Pharmacological blockade of PCAF ameliorates osteoarthritis development via dual inhibition of TNF-α-driven inflammation and ER stressResearch in context
Deheng Chen,
Di Lu,
Haixiao Liu,
Enxing Xue,
Yu Zhang,
Ping Shang,
Xiaoyun Pan
Affiliations
Deheng Chen
Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109, Xueyuanxi road, Wenzhou, Zhejiang 325027, China; Bone Research Institute, The Key Orthopaedic Laboratory of Zhejiang Province, 109, Xueyuanxi road, Wenzhou, Zhejiang 325027, China
Di Lu
Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109, Xueyuanxi road, Wenzhou, Zhejiang 325027, China; Bone Research Institute, The Key Orthopaedic Laboratory of Zhejiang Province, 109, Xueyuanxi road, Wenzhou, Zhejiang 325027, China
Haixiao Liu
Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109, Xueyuanxi road, Wenzhou, Zhejiang 325027, China; Bone Research Institute, The Key Orthopaedic Laboratory of Zhejiang Province, 109, Xueyuanxi road, Wenzhou, Zhejiang 325027, China
Enxing Xue
Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109, Xueyuanxi road, Wenzhou, Zhejiang 325027, China; Bone Research Institute, The Key Orthopaedic Laboratory of Zhejiang Province, 109, Xueyuanxi road, Wenzhou, Zhejiang 325027, China
Yu Zhang
Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109, Xueyuanxi road, Wenzhou, Zhejiang 325027, China; Bone Research Institute, The Key Orthopaedic Laboratory of Zhejiang Province, 109, Xueyuanxi road, Wenzhou, Zhejiang 325027, China
Ping Shang
Department of Rehabilitation, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109, Xueyuanxi road, Wenzhou, Zhejiang 325027, China; Corresponding author.
Xiaoyun Pan
Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109, Xueyuanxi road, Wenzhou, Zhejiang 325027, China; Bone Research Institute, The Key Orthopaedic Laboratory of Zhejiang Province, 109, Xueyuanxi road, Wenzhou, Zhejiang 325027, China; Corresponding author at: Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109, Xueyuanxi road, Wenzhou, Zhejiang 325027, China.
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. Keywords: PCAF, Salidroside, Osteoarthritis, NF-κB, ER stress
