Pharmacological targeting of the mammalian clock reveals a novel analgesic for osteoarthritis-induced pain.
Pharmacological targeting of the mammalian clock reveals a novel analgesic for osteoarthritis-induced pain.
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DOI：
10.1016/j.gene.2018.02.048
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发表时间：
2018-05-20
期刊：
影响因子：
3.5
通讯作者：
Im HJ
中科院分区：
文献类型：
--
作者：
Das V;Kc R;Li X;Varma D;Qiu S;Kroin JS;Forsyth CB;Keshavarzian A;van Wijnen AJ;Park TJ;Stein GS;O-Sullivan I;Burris TP;Im HJ
环境对昼夜节律的破坏与骨关节炎（OA）引起的疼痛增加有关。我们的目的是更系统地使用遗传学和药理学方法来表征时钟基因在OA诱导的疼痛中的作用。通过从Nav1.8感觉神经元中删除关键时钟基因bmal 1而产生的转基因小鼠（bmal 1f/fNav1.8CreERT小鼠）对膝关节部分内侧半月板切除术（PMM）诱导的OA相关的机械性痛觉过敏的发展具有抗性。在野生型小鼠中，通过PMM手术诱导OA导致DRG神经元中BMAL 1表达显著增加。有趣的是，用SR9009药理学激活REV-ERB（bmal 1转录的负调节因子）导致BMAL 1表达减少，并且与OA相关的机械性痛觉过敏显著减少。在用REV-ERB激动剂SR9009处理的小鼠中，软骨变性也显著减少。基于这些数据，我们还使用环境昼夜节律破坏及其相关机械性痛觉过敏模型评估了REV-ERB的药理学激活作用，并注意到SR9009在该模型中也是一种有效的镇痛剂。我们的数据清楚地表明，通过删除背根神经节感觉神经元中的bmal 1，分子钟的遗传破坏减少了OA模型中的疼痛。此外，REV-ERB的药理学激活导致BMAL 1表达的抑制可能是治疗OA相关疼痛以及减少与这种疾病相关的关节损伤的有效方法。
Environmental disruption of the circadian rhythm is linked with increased pain due to osteoarthritis (OA). We aimed to characterize the role of the clock gene in OA-induced pain more systemically using both genetic and pharmacological approaches. Genetically modified mice, (bmal1f/fNav1.8CreERT mice), generated by deleting the critical clock gene, bmal1, from Nav1.8 sensory neurons, were resistant to the development of mechanical hyperalgesia associated with OA induced by partial medial meniscectomy (PMM) of the knee. In wild-type mice, induction of OA by PMM surgery led to a substantial increase in BMAL1 expression in DRG neurons. Interestingly, pharmacological activation of the REV-ERB (a negative regulator of bmal1 transcription) with SR9009 resulted in reduction of BMAL1 expression, and a significant decrease in mechanical hyperalgesia associated with OA. Cartilage degeneration was also significantly reduced in mice treated with the REV-ERB agonist SR9009. Based on these data, we also assessed the effect of pharmacological activation of REV-ERB using a model of environmental circadian disruption with its associated mechanical hyperalgesia, and noted that SR9009 was an effective analgesic in this model as well. Our data clearly demonstrate that genetic disruption of the molecular clock, via deletion of bmal1 in the sensory neurons of the DRG, decreases pain in a model of OA. Furthermore, pharmacological activation of REV-ERB leading to suppression of BMAL1 expression may be an effective method for treating OA-related pain, as well as to reduce joint damage associated with this disease.
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影响因子：
82.9
作者：
Alexandre C;Latremoliere A;Ferreira A;Miracca G;Yamamoto M;Scammell TE;Woolf CJ
通讯作者：
Woolf CJ
影响因子：
--
作者：
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通讯作者：
Griffin PR
影响因子：
16.6
作者：
Banerjee, Subhashis;Wang, Yongjun;Burris, Thomas P.
通讯作者：
Burris, Thomas P.
影响因子：
--
作者：
Alford, Les
通讯作者：
Alford, Les
影响因子：
3.7
作者：
Crumbley C;Burris TP
通讯作者：
Burris TP