Mazaki Ai, Orita Sumihisa, Inage Kazuhide, Suzuki Miyako, Abe Kohki, Shiga Yasuhiro, Inoue Masahiro, Norimoto Masaki, Umimura Tomotaka, Ohtori Seiji, Yamauchi Kazuyo
Department of Orthopaedic Surgery, Graduate School of Medicine, The Chiba University, Chiba, Japan.
Spine Surg Relat Res. 2019 Apr 5;3(3):261-266. doi: 10.22603/ssrr.2018-0106. eCollection 2019.
Causes of pain due to spinal metastases have been insufficiently investigated. Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were the focus of this study. Both are known as proinflammatory cytokines associated with the pathophysiology of pain syndromes . It is well known that cancer cells produce these cytokines, but whether osteoclasts produce them as well remains unclear. We hypothesize that osteoclasts produce these cytokines; in other words, pain from spinal metastasis is stronger than pain from the primary tumor.
We made a rat spinal metastasis model of breast cancer (metastasis group) and models with a hole in the vertebrae (puncture group) and resected the vertebrae. Tartrate-resistant acid phosphatase (TRAP) staining was performed to reconfirm that osteoclasts increase in vertebrae with spinal metastasis. We then evaluated TNF-α and IL-6 expression using immunohistochemistry and real-time polymerase chain reaction (PCR).
The results of TRAP staining showed that osteoclasts increase in metastatic vertebrae. The osteoclasts in the puncture models were TNF-α negative but were TNF-α positive in the metastasis model. The osteoclasts in the puncture models and metastasis model were both IL-6 positive. According to the real-time PCR results, TNF-α in vertebrae increased in the metastasis model, but IL-6 did not increase in the metastasis model compared with in the puncture model.
The number of osteoclasts is higher in the metastasis model. While TNF in the osteoclasts increased in the spinal metastasis model, IL-6 did not. This probably means that breast cancer affects TNF production in osteoclasts. This increase of TNF-α may lead to pain from spinal metastasis.
脊柱转移瘤所致疼痛的病因尚未得到充分研究。肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）是本研究的重点。二者均为与疼痛综合征病理生理学相关的促炎细胞因子。众所周知，癌细胞会产生这些细胞因子，但破骨细胞是否也会产生它们尚不清楚。我们推测破骨细胞会产生这些细胞因子；换句话说，脊柱转移瘤引起的疼痛比原发肿瘤引起的疼痛更强烈。
我们制作了乳腺癌大鼠脊柱转移模型（转移组）以及椎骨有孔的模型（穿刺组）并切除椎骨。进行抗酒石酸酸性磷酸酶（TRAP）染色以再次确认脊柱转移时椎骨中的破骨细胞会增多。然后我们使用免疫组织化学和实时聚合酶链反应（PCR）评估TNF-α和IL-6的表达。
TRAP染色结果显示转移椎骨中的破骨细胞增多。穿刺模型中的破骨细胞TNF-α呈阴性，但在转移模型中TNF-α呈阳性。穿刺模型和转移模型中的破骨细胞IL-6均呈阳性。根据实时PCR结果，转移模型中椎骨的TNF-α增加，但与穿刺模型相比，转移模型中IL-6未增加。
转移模型中破骨细胞数量更多。虽然脊柱转移模型中破骨细胞的TNF增加，但IL-6没有。这可能意味着乳腺癌会影响破骨细胞中TNF的产生。TNF-α的这种增加可能导致脊柱转移瘤引起的疼痛。
