Department of Orthopedics Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
J Orthop Surg Res. 2024 Oct 12;19(1):645. doi: 10.1186/s13018-024-05121-z.
Our previous research revealed a close association between the acetylation of peroxisome proliferator-activated receptor γ (PPARγ) histone H3K27 and the adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). We preliminarily explored the epigenetic mechanism of steroid-induced avascular necrosis of the femoral head (SANFH) development, but the specific histone deacetylase (HDAC) involved in this regulatory process remains unknown. In this study, we combined cell, animal, and clinical specimen experiments to screen for specific HDAC genes that could regulate BMSC adipogenic differentiation and to explore their roles. The results showed that dexamethasone (DEX) significantly exacerbated the imbalance between the adipogenic and osteogenic differentiation of BMSCs, and there were differences in HDAC expression in the adipogenic differentiation cell models, with histone deacetylase 10 (HDAC10) showing the most significant decrease in expression. Subsequent use of a chromatin immunoprecipitation assay kit and quantitative polymerase chain reaction (ChIP‒qPCR) revealed a decrease in HDAC10 expression at predicted potential sites within the PPARγ promoter, indicating a significant decrease in HDAC10 enrichment in the PPARγ promoter region of BMSCs, thereby promoting sustained PPARγ expression. Additionally, immunohistochemistry of samples collected from mice and humans with SANFH and normal femoral heads revealed an imbalance between adipogenic and osteogenic differentiation in the necrotic area of femoral heads, with a significant decrease in the relative expression of HDAC10 in the necrotic area of femoral heads with SANFH. In summary, we speculate that HDAC10 affects the progression of SANFH by regulating BMSC adipogenic differentiation, a process possibly related to PPARγ histone acetylation. These findings provide a promising direction for the treatment of SANFH.
我们之前的研究揭示了过氧化物酶体增殖物激活受体γ（PPARγ）组蛋白 H3K27 的乙酰化与骨髓间充质干细胞（BMSCs）的成脂分化密切相关。我们初步探讨了类固醇诱导性股骨头坏死（SANFH）发展的表观遗传机制，但该调节过程中涉及的特定组蛋白去乙酰化酶（HDAC）尚不清楚。在这项研究中，我们结合细胞、动物和临床标本实验，筛选出可调节 BMSC 成脂分化的特定 HDAC 基因，并探讨其作用。结果表明，地塞米松（DEX）显著加剧了 BMSCs 成脂和成骨分化之间的失衡，成脂分化细胞模型中 HDAC 的表达存在差异，其中组蛋白去乙酰化酶 10（HDAC10）的表达下降最为显著。随后使用染色质免疫沉淀试剂盒和定量聚合酶链反应（ChIP‒qPCR）检测到 PPARγ 启动子内预测的潜在位点处 HDAC10 表达减少，表明 BMSCs 中 PPARγ 启动子区域的 HDAC10 富集显著减少，从而促进了 PPARγ 的持续表达。此外，对 SANFH 和正常股骨头患者样本进行免疫组织化学染色，结果显示股骨头坏死区存在成脂和成骨分化失衡，SANFH 股骨头坏死区的 HDAC10 相对表达显著降低。综上所述，我们推测 HDAC10 通过调节 BMSC 成脂分化来影响 SANFH 的进展，该过程可能与 PPARγ 组蛋白乙酰化有关。这些发现为治疗 SANFH 提供了有希望的方向。
