Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
Orthopedic Institute, Medical College, Soochow University, Suzhou, Jiangsu, China.
J Cell Physiol. 2019 May;234(5):5362-5371. doi: 10.1002/jcp.27507. Epub 2018 Oct 26.
Intervertebral disc (IVD) degeneration is the major contributor to low back pain, a highly prevalent musculoskeletal problem that represents the leading cause of disability. Proinflammatory M1 macrophages were identified in degenerated IVDs. However, their role in the pathogenesis of IVD degeneration and the underlying mechanism was largely unknown. In this study, we explored the combined effects of molecules secreted by M1 macrophages on nucleus pulposus cells, by treating rat nucleus pulposus cells (rNP) with the conditioned medium collected from M1-polarized RAW264.7 cells (MФCM). We found that MФCM caused molecular changes associated with IVD degeneration, including increased expression of key matrix catabolic genes (Adamts4, Adamts5, Mmp3, and Mmp13), reduced the expression of major matrix-associated anabolic genes ( Sox9, Acan, and Col2a1), and upregulated transcription of inflammation-related genes ( IL-1b, IL-6, Ccl2, and Ccl3), in rNP cells. Moreover, we found that MФCM activated both ERK and JNK pathways in these cells, and that inhibition of JNK pathway attenuated MФCM-induced expression of both catabolic and inflammatory genes, whereas ERK inhibition only suppressed induction of catabolic, but not inflammatory genes. Together, our data demonstrated that proinflammatory macrophages promoted the degenerative phenotypes in rNP cells in part through ERK and JNK signaling, and suggested that inhibition of these pathways may serve as a potential therapeutic approach for the treatment of IVD degeneration.
椎间盘（IVD）退变是导致腰痛的主要原因，腰痛是一种高发的肌肉骨骼疾病，也是导致残疾的主要原因。在退变的 IVD 中发现了促炎 M1 巨噬细胞。然而，它们在 IVD 退变发病机制中的作用及其潜在机制在很大程度上尚不清楚。在这项研究中，我们通过用 M1 极化 RAW264.7 细胞（MФCM）收集的条件培养基处理大鼠髓核细胞（rNP），来探索 M1 巨噬细胞分泌的分子对髓核细胞的综合影响。我们发现 MФCM 导致与 IVD 退变相关的分子变化，包括关键基质分解代谢基因（Adamts4、Adamts5、Mmp3 和 Mmp13）的表达增加，主要基质相关合成代谢基因（Sox9、Acan 和 Col2a1）的表达减少，以及炎症相关基因（IL-1b、IL-6、Ccl2 和 Ccl3）的转录上调。此外，我们发现 MФCM 在这些细胞中激活了 ERK 和 JNK 通路，而 JNK 通路的抑制减弱了 MФCM 诱导的分解代谢和炎症基因的表达，而 ERK 抑制仅抑制了分解代谢基因的诱导，但不抑制炎症基因的诱导。总之，我们的数据表明，促炎巨噬细胞通过 ERK 和 JNK 信号通路促进 rNP 细胞的退行性表型，并表明抑制这些通路可能是治疗 IVD 退变的一种潜在治疗方法。
