HDAC4 突变体通过定位于细胞核抑制软骨细胞肥大，并减轻创伤性骨关节炎的疾病进展。
HDAC4 mutant represses chondrocyte hypertrophy by locating in the nucleus and attenuates disease progression of posttraumatic osteoarthritis.
机构信息
Department of Orthopaedics, Shanxi Bethune Hospital, Longcheng Road 99, Taiyuan, 030032, China.
Department of Orthopaedics, The Second Hospital of Shanxi Medical University, Shanxi Key Laboratory of Bone and Soft Tissue Injury Repair, Wuyi Road 382, Taiyuan, 030001, China.
出版信息
BMC Musculoskelet Disord. 2022 Jan 3;23(1):8. doi: 10.1186/s12891-021-04947-6.
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 Col 10a1, but increased the levels of Col 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.
背景
本研究旨在评估组蛋白去乙酰化酶 4（HDAC4）的第 246/467/632 位丝氨酸突变（m-HDAC4）是否具有增强的功能，从而减轻骨关节炎（OA）大鼠模型中的软骨退变。
方法
用 Ad-m-HDAC4-GFP 或 Ad-HDAC4-GFP 感染软骨细胞 24 小时，用白细胞介素-1β（IL-1β，10ng/mL）孵育 24 小时，然后进行 RT-qPCR 检测。雄性 Sprague-Dawley 大鼠（n=48）随机分为 4 组，并转导不同的载体：ACL/Ad-GFP、ACL/Ad-HDAC4-GFP、ACL/Ad-m-HDAC4-GFP 和 sham/Ad-GFP。所有大鼠均在术后 48 小时内进行关节内注射，此后每 3 周进行一次。通过放射摄影和番红 O 染色评估软骨损伤，并使用 OARSI 评分进行定量。通过免疫组织化学和 RT-qPCR 检测肥大和合成分子。
结果
在 IL-1β诱导的软骨细胞 OA 模型中，m-HDAC4 比 HDAC4 更有效地降低了 Runx-2、Mmp-13 和 Col 10a1 的表达水平，但更有效地增加了 Col 2a1 和 ACAN 的水平；在大鼠 OA 模型中上调 HDAC4 和 m-HDAC4 可抑制 Runx-2 和 MMP-13 的产生，并增强 Col 2a1 和 ACAN 的合成。用 m-HDAC4 处理的大鼠的番红 O 染色更强。与 Ad-HDAC4 组（9.67±1.83）相比，Ad-m-HDAC4 组（5.80±0.45）的 OARSI 评分更低（P=0.045）。用 Ad-GFP 对照腺病毒载体处理的 ACLT 大鼠的 OARSI 评分最高（14.93±2.14，与 Ad-HDAC4 组相比，P=0.019；与 Ad-m-HDAC4 组相比，P=0.003）。用 m-HDAC4 处理的大鼠的 Runx-2 和 MMP-13 产生较少，Col 2a1 和 ACAN 合成较强。
结论
m-HDAC4 抑制软骨细胞肥大并诱导软骨细胞合成代谢。m-HDAC4 比 HDAC4 更有效地减轻关节软骨损伤。
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