and p53 are involved in the differentiation of osteoblasts and osteoclasts regulated by autophagy. 34,35,54,55 AMPK activation stimulates autophagy by enhancing LC3 expression and density of autophagosomes in MC3T3-E1 cells, and decreased p62 expression; it is mediated by Beclin1 in vitro. 56 Osteoblastogenesis in human gingival mesenchymal stem cells is induced by Beclin1-dependent autophagy, and is regulated by AMPK in osteoblastic differentiation.…”

Section: Discussionmentioning

confidence: 99%

Puerarin alleviates cadmium‐induced oxidative damage to bone by reducing autophagy in rats

Tong

Guo

Liu

et al. 2021

Environmental Toxicology

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Autophagy is a regulatory mechanism involved in cadmium (Cd)-induced bone toxicity and is suppressed by various stimuli, including oxidative stress. Puerarin is an isoflavonoid compound isolated from Pueraria, a plant used in traditional Chinese medicine. The underlying mechanisms of action of puerarin remain unclear. The objective of this study was to explore the mitigating effects of puerarin on cadmiuminduced oxidative damage in the bones of rats. Cadmium exposure increased oxidative damage in rat bones; this was markedly decreased by puerarin treatment, as demonstrated by changes in the activity of antioxidative enzymes. Cadmium-induced blockage of the expression of key bone regulatory proteins, autophagy-related markers, and signaling molecules was also alleviated by puerarin treatment. Additionally, cadmium reduced expression of the autophagic protein Rab7 and of late endosomal/lysosomal adaptor and MAPK and mTOR activator 1 (LAMTOR1); the decrease in these proteins was not restored by puerarin treatment. We speculate that puerarin relieves the inhibition of fusion of autophagosomes with lysosomes that is induced by cadmium; however, this specific effect of puerarin and downstream effects on bone regulatory mechanisms require further investigation. In conclusion, puerarin alleviates cadmium-induced oxidative damage in the bones of rats by attenuating autophagy, which is likely associated with the antioxidant activity of puerarin.

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Overexpression of c‐Fos reverses osteoprotegerin‐mediated suppression of osteoclastogenesis by increasing the Beclin1‐induced autophagy

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 10 publications

References 48 publications

Toll-like receptor 9 deficiency induces osteoclastic bone loss via gut microbiota-associated systemic chronic inflammation

Toll-like receptor 9 deficiency induces osteoclastic bone loss via gut microbiota-associated systemic chronic inflammation

Molecular mechanism analysis of m6A modification-related lncRNA-miRNA-mRNA network in regulating autophagy in acute pancreatitis

Puerarin alleviates cadmium‐induced oxidative damage to bone by reducing autophagy in rats

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