Department of Orthopaedics, The Second Hospital of Shanxi Medical University, Shanxi Key Laboratory of Bone and Soft Tissue Injury Repair, Taiyuan, Shanxi, PR China.
Department of Orthopedics, Warren Alpert Medical School of Brown University, Providence, RI, USA.
Int Immunopharmacol. 2019 Oct;75:105752. doi: 10.1016/j.intimp.2019.105752. Epub 2019 Jul 13.
Downregulation of histone deacetylase-4 (HDAC4) contributes to cartilage degeneration in osteoarthritis (OA) because it promotes upregulation of runt-related transcription factor-2 (Runx-2) and osteoarthritis-related genes. The effect of HDAC4 upregulation on cartilage damage in OA remains unknown.
Rat chondrocytes were infected with Ad-GFP or Ad-HDAC4-GFP for 48 h, stimulated with interleukin-1β (IL-1β, 10 ng/mL) for 24 h, and then harvested for RT-qPCR. Male Sprague-Dawley rats in 3 groups were given anterior cruciate ligament transection (ACLT) or sham operation, and knee injections with different adenovirus (Ad) vectors at 48 h after surgery and every 3 weeks thereafter: ACLT+Ad-GFP (n = 17); ACLT+Ad-HDAC4-GFP (n = 20); and sham+Ad-GFP (n = 15). Three ACLT-Ad-HDAC4-GFP rats were sacrificed at different times to examine the expression of HDAC4. Two ACLT-Ad-GFP rats and two ACLT-Ad-HDAC4-GFP rats were euthanized at week-2; articular cartilage was harvested and expression of HDAC4 was determined by RT-qPCR. All other rats were euthanized at week-8. Cartilage damage and OA progression was assessed using radiography, fluorescence molecular tomography (FMT), histology, immunohistochemistry (IHC), ELISA, and RT-qPCR.
Overexpression of HDAC4 in chondrocytes stimulated by IL-1β reduced the levels of Runx-2, MMP-13, and Collagen X, but increased the levels of Collagen II and Aggrecan. Upregulation of HDAC4 reduced osteophyte formation and cartilage damage, and increased articular cartilage anabolism.
HDAC4 attenuated articular cartilage damage by repression of Runx-2, MMP-13, and collagen X and induction of collagen II and ACAN in this rat model of OA. Upregulation of HDAC4 may provide chondroprotection in OA patients.
组蛋白去乙酰化酶-4 (HDAC4) 的下调导致骨关节炎 (OA) 中的软骨退化，因为它促进了 runt 相关转录因子-2 (Runx-2) 和骨关节炎相关基因的上调。HDAC4 上调对 OA 中软骨损伤的影响尚不清楚。
将大鼠软骨细胞感染 Ad-GFP 或 Ad-HDAC4-GFP 48 小时，用白细胞介素-1β (IL-1β，10ng/mL) 刺激 24 小时，然后进行 RT-qPCR 分析。3 组雄性 Sprague-Dawley 大鼠行前交叉韧带切断术 (ACLT) 或假手术，术后 48 小时及此后每 3 周膝关节注射不同的腺病毒 (Ad) 载体：ACLT+Ad-GFP (n=17)；ACLT+Ad-HDAC4-GFP (n=20)； sham+Ad-GFP (n=15)。3 只 ACLT-Ad-HDAC4-GFP 大鼠在不同时间点处死，检测 HDAC4 的表达。2 只 ACLT-Ad-GFP 大鼠和 2 只 ACLT-Ad-HDAC4-GFP 大鼠于第 2 周处死，取关节软骨，用 RT-qPCR 检测 HDAC4 的表达。其余所有大鼠于第 8 周处死。采用放射学、荧光分子断层扫描 (FMT)、组织学、免疫组织化学 (IHC)、ELISA 和 RT-qPCR 评估软骨损伤和 OA 进展。
IL-1β 刺激的软骨细胞中 HDAC4 的过表达降低了 Runx-2、MMP-13 和 Collagen X 的水平，但增加了 Collagen II 和 Aggrecan 的水平。HDAC4 的上调减少了骨赘形成和软骨损伤，并增加了关节软骨的合成代谢。
在该 OA 大鼠模型中，HDAC4 通过抑制 Runx-2、MMP-13 和 Collagen X，诱导 Collagen II 和 ACAN 的表达，减轻了关节软骨的损伤。HDAC4 的上调可能为 OA 患者提供软骨保护作用。
