School of Pharmacy, Hubei University of Science and Technology, Xianning, Hubei 437100, P.R. China.
Xianning Central Hospital, First Affiliated Hospital of Hubei University of Science and Technology, Xianning, Hubei 437199, P.R. China.
Int J Mol Med. 2024 Jan;53(1). doi: 10.3892/ijmm.2023.5328. Epub 2023 Nov 24.
Cancer‑induced bone pain (CIBP) is characterized as moderate to severe pain that negatively affects the daily functional status and quality of life of patients. When cancer cells metastasize and grow in bone marrow, this activates neuroinflammation in the spinal cord, which plays a vital role in the generation and persistence of chronic pain. In the present study, a model of CIBP was constructed by inoculating of MRMT‑1 rat breast carcinoma cells into the medullary cavity of the tibia in male Sprague‑Dawley rats. Following two weeks of surgery, CIBP rats exhibited damaged bone structure, increased pain sensitivity and impaired motor coordination. Neuroinflammation was activated in the spinal cords of CIBP rats, presenting with extensive leukocyte filtration, upregulated cytokine levels and activated astrocytes. Histone deacetylase 6 (HDAC6) works as a therapeutic target for chronic pain. The intrathecal injection of the HDAC6 inhibitor tubastatin A (TSA) in the lumbar spinal cord resulted in decreased spinal inflammatory cytokine production, suppressed spinal astrocytes activation and reduced NOD‑like receptor pyrin domain containing 3 (NLRP3) inflammasome activity. Consequently, this effect alleviated spontaneous pain and mechanical hyperalgesia and recovered motor coordination in CIBP rats. It was demonstrated by immunoprecipitation assay that TSA treatment reduced the interaction between HDAC6 and NLRP3. Cell research on C6 rat glioma cells served to verify that TSA treatment reduced HDAC6 and NLRP3 expression. In summary, the findings of present study indicated that TSA treatment alleviated cancer‑induced bone pain through the inhibition of HDAC6/NLRP3 inflammasome signaling in the spinal cord.
癌症骨痛（CIBP）的特征为中重度疼痛，会对患者的日常功能状态和生活质量产生负面影响。当癌细胞转移并在骨髓中生长时，这会激活脊髓中的神经炎症，而神经炎症在慢性疼痛的产生和持续中起着至关重要的作用。在本研究中，通过将 MRMT-1 大鼠乳腺癌细胞接种到雄性 Sprague-Dawley 大鼠的胫骨骨髓腔中，构建了 CIBP 模型。手术后两周，CIBP 大鼠表现出骨结构受损、疼痛敏感性增加和运动协调能力受损。脊髓中的神经炎症被激活，表现为广泛的白细胞滤过、细胞因子水平上调和星形胶质细胞激活。组蛋白去乙酰化酶 6（HDAC6）是慢性疼痛的治疗靶点。鞘内注射 HDAC6 抑制剂 tubastatin A（TSA）到腰椎脊髓中，导致脊髓中炎症细胞因子的产生减少，抑制了脊髓星形胶质细胞的激活，并降低了 NOD-样受体含 pyrin 结构域 3（NLRP3）炎性小体的活性。因此，这种作用缓解了 CIBP 大鼠的自发性疼痛和机械性痛觉过敏，并恢复了运动协调能力。免疫沉淀测定表明，TSA 处理减少了 HDAC6 和 NLRP3 之间的相互作用。C6 大鼠神经胶质瘤细胞的细胞研究验证了 TSA 处理降低了 HDAC6 和 NLRP3 的表达。综上所述，本研究结果表明，TSA 治疗通过抑制脊髓中 HDAC6/NLRP3 炎性小体信号通路缓解了癌症骨痛。
