A reduced level of the long non-coding RNA SNHG8 activates the NF-kappaB pathway by releasing functional HIF-1alpha in a hypoxic inflammatory microenvironment

Abstract

Background A series of biochemical responses, including hypoxia and aseptic inflammation, occur in periodontal ligament cells (PDLCs) during periodontal tissue remodeling of orthodontic tooth movement (OTM). However, the role of long non-coding RNA (lncRNA) in these responses is still largely unknown. We investigated the role of the lncRNA SNHG8 in hypoxic and inflammatory responses during OTM and explored the underlying mechanisms. Methods The expression pattern of SNHG8, and hypoxic and inflammatory responses under compressive force were analyzed by qRT-PCR, immunohistochemistry, and western blotting, in vivo and in vitro. The effect of overexpression or knockdown of SNHG8 on the nuclear factor-kappaB (NF-κB) pathway was evaluated. RNA sequencing was performed for mechanistic analysis. The interaction between SNHG8 and hypoxia-inducible factor (HIF)-1α was studied using catRAPID, RNA immunoprecipitation, and RNA pulldown assays. The effect of the SNHG8–HIF-1α interaction on the NF-κB pathway was determined by western blotting. Results The NF-κB pathway was activated, and HIF-1α release was stabilized, in PDLCs under compressive force as well as in OTM model rats. The SNHG8 level markedly decreased both in vivo and in vitro. Overexpression of SNHG8 decreased the expression levels of inflammatory cytokines, the phosphorylation of p65, and the degradation of IκBα in PDLCs, whereas knockdown of SNHG8 reversed these effects. Mechanically, RNA sequencing showed that differentially expressed genes were enriched in cellular response to hypoxia after SNHG8 overexpression. SNHG8 binds to HIF-1α, thus preventing HIF-1 from activating downstream genes, including those related to the NF-κB pathway. Conclusion SNHG8 binds to HIF-1α. During OTM, the expression of SNHG8 dramatically decreased, releasing free functional HIF-1α and activating the downstream NF-κB pathway. These data suggest a novel lncRNA-regulated mechanism during periodontal tissue remodeling in OTM.

The Roles of SNHG Family in Osteoblast Differentiation

“…Sesamin increased osteogenesis by activating the Wnt/β-catenin pathway and decreased osteoclastogenesis via deactivating the NF-κB signaling pathway. Previous studies confirmed that deactivating the NF-κB signaling pathway inhibited osteoclast formation [ 53 ]. Further studies revealed that sesamin’s promoting effects on osteoblast were attributable to downregulation of DANCR expression.…”

“…For example, we found that SNHG5 mediated periodontal inflammation via the NF-κB signaling pathway [ 41 ]. Another SNHG family member, SNHG8 , also affected the NF-κB signaling pathway and inflammatory processes [ 53 ]. We observed that in a hypoxic inflammatory microenvironment, decreased SNHG8 expression activated the downstream NF-κB signaling pathway.…”

Long non-coding RNASNHG8drives stress granule formation in tauopathies

“…The role of SNHG8 in brain function and disease is not well investigated. Recently, SNHG8 was reported to be involved in inflammation and microglial response by sponging miR-425-5p and SIRT1/NF-κB signaling (Tian et al 2021) and in orthodontic tooth movement (OTM)(C. Wang et al 2022). SNHG8 has been associated with an inflammatory response: reducing SNHG8, which binds to HIF-1α, leads to free functional HIF-1α and activation of the downstream NF-κB pathway (C. Wang et al 2022).…”

“…Recently, SNHG8 was reported to be involved in inflammation and microglial response by sponging miR-425-5p and SIRT1/NF-κB signaling (Tian et al 2021) and in orthodontic tooth movement (OTM)(C. Wang et al 2022). SNHG8 has been associated with an inflammatory response: reducing SNHG8, which binds to HIF-1α, leads to free functional HIF-1α and activation of the downstream NF-κB pathway (C. Wang et al 2022). The consideration of therapeutic strategies involving SNHG8 replacement will require an evaluation of the landscape of SNHG8 effects.…”

“…The role of SNHG8 in brain function and disease is not well investigated. Recently, SNHG8 was reported to be involved in inflammation and microglial response by sponging miR-425-5p and SIRT1/NF-κB signaling (Tian et al 2021) and in orthodontic tooth movement (OTM)(C. Wang et al 2022).…”