Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing, China; National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing, China; Beijing Key Laboratory of Digital Stomatology, 22# Zhongguancun South Avenue, Haidian District, Beijing, 100081, China.
Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing, China; National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing, China; Beijing Key Laboratory of Digital Stomatology, 22# Zhongguancun South Avenue, Haidian District, Beijing, 100081, China; Center for Temporomandibular Disorders and Orofacial Pain, Peking University School and Hospital of Stomatology, Haidian District, Beijing, China; Central Laboratory, Peking University School and Hospital of Stomatology, Haidian District, Beijing, China.
Osteoarthritis Cartilage. 2022 Aug;30(8):1140-1153. doi: 10.1016/j.joca.2022.04.002. Epub 2022 May 2.
This study aimed to explore the effect and mechanism of chondrocyte apoptosis on the chemotaxis of osteoclast precursors (OCPs) during bone destruction.
The relationship between cartilage and bone destruction was verified with a rat temporomandibular joint osteoarthritis (TMJOA) model. The pan-caspase inhibitor Z-VAD-FMK (ZVAD) was applied to confirm the chemotactic effect of chondrocyte apoptosis on OCPs. Synthesis and release of the key chemokine CX3CL1 in apoptotic and non-apoptotic chondrocytes was assessed with IHC, IF, WB, and ELISA. The function of CX3CL1-CX3CR1 axis in the chemotaxis of OCPs was examined by CX3XR1 inhibitor AZD8797 (AZD) and si-CX3CL1. The regulatory effect of p38 MAPK on CX3CL1 release was verified by p38 inhibitor PH-797804.
A temporal and spatial association between cartilage degradation and bone resorption was found in the TMJOA model. The caspase-dependent chondrocyte apoptosis promoted chemotaxis of OCPs, which can be restrained by ZVAD. CX3CL1 was significantly upregulated when chondrocytes underwent apoptosis, and it played a critical role in the recruitment of OCPs, blockage of CX3CL1-CX3CR1 axis resulted in less bone resorption in TMJOA. P38 MAPK was activated in apoptotic chondrocytes, and had a regulatory effect on the synthesis and release of CX3CL1. After inhibition of p38 by PH-797804, the chemotactic effect of apoptotic chondrocytes on OCPs was limited.
This study indicates that apoptosis of chondrocytes in TMJOA enhances chemotaxis of OCPs toward osteoclast precursors through upregulation of the p38-CX3CL1 axis, thereby promoting the activation of local osteoclasts.
本研究旨在探讨软骨细胞凋亡对破骨细胞前体细胞（OCPs）趋化作用的影响及其机制。
采用大鼠颞下颌关节骨关节炎（TMJOA）模型验证软骨与骨破坏的关系。应用泛半胱天冬酶抑制剂 Z-VAD-FMK（ZVAD）证实软骨细胞凋亡对 OCPs 的趋化作用。采用免疫组化、免疫荧光、Western blot 和 ELISA 检测凋亡和非凋亡软骨细胞中关键趋化因子 CX3CL1 的合成和释放。通过 CX3CR1 抑制剂 AZD8797（AZD）和 si-CX3CL1 检测 CX3CL1-CX3CR1 轴在 OCPs 趋化中的作用。通过 p38 抑制剂 PH-797804 验证 p38 MAPK 对 CX3CL1 释放的调节作用。
在 TMJOA 模型中发现软骨降解与骨吸收存在时空关联。依赖于半胱天冬酶的软骨细胞凋亡促进 OCPs 的趋化作用，ZVAD 可抑制该作用。当软骨细胞发生凋亡时，CX3CL1 显著上调，并在招募 OCPs 中发挥关键作用，阻断 CX3CL1-CX3CR1 轴导致 TMJOA 中骨吸收减少。凋亡软骨细胞中 p38 MAPK 被激活，对 CX3CL1 的合成和释放有调节作用。用 PH-797804 抑制 p38 后，凋亡软骨细胞对 OCPs 的趋化作用受到限制。
本研究表明，TMJOA 中软骨细胞的凋亡通过上调 p38-CX3CL1 轴增强 OCPs 向破骨细胞前体的趋化作用，从而促进局部破骨细胞的激活。
