Circulating microRNAs from the mouse tibia fracture model reflect the signature from patients with complex regional pain syndrome

Abstract

Introduction: Complex regional pain syndrome (CRPS) often results from an initial trauma that later produces a disproportionate amount of pain. The mechanisms underlying CRPS have been studied using a tibia fracture model (TFM) in rodents because this model closely mimics symptoms and has several molecular correlates observed in patients with CRPS.Objective: Here, we determined whether the TFM has alterations in circulating microRNAs (miRNAs) and cytokines transported by small extracellular vesicles (sEVs) that faithfully model previously reported miRNA alterations from patients with CRPS. Methods: We isolated and characterized serum-derived sEVs from mice 3 weeks after fracture when symptoms such as pain hypersensitivity develop. Whole-transcriptome profiling was used to determine sEV miRNAs, and Bio-Plex Pro Mouse Cytokine 23plex assay was used to measure cytokines. Differentially expressed miRNAs from TFM were compared with previously reported circulating miRNA alterations from patients with CRPS. Results: Although sEV cytokine levels were unchanged, there were significant changes in sEV miRNA profiles. Differentially expressed miRNAs from TFM sEVs significantly overlapped with those previously reported in patients with CRPS. Of the 57 sEV miRNAs dysregulated in the TFM, 30 were previously reported in patients with CRPS compared with healthy control donors both in sEVs and 23 in whole blood. Conclusions: These findings enhance the validity of TFM as a model for CRPS and suggest that specific miRNA dysregulation may be a shared feature of CRPS and the TFM. These dysregulated miRNAs could help identify mechanistic targets or serve as biomarker candidates for both diagnosis and treatment responses in clinical trials.

Schwann cell-derived extracellular vesicles promote memory impairment associated with chronic neuropathic pain

“…Existing studies have linked chronic inflammatory diseases to elevated EV concentrations and altered EV composition [ 50 ]. Some researchers have found that EV concentrations in plasma from a tibia fracture model (closely mimic complex regional pain syndrome), although comparable to controls, are significantly larger in particle size than in control mice [ 51 ]. Studies have found that circulating EV counts are significantly increased in patients with Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS, debilitating disease with multiple symptoms, including pain, depression, and neurocognitive deterioration in function) and that circulating EV counts correlate significantly with serum C-reactive protein levels and have reported that circulating EV counts and EV-specific proteins can be used as novel biomarkers for the diagnosis of ME/CFS [ 52 ].…”

The emerging power and promise of non-coding RNAs in chronic pain

“…Circulating miRNAs, most encapsulated in small extracellular vehicles (sEVs) or exosomes, are stable in intercellular communication and may become an original biomarker or risk factor for CRPS ( Ramanathan et al, 2019a ; Wickman et al, 2021 ). Wickman et al (2021) have purified and identified both cytokine and miRNA levels in serum sEVs in a tibia fracture model (TFM) induced-CRPS. The results have shown an unchanged level of cytokines but significantly differential expression of miRNAs.…”

Exploring the Secretome’s Biomarker and Analgesic Potential

“…The most studied EV ncRNAs are miRNAs which are ∼22 nt and negatively regulate gene expression at protein level by either mRNA degradation or translational inhibition [15]. MiRNAs present in circulating EVs have been linked to neurodegenerative disorders and pain [16][17][18][19] and have been proposed as biomarkers for cancer diagnostics, [20][21][22] and for neuropathic injury [1].…”