Inhibition of HDAC6 alleviates cancer‑induced bone pain by reducing the activation of NLRP3 inflammasome

Hu,Yin-Di; Wang,Zhao-Di; Yue,Yuan-Fen; Li,Dai; Zhen,Shu-Qing; Ding,Jie-Qiong; Meng,Wei; Zhu,Hai-Li; Xie,Min; Liu,Ling

doi:10.3892/ijmm.2023.5328

Inhibition of HDAC6 alleviates cancer‑induced bone pain by reducing the activation of NLRP3 inflammasome

Authors:
- Yin-Di Hu
- Zhao-Di Wang
- Yuan-Fen Yue
- Dai Li
- Shu-Qing Zhen
- Jie-Qiong Ding
- Wei Meng
- Hai-Li Zhu
- Min Xie
- Ling Liu
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Affiliations: 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, Hubei Key Laboratory of Diabetes and Angiopathy, School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei 437100, P.R. China, Matang Hospital of Traditional Chinese Medicine, Xianning, Hubei 437000, P.R. China
Published online on: November 17, 2023 https://doi.org/10.3892/ijmm.2023.5328
Article Number: 4
Copyright: © Hu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

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.

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