Cyclin D1 mediates pain behaviour in a rat model of breast cancer-induced bone pain by a mechanism involving regulation of the proliferation of spinal microglia

• Published in: Bone & joint research Vol. 11; no. 11; pp. 803 - 813
• Main Authors: Guan, Xuehai, Gong, Xiaofang, Jiao, Ziyin Y., Cao, Huiyu Y., Liu, Susu, Lin, Chengxin, Huang, Xiaofang, Lan, Hongmeng, Ma, Li, Xu, Bing
• Format: Journal Article
• Language: English
• Published: London British Editorial Society of Bone & Joint Surgery 01.11.2022; The British Editorial Society of Bone & Joint Surgery
• Subjects: Bone Biology; Bone cancer; Bone cancer induced pain; Breast cancer; Cell cycle; Cyclin D1; Cyclin-dependent kinase; Cyclin-dependent kinases; Enzyme inhibitors; Flavopiridol; Gene expression; Immunohistochemistry; Latency; Microglia; Minocycline; Pain; Polymerase chain reaction; Proliferation; Reverse transcription; Rodents; Spinal cord; spinal microglia
• ISSN: 2046-3758; 2046-3758
• DOI: 10.1302/2046-3758.1111.BJR-2022-0018.R1

Aims The involvement of cyclin D1 in the proliferation of microglia, and the generation and maintenance of bone cancer pain (BCP), have not yet been clarified. We investigated the expression of microglia and cyclin D1, and the influences of cyclin D1 on pain threshold. Methods Female Sprague Dawley (SD) rats were used to establish a rat model of BCP, and the messenger RNA (mRNA) and protein expression of ionized calcium binding adaptor molecule 1 (IBA1) and cyclin D1 were detected by reverse transcription-polymerase chain reaction (RT-PCR) and western blot, respectively. The proliferation of spinal microglia was detected by immunohistochemistry. The pain behaviour test was assessed by quantification of spontaneous flinches, limb use, and guarding during forced ambulation, mechanical paw withdrawal threshold, and thermal paw withdrawal latency. Results IBA1 and cyclin D1 in the ipsilateral spinal horn increased in a time-dependent fashion. Spinal microglia proliferated in BCP rats. The microglia inhibitor minocycline attenuated the pain behaviour in BCP rats. The cyclin-dependent kinase inhibitor flavopiridol inhibited the proliferation of spinal microglia, and was associated with an improvement in pain behaviour in BCP rats. Conclusion Our results revealed that the inhibition of spinal microglial proliferation was associated with a decrease in pain behaviour in a rat model of BCP. Cyclin D1 acts as a key regulator of the proliferation of spinal microglia in a rat model of BCP. Disruption of cyclin D1, the restriction-point control of cell cycle, inhibited the proliferation of microglia and attenuated the pain behaviours in BCP rats. Cyclin D1 and the proliferation of spinal microglia may be potential targets for the clinical treatment of BCP. Cite this article: Bone Joint Res 2022;11(11):803–813.