组蛋白去乙酰化酶4水平与衰老性软骨退变及软骨细胞肥大相关。
The Level of Histone Deacetylase 4 is Associated with Aging Cartilage Degeneration and Chondrocyte Hypertrophy.
作者信息
Dong Zhengquan, Ma Zhou, Yang Meiju, Cong Linlin, Zhao Ruipeng, Cheng Liyun, Sun Jian, Wang Yunfei, Yang Ruijia, Wei Xiaochun, Li Pengcui
机构信息
Department of Orthopaedic, Shanxi Key Laboratory of Bone and Soft Tissue Injury Repair, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, People's Republic of China.
Department of Biochemistry and Molecular Biology, the Shanxi Medical University, Taiyuan, Shanxi, People's Republic of China.
出版信息
J Inflamm Res. 2022 Jun 16;15:3547-3560. doi: 10.2147/JIR.S365545. eCollection 2022.
PURPOSE
To determine the role of histone deacetylase 4 (HDAC4)-controlled chondrocyte hypertrophy in the onset and development of age-related osteoarthritis (OA).
METHODS
Morphological analysis of human knee cartilages was performed to observe structural changes during cartilage degeneration. HDAC4 expression was deleted in adult aggrecan (Acan)-CreERT2; HDAC4fl/fl transgenic mice. The onset and development of age-related OA were investigated in transgenic and control mice using hematoxylin and eosin (H&E) and Safranin O staining. Furthermore, the progression of ACLT-induced OA following adenovirus-mediated HDAC4 overexpression was explored in rats. The expression levels of genes related to hypertrophy, cartilage matrix and its digestion, and chondrocyte proliferation were investigated using qPCR. Immunohistochemistry (IHC) was used to explore the mechanisms underlying HDAC4-controlled age-related changes in OA progression.
RESULTS
In human cartilage, we performed morphological analysis and IHC, the results showed that hypertrophy-related structural changes are related to HDAC4 expression. Age-related OA was detected early (OARSI scores 2.7 at 8-month-old) following HDAC4 deletion in 2-month-old mice. Furthermore, qPCR and IHC results showed changes in hypertrophy-related genes Col10a1, Runx2 and Sox9 in chondrocytes, particularly in the expression of Runt-related transcription factor 2 (Runx2, 13.29±0.99 fold). The expression of the main cartilage matrix-related genes Col2a1 and Acan decreased, that of cartilage matrix digestion-related gene MMP-13 increased, while that of chondrocyte proliferation-related genes PTHrP, Ihh and Gli1 changed. In contrast, rat cartilage's qPCR and IHC results showed opposite outcomes after HDAC4 overexpression.
CONCLUSION
Based on the results above, we concluded that HDAC4 expression regulates the onset and development of age-related OA by controlling chondrocyte hypertrophy. These results may help in the development of early diagnosis and treatment of age-related OA.
目的
确定组蛋白去乙酰化酶4（HDAC4）调控的软骨细胞肥大在年龄相关性骨关节炎（OA）发病及发展过程中的作用。
方法
对人膝关节软骨进行形态学分析，以观察软骨退变过程中的结构变化。在成年聚集蛋白聚糖（Acan）-CreERT2；HDAC4fl/fl转基因小鼠中缺失HDAC4表达。使用苏木精和伊红（H&E）染色及番红O染色，对转基因小鼠和对照小鼠年龄相关性OA的发病及发展情况进行研究。此外，在大鼠中探索腺病毒介导的HDAC4过表达后前交叉韧带切断术（ACLT）诱导的OA进展情况。采用实时定量聚合酶链反应（qPCR）检测与肥大、软骨基质及其降解以及软骨细胞增殖相关基因的表达水平。运用免疫组织化学（IHC）方法探究HDAC4调控的年龄相关性OA进展变化的潜在机制。
结果
在人软骨中，我们进行了形态学分析和免疫组织化学检测，结果显示与肥大相关的结构变化与HDAC4表达有关。在2月龄小鼠中缺失HDAC4后，早期（8月龄时骨关节炎研究学会国际联盟（OARSI）评分为2.7）检测到年龄相关性OA。此外，qPCR和免疫组织化学结果显示软骨细胞中与肥大相关基因Col10a1、Runx2和Sox9发生变化，特别是 runt相关转录因子2（Runx2，13.29±0.99倍）的表达。主要软骨基质相关基因Col2a1和Acan的表达降低，软骨基质降解相关基因MMP-13的表达增加，而软骨细胞增殖相关基因PTHrP、Ihh和Gli1的表达发生改变。相比之下，大鼠软骨的qPCR和免疫组织化学结果显示HDAC4过表达后结果相反。
结论
基于上述结果，我们得出结论，HDAC4表达通过控制软骨细胞肥大来调节年龄相关性OA的发病及发展。这些结果可能有助于年龄相关性OA的早期诊断和治疗的发展。
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