The Level of Histone Deacetylase 4 is Associated with Aging Cartilage Degeneration and Chondrocyte Hypertrophy

Zhengquan Dong; Zhou Ma; Meiju Yang; Linlin Cong; Ruipeng Zhao; Liyun Cheng; Jian Sun; Yunfei Wang; Ruijia Yang; Xiaochun Wei; Pengcui Li

doi:10.2147/JIR.S365545

The Level of Histone Deacetylase 4 is Associated with Aging Cartilage Degeneration and Chondrocyte Hypertrophy

J Inflamm Res. 2022 Jun 16:15:3547-3560. doi: 10.2147/JIR.S365545. eCollection 2022.

Authors

Affiliations

¹ 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.
² Department of Biochemistry and Molecular Biology, the Shanxi Medical University, Taiyuan, Shanxi, People's Republic of China.
³ Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, People's Republic of China.

Abstract

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.

Keywords: HDAC4; cartilage; chondrocytes; degeneration; osteoarthritis.

Grants and funding

Supported by the National Natural Science Foundation of China (grant 8217250), the Natural Science Foundation of Shanxi Fundamental Research Project (project 20210302123263 and project 20210302123270) and Shanxi Scholarship Council of China (project HGKY2019099). The funding source had no active role in the study.