LAUSR

Background The aim of this study was to evaluate whether histone deacetylase 4 S246/467/632A mutant (m-HDAC4) has enhanced function at histone deacetylase 4 (HDAC4) to attenuate cartilage degeneration in a rat model of osteoarthritis (OA). Methods Chondrocytes were infected with Ad-m- HDAC4-GFP or Ad- HDAC4-GFP for 24 h, incubated with interleukin-1β (IL-1β 10 ng/mL) for 24 h, and then measured by RT-qPCR. Male Sprague-Dawley rats ( n  = 48) were randomly divided into four groups and transduced with different vectors: ACLT/Ad- GFP , ACLT/Ad- HDAC4-GFP , ACLT/Ad-m- HDAC4-GFP, and sham/Ad- GFP . All rats received intra-articular injections 48 h after the operation and every 3 weeks thereafter. Cartilage damage was assessed using radiography and Safranin O staining and quantified using the OARSI score. The hypertrophic and anabolic molecules were detected by immunohistochemistry and RT-qPCR. Results M- HDAC4 decreased the expression levels of Runx-2 , Mmp-13 , and C ol 10a1 , but increased the levels of C ol 2a1 and ACAN more effectively than HDAC4 in the IL-1β-induced chondrocyte OA model; upregulation of HDAC4 and m -HDAC4 in the rat OA model suppressed Runx-2 and MMP-13 production, and enhanced Col 2a1 and ACAN synthesis. Stronger Safranin O staining was detected in rats treated with m- HDAC4 than in those treated with HDAC4 . The resulting OARSI scores were lower in the Ad-m- HDAC4 group (5.80 ± 0.45) than in the Ad- HDAC4 group (9.67 ± 1.83, P  = 0.045). The OARSI scores were highest in rat knees that underwent ACLT treated with Ad- GFP control adenovirus vector (14.93 ± 2.14, P  = 0.019 compared with Ad- HDAC4 group; P  = 0.003 compared with Ad-m- HDAC4 group). Lower Runx-2 and MMP-13 production, and stronger Col 2a1 and ACAN synthesis were detected in rats treated with m- HDAC4 than in those treated with HDAC4 . Conclusions M-HDAC4 repressed chondrocyte hypertrophy and induced chondrocyte anabolism in the nucleus. M-HDAC4 was more effective in attenuating articular cartilage damage than HDAC4.