School of Medicine, Shandong University, Jinan 250012, China.
Department of Orthopaedics, Tengzhou Central People's Hospital, Tengzhou 277500, China.
Exp Mol Pathol. 2021 Feb;118:104590. doi: 10.1016/j.yexmp.2020.104590. Epub 2020 Dec 5.
Endplate degeneration is characterized by an unbalance between the anabolism and catabolism of endplate chondrocyte (CH). Fibroblast growth factor 2 (FGF2) has been shown to promote cartilage repair by increasing articular CH anabolic activity. We aimed to explore the effect of FGF2 on the metabolism of endplate CH to elucidate whether FGF2 could be used as a therapy to delay the endplate degeneration.
We collected the endplate tissue from the patients and tested the collagen II mRNA level as the anabolic marker and the MMP-13 and TIMP-4 expression as the catabolic markers. The FGF2, FGF receptor 1 (FGFR1), and FGFR3 mRNA expression of the endplate tissue were also analyzed. Besides, we treated the CHs with exogenic FGF2 protein, measured the markers mentioned above, the proliferation and the apoptosis of the CHs. To compare the effect of FGF2 on the CHs with or without degeneration, we also induced CHs degeneration by interleukin-1β (IL-1β) stimulation and used the FGF2 protein to treat the degenerative CHs.
Severely degenerative endplate had a lower collagen II and TIMP-4 mRNA level, but it expressed a more massive amount of MMP-13, FGF2, and FGFR1. FGF2 supplement upregulated the FGFR1/FGFR3, TIMP-4, collagen II expression, and promoted the CHs proliferation. In the first 24 h of IL-1β treatment, the FGF2 mRNA expression was suppressed, but it significantly increased 48 h later. Meanwhile, the FGFR1 was upregulated, and FGFR3 was inhibited by IL-1β treatment. Interestingly, the FGF2 protein supplement accelerated the degenerative CHs catabolism by decreasing collagen II and TIPM-4 expression but increasing MMP-13. However, the FGF2 could promote the anabolism process in case of the blocking of FGFR1. The FGF2 supplement could also promote the proliferation and inhibited the apoptosis of degenerative CHs, which could be magnified by FGFR1 blocking.
The results demonstrate that FGF2 is upregulated in the highly degenerative endplate. The supplement of FGF2 contributes to the anabolism in the early phase of endplate degeneration. In the later stage of endplate degeneration, FGF2 turns to accelerate the catabolism, which can be rejected by the reasonable use of FGFR1 inhibitors.
终板退变的特征是终板软骨细胞（CH）的合成代谢与分解代谢失衡。成纤维细胞生长因子 2（FGF2）已被证明可通过增加关节 CH 的合成代谢活性来促进软骨修复。我们旨在探讨 FGF2 对终板 CH 代谢的影响，以阐明 FGF2 是否可作为一种延缓终板退变的治疗方法。
我们收集了患者的终板组织，并测试了胶原蛋白 II mRNA 水平作为合成代谢标志物，以及 MMP-13 和 TIMP-4 表达作为分解代谢标志物。还分析了终板组织中的 FGF2、FGFR1 和 FGFR3 mRNA 表达。此外，我们用外源性 FGF2 蛋白处理 CH，测量了上述标志物、CH 增殖和凋亡。为了比较 FGF2 对退变 CH 和未退变 CH 的影响，我们还通过白细胞介素-1β（IL-1β）刺激诱导 CH 退变，并使用 FGF2 蛋白治疗退行性 CH。
严重退变的终板中胶原蛋白 II 和 TIMP-4 mRNA 水平较低，但表达大量 MMP-13、FGF2 和 FGFR1。FGF2 补充上调了 FGFR1/FGFR3、TIMP-4 和胶原蛋白 II 表达，并促进了 CH 的增殖。在 IL-1β 处理的前 24 小时，FGF2 mRNA 表达受到抑制，但 48 小时后显著增加。同时，FGFR1 上调，FGFR3 受 IL-1β 处理抑制。有趣的是，FGF2 蛋白补充通过降低胶原蛋白 II 和 TIMP-4 表达但增加 MMP-13 来加速退行性 CH 的分解代谢。然而，在阻断 FGFR1 的情况下，FGF2 可以促进 CH 的合成代谢过程。FGF2 补充还可以促进退行性 CH 的增殖并抑制其凋亡，而阻断 FGFR1 可放大这种作用。
结果表明，FGF2 在高度退变的终板中上调。FGF2 的补充有助于终板退变早期的合成代谢。在终板退变的后期阶段，FGF2 转而加速分解代谢，这可以通过合理使用 FGFR1 抑制剂来阻止。
