Specific PFKFB3 Inhibitor Memorably Ameliorates Intervertebral Disc Degeneration via Inhibiting NF-κB and MAPK Signaling Pathway and Reprogramming of Energy Metabolism of Nucleus Pulposus Cells.
Specific PFKFB3 Inhibitor Memorably Ameliorates Intervertebral Disc Degeneration via Inhibiting NF-κB and MAPK Signaling Pathway and Reprogramming of Energy Metabolism of Nucleus Pulposus Cells.
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特定的PFKFB3抑制剂可令人难忘地通过抑制NF-κB和MAPK信号传导途径以及对核细胞核细胞的能量代谢的重编程来缓解椎间盘变性。
DOI：
10.1155/2022/7548145
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发表时间：
2022
影响因子：
--
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中科院分区：
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椎间盘退变（IVD degeneration，IVDD）是以髓核（Nucleus pulposus，NP）细胞衰老、细胞外基质（extracellular matrix，ECM）合成异常和分布不规则以及肿瘤坏死因子-α（tumor necrosis factor-α，TNF-α）诱导的炎症反应为特征的主要病理过程。近年来，IVD酸环境的改变对上述病理过程的加速作用引起了研究者的关注。KAN 0438757（KAN）是选择性代谢激酶磷酸果糖激酶-2/果糖-2，6-二磷酸酶3（PFKFB 3）的有效抑制剂，具有能量代谢重编程和抗炎作用。因此，KAN的潜在治疗益处在于其抑制IVDD发展的能力。本研究检测了NP原代细胞（NPP）中的体外KAN毒性。此外，KAN还可影响肿瘤坏死因子-α（TNF-α）诱导的ECM的增殖和分化，并可影响NPPs的炎症信号通路激活和能量代谢表型。并采用大鼠尾椎间盘穿刺模型，在体内研究了KAN的治疗作用。从表型上看，KAN治疗部分挽救了TNF-α诱导的NPP的ECM降解和糖酵解能量代谢表型。其作用机制为抑制TNF-α诱导的MAPK和NF-κB炎症信号通路的激活，使能量代谢重编程。在治疗方面，大鼠尾椎间盘穿刺模型表明，康安对IVDD的进展有明显的改善作用。综上所述，我们的研究成功验证了KAN对IVDD的潜在治疗作用，并阐明了其新型能量代谢重编程和常规抗炎作用的机制。
Intervertebral disc (IVD) degeneration (IVDD) is a characteristic of the dominating pathological processes of nucleus pulposus (NP) cell senescence, abnormal synthesis and irregular distribution of extracellular matrix (ECM), and tumor necrosis factor-α (TNF-α) induced inflammation. Nowadays, IVD acid environment variation which accelerates the pathological processes mentioned above arouses researchers' attention. KAN0438757 (KAN) is an effective inhibitor of selective metabolic kinase phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3) that has both energy metabolism reprogramming and anti-inflammatory effects. Therefore, a potential therapeutic benefit of KAN lies in its ability to inhibit the development of IVDD. This study examined in vitro KAN toxicity in NP primary cells (NPPs). Moreover, KAN influenced tumor necrosis factor-α (TNF-α) induced ECM anabolism and catabolism; the inflammatory signaling pathway activation and the energy metabolism phenotype were also examined in NPPs. Furthermore, KAN's therapeutic effect was investigated in vivo using the rat tail disc puncture model. Phenotypically speaking, the KAN treatment partially rescued the ECM degradation and glycolysis energy metabolism phenotypes of NPPs induced by TNF-α. In terms of mechanism, KAN inhibited the activation of MAPK and NF-κB inflammatory signaling pathways induced by TNF-α and reprogramed the energy metabolism. For the therapeutic aspect, the rat tail disc puncture model demonstrated that KAN has a significant ameliorated effect on the progression of IVDD. To sum up, our research successfully authenticated the potential therapeutic effect of KAN on IVDD and declaimed its mechanisms of both novel energy metabolism reprogramming and conventional anti-inflammation effect.
影响因子：
5.2
作者：
Ninou AH;Lehto J;Chioureas D;Stigsdotter H;Schelzig K;Åkerlund E;Gudoityte G;Joneborg U;Carlson J;Jonkers J;Seashore-Ludlow B;Gustafsson NMS
通讯作者：
Gustafsson NMS