Mutual inhibition between HDAC9 and miR-17 regulates osteogenesis of human periodontal ligament stem cells in inflammatory conditions

Abstract

Histone deacetylases (HDAC) plays important roles in the post-translational modifications of histone cores as well as non-histone targets. Many of them are involved in key inflammatory processes. Despite their importance, whether and how HDAC9 is regulated under inflammatory conditions remains unclear. The aim of this study was to evaluate the effects of HDAC9 under chronic inflammation condition in human periodontal ligament stromal cell (PDLSCs) and to explore the underlying regulatory mechanism. PDLSCs from healthy or periodontitis human tissue was compared. The therapeutic effects of HDAC inhibitors was determined in PDLSC pellet transplanted nude mice and LPS-induced rat periodontitis. We report that HDAC9 was the most affected HDAC family member under inflammatory conditions in PDLSCs. HDAC9 impaired osteogenic differentiation capacity of PDLSCs under inflammatory conditions. Downregulation of HDAC9 by HDAC inhibitors or si-HDAC9 rescued the osteogenic differentiation capacity of inflammatory PDLSC to a similar level with the healthy PDLSC. In this context, HDAC9 and miR-17 formed an inhibitory loop. The inhibition of miR-17 aggravated loss of calcified nodules in inflamed PDLSCs and interrupted the effect of HDAC inhibitor in rescuing osteogenesis. In vivo experiments using nude mice and LPS-induced periodontitis model confirmed that HDAC inhibitors could improve new bone formation. We conclude that HDAC inhibitors improved osteogenesis of PDLSCs in vitro and periodontitis in vivo.

Impaired autophagy triggered by HDAC9 in mesenchymal stem cells accelerates bone mass loss

“…The same results were also observed in senescent BMMSCs. Our previous works found that HDAC9 expression signi cantly increased in human periodontal ligament stem cells (PDLSCs) under in ammatory microenvironment [31]. Kofman et al showed that HDAC9 expression increased in aging spermatogonial stem cells, and then decreased when cells were exposed to the anti-aging drug, rapamycin [32], which is consistent with our ndings.…”

“…In this study, we found modulating HDAC9 expression in BMMSCs could regulate the levels of the senescencerelated proteins p53 and p-p53. In addition, increased HDAC9 expression impaired the osteogenesis capacity of both aged BMMSCs and in ammatory PDLSCs [31]. Meanwhile, increased HDAC9 expression facilitated adipogenic differentiation in BMMSCs.…”

LIPUS inhibited the expression of inflammatory factors and promoted the osteogenic differentiation capacity of hPDLCs by inhibiting the NF‐κB signaling pathway

“…It is well known that inflammation attenuated stem cell multiple differentiation and self‐renewal, which largely diminish cells’ osteogenic capability . A previous study also demonstrated that the inflammatory environment could hinder the multiple differentiation ability of hPDLCs . The mechanical stimulation of ultrasound could promote osteoblast maturation and differentiation in MC3T3‐E1 cells .…”

“…In our study, according to Nakao's study and our previous study, 21 the duration of LIPUS stimulation for investigating the inhibitory effect was 2 hours. In addition, according to Tanaka 36 The mechanical stimulation of ultrasound could promote osteoblast maturation and differentiation in MC3T3-E1 cells. 37 Additionally, LIPUS has been proven to have multiple therapeutic benefits and stimulate bone formation both in vivo and in vitro.…”

Impaired autophagy triggered by HDAC9 in mesenchymal stem cells accelerates bone mass loss

“…The same results were also observed in senescent BMMSCs. Our previous works found that HDAC9 expression significantly increased in human periodontal ligament stem cells (PDLSCs) under inflammatory microenvironment [31]. Kofman et al showed that HDAC9…”