Dnmt3b 缺失通过调控细胞凋亡影响骨折修复过程。
Dnmt3b ablation affects fracture repair process by regulating apoptosis.
机构信息
Institute of Orthopedics and Traumatology, the First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang Province, China.
The First College of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, China.
出版信息
BMC Musculoskelet Disord. 2024 Feb 27;25(1):180. doi: 10.1186/s12891-024-07283-7.
PURPOSE
Previous studies have shown that DNA methyltransferase 3b (Dnmt3b) is the only Dnmt responsive to fracture repair and Dnmt3b ablation in Prx1-positive stem cells and chondrocyte cells both delayed fracture repair. Our study aims to explore the influence of Dnmt3b ablation in Gli1-positive stem cells in fracture healing mice and the underlying mechanism.
METHODS
We generated Gli1-CreERT2; Dnmt3bflox/flox (Dnmt3b) mice to operated tibia fracture. Fracture callus tissues of Dnmt3b mice and control mice were collected and analyzed by X-ray, micro-CT, biomechanical testing, histopathology and TUNEL assay.
RESULTS
The cartilaginous callus significantly decrease in ablation of Dnmt3b in Gli1-positive stem cells during fracture repair. The chondrogenic and osteogenic indicators (Sox9 and Runx2) in the fracture healing tissues in Dnmt3b mice much less than control mice. Dnmt3b mice led to delayed bone callus remodeling and decreased biomechanical properties of the newly formed bone during fracture repair. Both the expressions of Caspase-3 and Caspase-8 were upregulated in Dnmt3b mice as well as the expressions of BCL-2.
CONCLUSIONS
Our study provides an evidence that Dnmt3b ablation Gli1-positive stem cells can affect fracture healing and lead to poor fracture healing by regulating apoptosis to decrease chondrocyte hypertrophic maturation.
目的
先前的研究表明，DNA 甲基转移酶 3b（Dnmt3b）是唯一对骨折修复有反应的 Dnmt，Prx1 阳性干细胞和软骨细胞中的 Dnmt3b 缺失均延迟了骨折修复。本研究旨在探讨 Dnmt3b 在Gli1 阳性干细胞中的缺失对骨折愈合小鼠的影响及其潜在机制。
方法
我们生成了 Gli1-CreERT2; Dnmt3bflox/flox（Dnmt3b）小鼠以进行胫骨骨折手术。收集和分析 Dnmt3b 小鼠和对照组小鼠的骨折愈合组织的 X 射线、微 CT、生物力学测试、组织病理学和 TUNEL 检测结果。
结果
在骨折修复过程中，Gli1 阳性干细胞中 Dnmt3b 的缺失导致软骨性骨痂明显减少。Dnmt3b 小鼠的骨折愈合组织中的软骨和成骨指标（Sox9 和 Runx2）明显少于对照组。Dnmt3b 小鼠导致骨痂重塑延迟，新形成的骨的生物力学性能降低。Dnmt3b 小鼠中的 Caspase-3 和 Caspase-8 表达上调，同时 BCL-2 表达也上调。
结论
本研究提供了证据表明，Gli1 阳性干细胞中 Dnmt3b 的缺失会影响骨折愈合，并通过调节细胞凋亡导致软骨细胞肥大成熟减少，从而导致骨折愈合不良。
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