Inhibition of Histone Deacetylase 6 by Tubastatin A Attenuates the Progress of Osteoarthritis via Improving Mitochondrial Function

Zheng, Yijing; Chen, Yuemiao; Lu, Xiaoyong; Weng, Qihao; Dai, Guang; Yu, Yang; Yu, Ke; Gao, Weiyang

doi:10.1016/j.ajpath.2020.08.013

Cited by 17 publications

(13 citation statements)

References 39 publications

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“…Herein inhibition of HDAC6 with Tubastatin A blocked cartilage degradation in line with the studies identifying protection against cartilage damage with Tubastatin A treatment in the DMM model of experimental OA 20 , 21 . Tubastatin A was developed to address issues with the high lipophilicity of Tubacin, which may account for Tubacin’s lack of effect in our 14 day cartilage degradation model 74 .…”

Section: Discussionsupporting

confidence: 68%

“…Shen et al showed that Tubastatin A treatment of chondrocytes and mice activated autophagy and increased cell viability while reducing cartilage degradation 20 . Zheng et al suggest that Tubastatin A disrupts regulation of mitochondrial connectivity and function by HDAC6 leading to ROS reduction and reduced cartilage damage 21 .…”

Section: Discussionmentioning

confidence: 99%

“…Recently inhibition of HDAC6 with Tubastatin A has been reported to reduce cartilage damage in experimental OA 20 , 21 . A role has also been proposed for HDAC6 in inflammatory gene expression and signalling, whereby HDAC6-sepecific inhibitors can reduce the levels of IL-6 in both serum and the paws of collagen-induced arthritic mice 22 , 23 .…”

Section: Introductionmentioning

confidence: 99%

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HDAC6 regulates NF-κB signalling to control chondrocyte IL-1-induced MMP and inflammatory gene expression

Barter

Butcher

Wang

et al. 2022

Sci Rep

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Elevated pro-inflammatory signalling coupled with catabolic metalloproteinase expression is a common feature of arthritis, leading to cartilage damage, deterioration of the joint architecture and the associated pain and immobility. Countering these processes, histone deacetylase inhibitors (HDACi) have been shown to suppress matrix metalloproteinase (MMP) expression, block cytokine-induced signalling and reduce the cartilage degradation in animal models of the arthritis. In order to establish which specific HDACs account for these chondro-protective effects an HDAC1-11 RNAi screen was performed. HDAC6 was required for both the interleukin (IL)-1 induction of MMP expression and pro-inflammatory interleukin expression in chondrocytes, implicating an effect on NF-κB signalling. Depletion of HDAC6 post-transcriptionally up-regulated inhibitor of κB (IκB), prevented the nuclear translocation of NF-κB subunits and down-regulated NF-κB reporter activation. The pharmacological inhibition of HDAC6 reduced MMP expression in chondrocytes and cartilage collagen release. This work highlights the important role of HDAC6 in pro-inflammatory signalling and metalloproteinase gene expression, and identifies a part for HDAC6 in the NF-κB signalling pathway. By confirming the protection of cartilage this work supports the inhibition of HDAC6 as a possible therapeutic strategy in arthritis.

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Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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HDAC6 regulates NF-κB signalling to control chondrocyte IL-1-induced MMP and inflammatory gene expression

Barter

Butcher

Wang

et al. 2022

Sci Rep

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“…It is possible that impaired energy production due to microtubule instability results in changes to CR control as a result of reduced activity in the mice. Mitochondrial dysfunction has been reported to be characteristic of CF cells, and Hdac6 inhibition is known to improve mitochondrial transport and function in different disease model systems ( 33 – 38 ). Finally, the relationship between circadian regulation and inflammation needs to be determined.…”

Section: Discussionmentioning

confidence: 99%

The circadian system in cystic fibrosis mice is regulated by histone deacetylase 6

Barbato

Darrah

Kelley

2022

American Journal of Physiology-Cell Physiology

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Disordered sleep experienced by people with cystic fibrosis (CF) suggest a possible disruption in circadian regulation being associated with the loss of cystic fibrosis transmembrane conductance regulator (Cftr) function. To test this hypothesis, circadian regulation was assessed in a F508del/F508del CF mouse model. CF mice exhibited significant alterations in both timing of locomotor activity and in mean activity per hour in both light-dark (LD) and dark-dark (DD) photoperiods compared to wild type (WT) controls. It was also noted that in DD, periodicity increased in CF mice, while shortening in WT mice as is expected. CF mice also exhibited altered timing of circadian gene expression and a reduction of melatonin production at all time points. Mechanistically, the role of microtubules in regulating these outcomes was explored. Mice lacking expression of tubulin polymerization promoting protein (Tppp) effectively mimicked CF mouse phenotypes with each measured outcome. Depleting expression of the microtubule regulatory protein histone deacetylase 6 (Hdac6) from CF mice (CF/Hdac6) resulted in the reversal of each phenotype to WT profiles. These data demonstrate an innate disruption of circadian regulation in CF mice and identify a novel microtubule-related mechanism leading to this disruption that can be targeted for therapeutic intervention.

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“…Few studies have investigated whether the acetylation of α-tubulin plays an important role in MT stabilization and cell morphology, and loss of α-tubulin acetylation is associated with epithelial-mesenchymal transition and chronic airway remodeling ( 21 , 22 ). In addition, inhibition of HDACs improves endothelial barrier function and attenuates the progression of osteoarthritis by suppressing α-tubulin deacetylation ( 47 , 48 ). In the present study, it was shown that the miR-29b-3p/MMP-9 axis decreased acetyl-α-tubulin levels and that overexpression of miR-29b-3p significantly decreased MMP-9 expression and increased the acetyl-α-tubulin levels in PHNECs.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of miR‑29b‑3p promotes α‑tubulin deacetylation by targeting the interaction of matrix metalloproteinase‑9 with integrin β1 in nasal polyps

Liu

et al. 2021

Int J Mol Med

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Matrix metalloproteinase (MMP)-9 is a key enzyme responsible for extracellular matrix degradation and contributes to the progressive histological changes observed in lower respiratory tract infections. Integrin β1 and α-tubulin are potential MMP-9-interacting proteins, and microRNA (miR)-29b-3p can regulate MMP-9 expression. MMP-9 is highly expressed in chronic rhinosinusitis with nasal polyps (cRSwNPs), regardless of its effects on miR-29b-3p, integrin β1 and α-tubulin expression. In the present study, samples from 100 patients with cRSwNPs were examined via reverse transcription-quantitative PcR to assess the mRNA expression of miR-29b-3p, and western blotting was performed to assess the protein expression of MMP-2, MMP-9, acetyl-α-tubulin, integrin β1 and tissue inhibitor of metalloproteinase 1 (TIMP-1). A dual-luciferase reporter assay was used to verify the direct binding of miR-29b-3p and MMP-2/MMP-9. co-immunoprecipitation (co-IP) and GST pull-down assays showed that integrin β1 and α-tubulin were MMP-9-interacting proteins. Cell viability, apoptosis and inflammatory cytokine levels were determined via a Cell Counting Kit-8 assay, flow cytometry and ELISA, respectively. miR-29b-3p expression was found to be positively correlated with MMP-2 and MMP-9 expression. Whereas, TIMP-1 expression was negatively correlated with MMP-2 and MMP-9 expression. The dual-luciferase assay revealed that miR-29b-3p targeted the 3' untranslated region of MMP-2/MMP-9. The co-IP and GST pull-down assays showed that MMP-9 could directly bind to integrin β1 and indirectly bind to α-tubulin. Finally, the overexpression of miR-29b-3p decreased the expression of MMP-9 and increased the levels of acetyl-α-tubulin. By contrast, the knockdown of miR-29b-3p increased the expression of MMP-9 and decreased the levels of acetyl-α-tubulin. Additionally, MMP-9 expression was found to be negatively correlated with acetyl-α-tubulin expression. Of note, the expression of integrin β1 did not change following the overexpression and knockdown of MMP-9. Finally, the overexpression of miR-29b-3p not only decreased MMP-9 expression, but also alleviated lipopolysaccharide-induced inflammation in NP69 cells. The results showed that the downregulation of miR-29b-3p promoted α-tubulin deacetylation by increasing the number of MMP-9-integrin β1 complexes in cRSwNPs, thus targeting miR-29b-3p/MMP-9 may be a potential novel strategy for the clinical treatment of cRSwNPs.

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Inhibition of Histone Deacetylase 6 by Tubastatin A Attenuates the Progress of Osteoarthritis via Improving Mitochondrial Function

Cited by 17 publications

References 39 publications

HDAC6 regulates NF-κB signalling to control chondrocyte IL-1-induced MMP and inflammatory gene expression

HDAC6 regulates NF-κB signalling to control chondrocyte IL-1-induced MMP and inflammatory gene expression

The circadian system in cystic fibrosis mice is regulated by histone deacetylase 6

Downregulation of miR‑29b‑3p promotes α‑tubulin deacetylation by targeting the interaction of matrix metalloproteinase‑9 with integrin β1 in nasal polyps

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