Editorial: The Impact of Micro RNA-320a Serum Level on Severity of Symptoms and Cerebral Processing of Pain in Patients with Fibromyalgia

Hussein et al. contribute to the growing body of literature focused on the role of non-coding RNAs in clinical conditions. The present study proposes microRNA-320a (miR-320a) as a candidate biomarker of fibromyalgia (FM) based on clinical evidence of upregulated miR-320a expression in circulating serum in FM patients compared to healthy patients [1, 2]. The miR-320a levels in circulation were correlated with the time since diagnosis of FM (duration) as well as pain and related symptom burden in FM patients. While these relationships don’t indicate causality, this kind of study is critical to the generation of testable hypotheses related to this particular miRNA and the development of chronic pain conditions. Prior work by Bjersing and colleagues (2015) reported an inverse relationship between miR-320a levels and pain within the same patient population [2, 3], so additional studies are needed to clarify the relationship between miR-320a and FM symptom profile.

The identification of miR-320a as a potential biomarker for fibromyalgia is novel since our understanding of the role of noncoding RNAs, including miRNA and long non-coding RNA, has lagged significantly behind that of the protein coding sequences within the genome and behind other regulatory mechanisms like DNA methylation or histone acetylation. miRNAs are a class of small non-protein coding RNAs, an average of 22 nucleotides in length, that play an important role in regulating gene expression post-transcriptionally. The miRNAs are often located in intronic sequences of protein-coding genes and may be either be coregulated with the gene in which they are imbedded or may have a dedicated promoter sequence that regulates the miRNA independently [4]. Hundreds of miRNAs are encoded in our genome and are most often transcribed and modified by multiple RNA polymerases and RNAs on their way to becoming functionally mature [5–10]. miRNAs regulate gene expression through two primary processes, both of which involve regulation of messenger RNA (mRNA). First, miRNA can bind to a target mRNA completely leading directly to degradation of the mRNA. The miRNAs can also bind to 3′ UTRs region of a target gene through incomplete complementarity at multiple sites, and thereby, negatively regulate target expression. In this way, miRNAs act as negative regulators of mRNA and, subsequently, protein, expression [11]. Any given miRNA is predicted to regulate multiple mRNAs and each mRNA may be regulated by multiple miRNAs [12–14]. The present study can generate specific hypotheses because it is the regulatory targets of miRNA-320a that provide the strongest targets for novel therapeutic intervention. Disruption of miRNA activity would be expected to have many off-target effects given the breadth of downstream mRNAs regulated by a single miRNA but now that the “haystack” has been defined, we can begin to search for the “needle.”

FM is a disorder that likely develops due to interactions of individual differences and environmental factors, and, as with other complex health conditions, there may be more than one pathological process underlying FM. One hypothesis suggests that FM reflects a process of neurogenic inflammation in which neurons release neuropeptides (e.g., SP and CGRP, etc.) leading to an inflammation (edema, immune cell infiltration, etc.) in the absence of a traditional stimulus. miR-320a, specifically, could play a role in regulating pain-relevant peptide signaling through downregulation of the substance P receptor, neurokinin receptor 1 (NK1) [15]. These receptors are found on spinal dorsal horn neurons and are activated when substance P is released from primary afferent neurons transmitting sensory information from the periphery. The miRNA-320a could work to reduce transmission of pain signals sent from inflamed or damaged tissues in the periphery. NK1 receptors are also found on immune cells, smooth muscle, and blood vessels where they can promote c-fiber mediated neurogenic inflammation resulting in pain [16, 17]. The direction of this relationship supports the inverse relationship between miR-320a and FM reported by Bjersing, but there could be other compensatory mechanisms engaged that disrupt the balance of neuropeptide, or other neurotransmitter, signaling at work.

Alternatively, reports indicate that miR-320a targets FOXM1 (forkhead box protein M1) expression, a critical proliferation-associated transcription factor that regulates transition between phases of the cell cycle [18]. When FOXM1 is upregulated, inflammatory cell injury is reduced. Regarding the relationship between FM pain states and miR-320a expression, if miR-320a expression is upregulated, then FOXM1 would be low, and low FOXM1 should result in higher inflammation/worse symptoms. This hypothesis would need further exploration, but the connection between miR-320a and FOXM1 to FM pain-related research to other conditions/diseases being studied. This type of specific hypothesis-driven investigation is a direct result of the foundational work being generated by groups like Hussein et al.

The present study represents a critical first step by observing a relationship between miR-320a and FM symptom burden, but subsequent studies are needed to understand whether miR-320a, and other miRNAs, are correlative disease biomarkers or causative agents of disease phenotypes. This discussion is particularly timely given a recent report suggesting downregulation of miR-320a in patients with COVID-19-induced respiratory failure may serve as a biomarker for severe thromboembolic disease in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and linking this downregulation to miR-320a to dysregulated inflammation and oxidative stress. In other work, miR-320a over-expression has been shown to impair TGF-β1 signaling, hindering inflammation and reactive oxygen species (ROS) production in a cellular model of diabetic retinopathy, but how these regulatory relationships contribute to FM symptom burden remains to be fully understood [19]. Should a specific miRNA play a more direct role in disease development or progression or have a protective influence, the exact downstream effectors and mechanisms evoked by the miRNA should be elucidated to design proper therapeutics. As precision medicine approaches evolve, the development of synthetic oligonucleotides that mimic a naturally occurring miRNA sequence and fulfill the miRNA’s original function may be on the horizon [20]. Alternatively, an anti-miRNA oligonucleotide could be administered to bind and inhibit miRNA function, thereby increasing translation of downstream mRNAs. miRNA targeting has already been leveraged in the treatment of cancer where anti-miRNAs are designed to block oncogenic miRNAs and inhibit cancer development and growth [20]. The authors provide the first glimpse of the potential of this approach in application to non-opioid pain therapeutics providing relief to patients with few effective options for their pain.

 

Funding sources: This project was supported by P20GM103418 (E.E.Y), and a K-INBRE recruitment startup package to E.E.Y.

Conflicts of interest: None of the authors have conflicts of interest to report.