Wang Shanzheng, Sun Guodong, Fan Pan, Huang Lei, Chen Yaofei, Chen Changhong
Department of Orthopedics, Affiliated Zhongda Hospital of Southeast University, Nanjing, Jiangsu, 210009, PR China.
Department of Orthopedics, First Affiliated Hospital, Jinan University, Guangzhou, 510632, PR China.
J Orthop Translat. 2021 Dec 3;31:62-72. doi: 10.1016/j.jot.2021.11.003. eCollection 2021 Nov.
Elevated tumor necrosis factor alpha (TNF-α) expression is correlated with the progression of intervertebral disc degeneration (IVDD). Progranulin binding to tumor necrosis factor receptor (TNFR) and its derivative Atsttrin are effective for treating inflammatory arthritis. We hypothesize that Atsttrin has a protective effect in IVDD through different roles of TNFR receptor type 1 (TNFR1) and TNFR receptor type 2 (TNFR2) in degenerated discs.
IVDD models were established in TNFR1, TNFR2 mice and their control littermates. Nucleus Pulpous (NP) samples from human patients and IVDD murine models were evaluated by X-ray, micro-MRI, μCT, histological staining and immunofluorescence staining. NP cells isolated from wild-type (WT), TNFR1 and TNFR2 mice were treated with TNF-α or Atsttrin and then assayed by Western blotting, qRT-PCR, and ELISA.
TNFR1 and TNFR2 expression was significantly elevated in the disc tissues of both human patients and IVDD murine models. TNFR1 knockout contributed to reduced disc degeneration. In contrast, TNFR2 knockout was associated with enhanced IVDD severity, including degraded cellular composition, increased cell apoptosis and elevated vertebral destruction. Atsttrin protected against IVDD in WT and TNFR1 mouse models but had no effect in TNFR2 IVDD models. Additionally, NP cell-based assays demonstrated that TNF-α-stimulated catabolism and Atsttrin-activated anabolism depended on TNFR1 and TNFR2, respectively.
TNFR1 is associated with the degenerative progression of IVDD, while TNFR2 contributes to the protective effect on the discs. Atsttrin protects against IVDD at least partially by inhibiting the TNFα/TNFR1 inflammatory/catabolic pathway and activating the TNFR2 protective/anabolic pathway.
This study demonstrates that TNFR1 and TNFR2 have disparate roles in disc degeneration and hlights the potential use of Atsttrin as a therapeutic agent against IVDD in mice.
肿瘤坏死因子α（TNF-α）表达升高与椎间盘退变（IVDD）的进展相关。前颗粒蛋白与肿瘤坏死因子受体（TNFR）及其衍生物Atsttrin对治疗炎性关节炎有效。我们假设Atsttrin通过TNFR1型受体（TNFR1）和TNFR2型受体（TNFR2）在退变椎间盘中的不同作用对IVDD具有保护作用。
在TNFR1、TNFR2小鼠及其对照同窝小鼠中建立IVDD模型。通过X射线、显微MRI、μCT、组织学染色和免疫荧光染色对人类患者和IVDD小鼠模型的髓核（NP）样本进行评估。用TNF-α或Atsttrin处理从野生型（WT）、TNFR1和TNFR2小鼠分离的NP细胞，然后通过蛋白质印迹、qRT-PCR和ELISA进行检测。
在人类患者和IVDD小鼠模型的椎间盘组织中，TNFR1和TNFR2表达均显著升高。TNFR1基因敲除导致椎间盘退变减轻。相反，TNFR2基因敲除与IVDD严重程度增加有关，包括细胞组成退化、细胞凋亡增加和椎体破坏加剧。Atsttrin在WT和TNFR1小鼠模型中对IVDD具有保护作用，但在TNFR2 IVDD模型中无效。此外，基于NP细胞的检测表明，TNF-α刺激的分解代谢和Atsttrin激活的合成代谢分别依赖于TNFR1和TNFR2。
TNFR1与IVDD的退变进展相关，而TNFR2对椎间盘具有保护作用。Atsttrin至少部分通过抑制TNFα/TNFR1炎症/分解代谢途径和激活TNFR2保护/合成代谢途径来预防IVDD。
本研究表明TNFR1和TNFR2在椎间盘退变中具有不同作用，并突出了Atsttrin作为小鼠IVDD治疗药物的潜在用途。
