The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, No. 237 Luoyu Road, Wuhan, 430079, Hubei, China.
Mol Cell Biochem. 2020 Nov;474(1-2):209-218. doi: 10.1007/s11010-020-03846-z. Epub 2020 Aug 3.
Local injection of tumor necrosis factor-alpha (TNF-α) at bone fracture sites during the early stage of the inflammatory response is reported to improve fracture repair in a murine model. However, the underlying mechanism is unclear. Endochondral bone formation, a process that is highly related to fracture repair, requires a certain amount of chondrocyte hypertrophy. This study aimed to investigate the effect of TNF-α on the differentiation of murine chondrogenic ATDC5 cells and the underlying mechanism. In this study, improved chondrogenic differentiation of ATDC5 cells was achieved by brief TNF-α stimulation. Moreover, the expression of Yes-associated protein 1 (YAP1) was suppressed after brief TNF-α stimulation. The expressions of inflammatory mediators and chondrogenic and hypertrophic-associated genes in ATDC5 cells triggered by TNF-α were suppressed in the YAP1 overexpression group but enhanced in the YAP1 knockdown group. Mechanistically, TNF-α-induced activation of the 5' AMP-activated protein kinase (AMPK) signaling pathway was regulated by YAP1, as revealed by the phosphorylated-AMPK/AMPK change ratios in the YAP1 overexpression and knockdown groups, respectively. Moreover, the potential for TNF-α to enhance chondrogenic differentiation could be partially reversed with an AMPK inhibitor. Taken together, we demonstrate, for the first time, that YAP1 modulates the ability of TNF-α to enhance chondrocyte differentiation partly through AMPK signaling.
局部注射肿瘤坏死因子-α（TNF-α）在炎症反应的早期阶段在骨折部位被报道改善了小鼠模型中的骨折修复。然而，其潜在机制尚不清楚。成软骨骨形成，这一过程与骨折修复密切相关，需要一定数量的软骨细胞肥大。本研究旨在探讨 TNF-α对鼠源软骨细胞 ATDC5 分化的影响及其潜在机制。在本研究中，短暂的 TNF-α 刺激促进了 ATDC5 细胞的成软骨分化。此外，短暂的 TNF-α 刺激后 YAP1 的表达受到抑制。在 YAP1 过表达组中，TNF-α 触发的 ATDC5 细胞中炎症介质和软骨形成及肥大相关基因的表达受到抑制，而在 YAP1 敲低组中则增强。在机制上，TNF-α 诱导的 5' AMP 激活蛋白激酶（AMPK）信号通路的激活受 YAP1 调节，这从 YAP1 过表达和敲低组中磷酸化-AMPK/AMPK 变化比可以看出。此外，用 AMPK 抑制剂部分逆转 TNF-α增强软骨分化的潜力。总之，我们首次证明，YAP1 通过 AMPK 信号部分调节 TNF-α增强软骨细胞分化的能力。
