Pharmacological blockade of PCAF ameliorates osteoarthritis development via dual inhibition of TNF-α-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-κB) 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-κB, 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-α)-treated human chondrocytes and a destabilized medial meniscus (DMM) mouse OA model. Findings: We found increased PCAF expression in human OA cartilage and TNF-α-driven chondrocytes. Meanwhile, silencing of PCAF attenuated nuclear p65 and C/EBP homologous protein levels in chondrocytes upon TNF-α stimulation. Furthermore, Sal was found to specifically bind to the inhibitory site of the PCAF protein structure, which subsequently reversed the TNF-α-induced activation of NF-κB 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.

Integrating Network Pharmacology and Experimental Validation to Explore the Key Mechanism of Gubitong Recipe in the Treatment of Osteoarthritis

“…The top 40 pathways of KEGG results were visualized with a dot plot ( Figure 3(a) ). KEGG results indicated that the PI3K/AKT pathway [ 35 ], Toll-like receptor pathway [ 36 ], NOD-like receptor pathway [ 37 ], TNF pathway [ 38 ], and HIF-1 pathway [ 39 ] were closely related to OA. A network of 6 OA-related pathways and their corresponding targets is shown in Figure 3(b) .…”

Salidroside Attenuates Cognitive Dysfunction in Senescence-Accelerated Mouse Prone 8 (SAMP8) Mice and Modulates Inflammation of the Gut-Brain Axis

“…Recent evidence has revealed that SAL provides neuroprotection by modulating mitochondrial biogenesis and microglial polarization ( Barhwal et al, 2015 ; Liu et al, 2018 ). Notably, SAL exhibits significant anti-inflammatory effects in multiple diseases, such as osteoarthritis ( Chen et al, 2019 ), colitis ( Liu et al, 2019 ), skeletal muscle atrophy ( Huang et al, 2019 ), renal interstitial fibrosis, ( Li et al, 2019 ) and CNS diseases ( Liu et al, 2018 ; Wang et al, 2018 ). Furthermore, recent findings have suggested that SAL alleviates liver injury by maintaining the balance of the gut microbiota ( Yuan et al, 2019 ).…”

Obeticholic Acid Derivative, T-2054 Suppresses Osteoarthritis via Inhibiting NF-κB-Signaling Pathway

“…Emerging studies reveal that inflammation is closely related to the NF-κB-signaling pathway, which binds to the target gene, facilitates the transcription of downstream inflammatory mediators and associates with developing articular cartilage damage in OA [ 26 , 27 ]. To investigate the anti-inflammatory mechanism of NF-κB, the phosphorylation level of NF-κB p65 was determined using Western blot in LPS-activated RAW 264.7 cells and TNF-α-induced ATDC5 cells.…”