HDAC4 regulates apoptosis in Acan-CreERT2;HDAC4d /d mice with osteoarthritis by downregulating ATF4.

Abstract

Several studies have previously shown that histone deacetylase 4 (HDAC4) can regulate endoplasmic reticulum stress-induced apoptosis through the activating transcription factor 4 (ATF4)/CAAT/enhancer binding protein homologous (CHOP) signaling pathway, thereby affecting the progression of osteoarthritis (OA). The present study investigated the regulatory mechanism of HDAC4 in chondrocyte apoptosis in OA using Acan-Cre^ERT2;HDAC4^fl/fl gene knockout mice. Forty mice were divided into four groups: TM-DMM group [tamoxifen (TM) injection at 2 months of age and destabilization of the medial meniscus (DMM) surgery at 3 months], TM-sham group (TM injection at 2 months of age and sham surgery at 3 months), no TM-DMM group (corn oil injection at 2 months of age and DMM surgery at 3 months) and no TM-sham group (corn oil injection at 2 months of age and sham surgery at 3 months). Apoptosis and cartilage damage were assessed through imaging, histological analysis, immunohistochemistry, reverse transcriptase-PCR and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining. HDAC4 knockdown resulted in increased osteophyte formation, significant narrowing of the joint space and increased articular cartilage damage. Furthermore, expression levels of key apoptosis-related markers, ATF4, CHOP, caspase-3 and caspase-9, were significantly higher in the TM groups than in their respective control groups. Taken together, our results suggest that HDAC4 deficiency leads to increased apoptosis induced by the ATF4/CHOP signaling pathway in the pathogenesis of OA. Therefore, upregulation of HDAC4 may represent a potential therapeutic strategy.