Mickiewicz Beata, Shin Sung Y, Pozzi Ambra, Vogel Hans J, Clark Andrea L
Department of Medicine, Vanderbilt University , Nashville, Tennessee 37232, United States.
Department of Medicine, Veterans Affairs Hospital , Nashville, Tennessee 37232, United States.
J Proteome Res. 2016 Mar 4;15(3):815-25. doi: 10.1021/acs.jproteome.5b00719. Epub 2016 Jan 28.
The risk of developing post-traumatic osteoarthritis (PTOA) following joint injury is high. Furthering our understanding of the molecular mechanisms underlying PTOA and/or identifying novel biomarkers for early detection may help to improve treatment outcomes. Increased expression of integrin α1β1 and inhibition of epidermal growth factor receptor (EGFR) signaling protect the knee from spontaneous OA; however, the impact of the integrin α1β1/EGFR axis on PTOA is currently unknown. We sought to determine metabolic changes in serum samples collected from wild-type and integrin α1-null mice that underwent surgery to destabilize the medial meniscus and were treated with the EGFR inhibitor erlotinib. Following (1)H nuclear magnetic resonance spectroscopy, we generated multivariate statistical models that distinguished between the metabolic profiles of erlotinib- versus vehicle-treated mice and the integrin α1-null versus wild-type mouse genotype. Our results show the sex-dependent effects of erlotinib treatment and highlight glutamine as a metabolite that counteracts this treatment. Furthermore, we identified a set of metabolites associated with increased reactive oxygen species production, susceptibility to OA, and regulation of TRP channels in α1-null mice. Our study indicates that systemic pharmacological and genetic factors have a greater effect on serum metabolic profiles than site-specific factors such as surgery.
关节损伤后发生创伤后骨关节炎（PTOA）的风险很高。进一步了解PTOA潜在的分子机制和/或识别早期检测的新型生物标志物可能有助于改善治疗效果。整合素α1β1表达增加和表皮生长因子受体（EGFR）信号传导抑制可保护膝关节免受自发性骨关节炎的影响；然而，整合素α1β1/EGFR轴对PTOA的影响目前尚不清楚。我们试图确定从接受内侧半月板失稳手术并接受EGFR抑制剂厄洛替尼治疗的野生型和整合素α1基因敲除小鼠收集的血清样本中的代谢变化。通过氢核磁共振波谱分析，我们生成了多变量统计模型，以区分厄洛替尼治疗组与溶剂对照组小鼠以及整合素α1基因敲除组与野生型小鼠基因型的代谢谱。我们的结果显示了厄洛替尼治疗的性别依赖性效应，并突出了谷氨酰胺作为一种可抵消这种治疗的代谢物。此外，我们在α1基因敲除小鼠中鉴定出一组与活性氧生成增加、骨关节炎易感性和TRP通道调节相关的代谢物。我们的研究表明，全身药理学和遗传因素对血清代谢谱的影响大于手术等部位特异性因素。
