Microtubule destabilization caused by silicate via HDAC6 activation contributes to autophagic dysfunction in bone mesenchymal stem cells

Li, Zheng; Liu, Shuhao; Fu, Tengfei; Peng, Yi; Zhang, Jian

doi:10.1186/s13287-019-1441-4

Cited by 7 publications

(7 citation statements)

References 45 publications

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“…Autophagolysosomes degrade the contents to achieve cell homeostasis and organelle renewal ( 31 ). HDAC6 is involved in the regulation of autophagy at multiple levels, including participation in post-translational modifications (PTM) of autophagy-related transcription factors ( 32 , 33 ), the formation of aggresomes that are routinely cleaned through the autophagy pathway ( 22 , 34 , 35 ), and the transportation and degradation of autophagosomes ( Figure 1 ) ( 23 , 25 ).…”

Section: The Role Of Hdac6 In Autophagymentioning

confidence: 99%

“…Furthermore, Li et at. found that HDAC6 inhibited the transportation of autophagosomes to fuse with lysosomes through the deacetylation of α-tubulin, resulting in the depolymerization of microtubules ( 25 ). In conclusion, HDAC6 suppresses the formation and degradation of autophagosome via deacetylation the microtubules.…”

Section: The Role Of Hdac6 In Autophagymentioning

confidence: 99%

“…Therefore, it is essential for multiple physiological and pathological processes. Recent studies have demonstrated that HDAC6 regulates autophagy and NLRP3 inflammasome activation through various mechanisms (14,(23)(24)(25)(26)(27). It is suggested that HDAC6 plays a possible role in the crosstalk between autophagy and NLRP3 inflammasome, although there is little direct evidence to date.…”

Section: Introductionmentioning

confidence: 99%

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The Role of HDAC6 in Autophagy and NLRP3 Inflammasome

Chang

et al. 2021

Front. Immunol.

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Autophagy fights against harmful stimuli and degrades cytosolic macromolecules, organelles, and intracellular pathogens. Autophagy dysfunction is associated with many diseases, including infectious and inflammatory diseases. Recent studies have identified the critical role of the NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasomes activation in the innate immune system, which mediates the secretion of proinflammatory cytokines IL-1β/IL-18 and cleaves Gasdermin D to induce pyroptosis in response to pathogenic and sterile stimuli. Accumulating evidence has highlighted the crosstalk between autophagy and NLRP3 inflammasome in multifaceted ways to influence host defense and inflammation. However, the underlying mechanisms require further clarification. Histone deacetylase 6 (HDAC6) is a class IIb deacetylase among the 18 mammalian HDACs, which mainly localizes in the cytoplasm. It is involved in two functional deacetylase domains and a ubiquitin-binding zinc finger domain (ZnF-BUZ). Due to its unique structure, HDAC6 regulates various physiological processes, including autophagy and NLRP3 inflammasome, and may play a role in the crosstalk between them. In this review, we provide insight into the mechanisms by which HDAC6 regulates autophagy and NLRP3 inflammasome and we explored the possibility and challenges of HDAC6 in the crosstalk between autophagy and NLRP3 inflammasome. Finally, we discuss HDAC6 inhibitors as a potential therapeutic approach targeting either autophagy or NLRP3 inflammasome as an anti-inflammatory strategy, although further clarification is required regarding their crosstalk.

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Section: The Role Of Hdac6 In Autophagymentioning

confidence: 99%

Section: The Role Of Hdac6 In Autophagymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Role of HDAC6 in Autophagy and NLRP3 Inflammasome

Chang

et al. 2021

Front. Immunol.

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“…This suggested HDAC6 inhibition would block the fusion stage of autophagosome and lysosome, then lead to decreased autophagy activity. However Zheng et al (2020b) found that HDAC6 inhibition restored autophagy flux in axonal regeneration and Li et al (2019) found HDAC6 inhibition induced autophagy flux in BMSCs. As HDAC6 regulates autophagy at multiple levels, it influences autophagy differently due to the cell type and the environment.…”

Section: Discussionmentioning

confidence: 99%

HDAC6 Regulates the Fusion of Autophagosome and Lysosome to Involve in Odontoblast Differentiation

Zhan

Wang

Zhang

et al. 2020

Front. Cell Dev. Biol.

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Odontoblast differentiation is an important process during tooth development in which pre-odontoblasts undergo elongation, polarization, and finally become mature secretory odontoblasts. Many factors have been found to regulate the process, and our previous studies demonstrated that autophagy plays an important role in tooth development and promotes odontoblastic differentiation in an inflammatory environment. However, it remains unclear how autophagy is modulated during odontoblast differentiation. In this study, we found that HDAC6 was involved in odontoblast differentiation. The odontoblastic differentiation capacity of human dental papilla cells was impaired upon HDAC6 inhibition. Moreover, we found that HDAC6 and autophagy exhibited similar expression patterns during odontoblast differentiation both in vivo and in vitro; the expression of HDAC6 and the autophagy related proteins ATG5 and LC3 increased as differentiation progressed. Upon knockdown of HDAC6, LC3 puncta were increased in cytoplasm and the autophagy substrate P62 was also increased, suggesting that autophagic flux was affected in human dental papilla cells. Next, we determined the mechanism during odontoblastic differentiation and found that the HDAC6 substrate acetylated-Tubulin was up-regulated when HDAC6 was knocked down, and LAMP2, LC3, and P62 protein levels were increased; however, the levels of ATG5 and Beclin1 showed no obvious change. Autophagosomes accumulated while the number of autolysosomes was decreased as determined by mRFP-GFP-LC3 plasmid labeling. This suggested that the fusion between autophagosomes and lysosomes was blocked, thus affecting the autophagic process during odontoblast differentiation. In conclusion, HDAC6 regulates the fusion of autophagosomes and lysosomes during odontoblast differentiation. When HDAC6 is inhibited, autophagosomes can't fuse with lysosomes, autophagy activity is decreased, and it leads to down-regulation of odontoblastic differentiation capacity. This provides a new perspective on the role of autophagy in odontoblast differentiation.

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“…Additionally, HDAC6 has a function in bone diseases. Li et al ( 24 ) revealed that HDAC6 activity was increased following high-dose silicate treatment, and HDAC6 inhibition could protect bone mesenchymal stem cells by improving the microtubule structure and autophagic activity. Wang et al ( 25 ) indicated that HDAC6 knockdown promoted ALP activity and mineralized nodule formation in dental mesenchymal stem cells.…”

Section: Discussionmentioning

confidence: 99%

ACY‑1215, a HDAC6 inhibitor, decreases the dexamethasone‑induced suppression of osteogenesis in MC3T3‑E1 cells

Wang

Chen

et al. 2020

Mol Med Rep

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Glucocorticoid-induced osteoporosis is the commonest form of drug-induced osteoporosis. Histone deacetylase 6 (HDAC6) is involved in the differentiation from mesenchymal stem cells to osteoblasts. However, the role of ricolinostat (ACY-1215, HDAC6 inhibitor) in the dexamethasone (Dex)-induced proliferation and differentiation of preosteoblasts remains to be elucidated. The protein expression and mRNA expression levels of HDAC6, osteopontin (OPN), runt-related transcription factor 2 (Runx2), osterix (Osx), collagen I (COL1A1) and glucocorticoid receptor (GR) in MC3T3-E1 cells were analyzed by western blot analysis and reverse transcription-quantitative PCR analysis. The cell viability was detected by CCK-8 assay. The alkaline phosphatase (ALP) activity and capacity of mineralization was determined by ALP assay kit and alizarin red staining. HDAC6 expression was increased in patient serum and Dex-induced MC3T3-E1 cells at a certain concentration range; 1 µM Dex was selected for further experimentation. Cell viability was decreased after Dex induction and restored following ACY-1215 treatment. The ALP activity and capability for mineralization was decreased when MC3T3-E1 cells were induced by 1 µM Dex and was gradually improved by the treatment of ACY-1215 at 1, 5 and 10 mM. The expression of OPN, Runx2, Osx and COL1A1 was similar, with the changes of capability for mineralization. Furthermore, GR expression was increased in Dex-induced MC3T3-E1 cells. ACY-1215 promoted the GR expression in MC3T3-E1 cells from 1–5 mM while GR receptor expression was increased with 10 mM ACY-1215 treatment. In conclusion, ACY-1215 reversed the Dex-induced suppression of proliferation and differentiation of MC3T3-E1 cells.

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Microtubule destabilization caused by silicate via HDAC6 activation contributes to autophagic dysfunction in bone mesenchymal stem cells

Cited by 7 publications

References 45 publications

The Role of HDAC6 in Autophagy and NLRP3 Inflammasome

The Role of HDAC6 in Autophagy and NLRP3 Inflammasome

HDAC6 Regulates the Fusion of Autophagosome and Lysosome to Involve in Odontoblast Differentiation

ACY‑1215, a HDAC6 inhibitor, decreases the dexamethasone‑induced suppression of osteogenesis in MC3T3‑E1 cells

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