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HDAC4 regulates apoptosis in Acan‐ Cre ERT2 ; HDAC4 d /d mice with osteoarthritis by downregulating ATF4

Year: 2025

Type: article

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.

Source: FEBS Open Bio

DOI: 10.1002/2211-5463.13965