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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.

HDAC4 mutant represses chondrocyte hypertrophy by locating in the nucleus and attenuates disease progression of posttraumatic osteoarthritis