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Pharmacological blockade of PCAF ameliorates osteoarthritis development via dual inhibition of TNF-?-driven inflammation and ER stress.

ABSTRACT: BACKGROUND:Epigenetic mechanisms have been reported to play key roles in osteoarthritis (OA) development. P300/CBP-associated factor (PCAF) is a member of the histone acetyltransferases, which exhibits a strong relationship with endoplasmic reticulum (ER) stress and transcription factor nuclear factor kappa B (NF-?B) signals. Salidroside, a natural histone acetylation inhibitor, showed its anti-inflammatory and anti-apoptotic effects in lipopolysaccharide (LPS)-stimulated microglia cells in our previous study. However, whether Sal has a protective effect against OA remains unknown, and its relationships to PCAF, NF-?B, and the ER stress pathway should be explored further. METHODS:We identified the role of PCAF in the pathogenesis of OA and determined the chondroprotective effect of Sal on both tumor necrosis factor alpha (TNF-?)-treated human chondrocytes and a destabilized medial meniscus (DMM) mouse OA model. FINDINGS:We found increased PCAF expression in human OA cartilage and TNF-?-driven chondrocytes. Meanwhile, silencing of PCAF attenuated nuclear p65 and C/EBP homologous protein levels in chondrocytes upon TNF-? stimulation. Furthermore, Sal was found to specifically bind to the inhibitory site of the PCAF protein structure, which subsequently reversed the TNF-?-induced activation of NF-?B signal and ER stress-related apoptosis in chondrocytes. In addition, the protective effect of Sal and its inhibitory effects on PCAF as well as inflammatory- and ER stress-related markers were also observed in the mouse DMM model. INTERPRETATION:Pharmacological blockade of PCAF by Sal ameliorates OA development via inhibition of inflammation and ER stress, which makes Sal a promising therapeutic agents for the treatment of OA.

SUBMITTER: Chen D

PROVIDER: S-EPMC6921217 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Pharmacological blockade of PCAF ameliorates osteoarthritis development via dual inhibition of TNF-α-driven inflammation and ER stress.

Chen Deheng D Lu Di D Liu Haixiao H Xue Enxing E Zhang Yu Y Shang Ping P Pan Xiaoyun X

EBioMedicine 20191114

<h4>Background</h4>Epigenetic mechanisms have been reported to play key roles in osteoarthritis (OA) development. P300/CBP-associated factor (PCAF) is a member of the histone acetyltransferases, which exhibits a strong relationship with endoplasmic reticulum (ER) stress and transcription factor nuclear factor kappa B (NF-κB) signals. Salidroside, a natural histone acetylation inhibitor, showed its anti-inflammatory and anti-apoptotic effects in lipopolysaccharide (LPS)-stimulated microglia cells ...[more]

PMID: 31735552

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Dataset Information

Pharmacological blockade of PCAF ameliorates osteoarthritis development via dual inhibition of TNF-?-driven inflammation and ER stress.

Publications

Pharmacological blockade of PCAF ameliorates osteoarthritis development via dual inhibition of TNF-α-driven inflammation and ER stress.

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