Groven Rald V M, Mert Ümit, Greven Johannes, Horst Klemens, Joris Virginie, Bini Lara, Poeze Martijn, Blokhuis Taco J, Huber-Lang Markus, Hildebrand Frank, van Griensven Martijn
Department of Cell Biology-Inspired Tissue Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Maastricht, the Netherlands.
Division of Trauma Surgery, Department of Surgery, Maastricht University Medical Center+, Maastricht, the Netherlands.
Bone Joint J. 2025 Feb 1;107-B(2):193-203. doi: 10.1302/0301-620X.107B2.BJJ-2024-0160.R3.
The aims of this study, using a porcine model of multiple trauma, were to investigate the expression of microRNAs at the fracture site, in the fracture haematoma (fxH) and in the fractured bone, compared with a remote unfractured long bone, to characterize the patterns of expression of circulating microRNAs in plasma, and identify and validate messenger RNA (mRNA) targets of the microRNAs.
Two multiple trauma treatment strategies were compared: early total care (ETC) and damage control orthopaedics (DCO). For this study, fxH, fractured bone, unfractured control bone, plasma, lung, and liver samples were harvested. MicroRNAs were analyzed using quantitative real-time polymerase chain reaction arrays, and the identified mRNA targets were validated in vivo in the bone, fxH, lung, and liver tissue.
MicroRNA expression was associated with the trauma treatment strategy and differed depending on the type of sample. In the ETC group, a more advanced fracture healing response, as reflected by the expression of osteogenic microRNAs, was seen compared with the DCO group. DCO treatment resulted in a more balanced immune response in the systemic circulation as represented by significant upregulations of several anti-inflammatory microRNAs. The in vivo validation of the abundance of putative mRNA targets reflected the levels of microRNAs which were identified.
Local and systemic microRNA patterns of expression were identified, specific for the treatment strategy in multiple trauma, which corresponded with the expression of mRNA at the fracture site and in target organs. These findings match clinical observations and offer insights into the cellular communication which may underlie the effects of using different surgical strategies in patients with multiple trauma, both locally and systemically. We also identified a systemic involvement of microRNAs in multiple trauma which may include distant cellular communication between injured tissues. Further research may further describe the temporospatial role of circulating microRNAs after multiple trauma, their potential role in communication between organs, and prospective therapeutic applications.
本研究采用猪多创伤模型，旨在研究骨折部位、骨折血肿（fxH）及骨折骨中微小RNA（miRNA）的表达情况，并与远处未骨折的长骨进行比较，以表征血浆中循环miRNA的表达模式，同时鉴定并验证miRNA的信使核糖核酸（mRNA）靶标。
比较了两种多创伤治疗策略：早期全面治疗（ETC）和损伤控制骨科（DCO）。在本研究中，采集了fxH、骨折骨、未骨折对照骨、血浆、肺和肝样本。使用定量实时聚合酶链反应阵列分析miRNA，并在骨、fxH、肺和肝组织中对鉴定出的mRNA靶标进行体内验证。
miRNA表达与创伤治疗策略相关，且因样本类型而异。与DCO组相比，ETC组中，成骨miRNA的表达反映出骨折愈合反应更高级。DCO治疗导致全身循环中的免疫反应更加平衡，表现为几种抗炎miRNA显著上调。对假定的mRNA靶标丰度进行的体内验证反映了所鉴定的miRNA水平。
确定了局部和全身miRNA的表达模式，这些模式特定于多创伤的治疗策略，与骨折部位和靶器官中mRNA的表达相对应。这些发现与临床观察结果相符，并为细胞通讯提供了见解，而细胞通讯可能是在多创伤患者中使用不同手术策略在局部和全身产生效果的基础。我们还确定了miRNA在多创伤中的全身参与，这可能包括受伤组织之间的远距离细胞通讯。进一步的研究可能会进一步描述多创伤后循环miRNA的时空作用、它们在器官间通讯中的潜在作用以及前瞻性治疗应用。
