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Previous studies have shown that common variants of the gene coding for FK506-binding protein 51 (), a critical regulator of glucocorticoid sensitivity, affect vulnerability to stress-related disorders. In a previous report, rs1360780 was identified as a functional variant because of its effect on gene methylation. Here we report evidence for a novel functional allele, rs3800373. This study assessed the association between rs3800373 and post-traumatic chronic pain in 1607 women and men from two ethnically diverse human cohorts. The molecular mechanism through which rs3800373 affects adverse outcomes was established via ,, and analyses. The rs3800373 minor allele predicted worse adverse outcomes after trauma exposure, such that individuals with the minor (risk) allele developed more severe post-traumatic chronic musculoskeletal pain. Among these individuals, peritraumatic circulating expression levels increased as cortisol and glucocorticoid receptor () mRNA levels increased, consistent with increased glucocorticoid resistance. Bioinformatic, , and mutational analyses indicate that the rs3800373 minor allele reduces the binding of a stress- and pain-associated microRNA, miR-320a, to via altering the mRNA 3'UTR secondary structure (i.e., is a riboSNitch). This results in relatively greater translation, unchecked by miR-320a. Overall, these results identify an important gene-miRNA interaction influencing chronic pain risk in vulnerable individuals and suggest that exogenous methods to achieve targeted reduction in poststress mRNA expression may constitute useful therapeutic strategies. is a critical regulator of the stress response. Previous studies have shown that dysregulation of the expression of this gene plays a role in the pathogenesis of chronic pain development as well as a number of comorbid neuropsychiatric disorders. In the current study, we identified a functional allele (rs3800373) in the 3'UTR of that influences vulnerability to chronic post-traumatic pain in two ethnic cohorts. Using multiple complementary experimental approaches, we show that the rs3800373 minor allele alters the secondary structure of mRNA, decreasing the binding of a stress- and pain-associated microRNA, miR-320a. This results in relatively greater translation, unchecked by miR-320a, increasing glucocorticoid resistance and increasing vulnerability to post-traumatic pain.

Study Design Prospective human cohort study combined with molecular studies. Background A microRNA is a small, noncoding RNA molecule that can play a role in disease onset. Recent studies found that circulating levels of microRNA 320a (miR-320a) are associated with musculoskeletal pain conditions and that miR-320a is stress responsive. Objectives To investigate whether circulating expression levels of miR-320a in the peritraumatic period predict persistent axial musculoskeletal pain 6 months after motor vehicle collision (MVC). Methods We evaluated whether (1) circulating miR-320a and related members of the miR-320a family predict axial musculoskeletal pain and other musculoskeletal pain outcomes 6 months following MVC, and (2) miR-320a regulates stress system and pain-related transcripts in cell culture. Given the wealth of data suggesting that biological mechanisms influencing pain outcomes are often sex and/or stress dependent, interactions between miR-320a, stress, and sex were evaluated. Results In primary analyses (n = 69), a significant crossover interaction was observed between the influence of circulating miR-320a and peritraumatic distress (β = -0.01, P = .002) on post-MVC axial musculoskeletal pain. Reduced peritraumatic miR-320a expression levels predicted axial musculoskeletal pain in distressed individuals (β = -0.12, P = .006) but not nondistressed individuals. In secondary analyses, miR-320a predicted widespread musculoskeletal pain, and related members of the miR-320a family also predicted axial and widespread musculoskeletal pain. In cell culture, miR-320a bound stress and pain-associated 3'UTR transcripts (FKBP5, ADCYAP1, PER2, and NR3C1). Conclusion These data suggest that miR-320a may help mediate regional and widespread changes in pain sensitivity after MVC. J Orthop Sports Phys Ther 2016;46(10):911-919. doi:10.2519/jospt.2016.6944.

Posttraumatic widespread pain (PTWP) and posttraumatic stress symptoms (PTSS) are frequent comorbid sequelae of trauma that occur at different rates in women and men. We sought to identify microRNA (miRNA) that may contribute to sex-dependent differences in vulnerability to these outcomes. Monte Carlo simulations (x10,000) identified miRNA in which predicted targeting of PTWP or PTSS genes was most enriched. Expression of the leading candidate miRNA to target PTWP/PTSS-related genes, miR-19b, has been shown to be influenced by estrogen and stress exposure. We evaluated whether peritraumatic miR-19b blood expression levels predicted PTWP and PTSS development in women and men experiencing trauma of motor vehicle collision (n = 179) and in women experiencing sexual assault trauma (n = 74). A sex-dependent relationship was observed between miR-19b expression levels and both PTWP (β = −2.41, P = 0.034) and PTSS (β = −3.01, P = 0.008) development 6 months after motor vehicle collision. The relationship between miR-19b and PTSS (but not PTWP) was validated in sexual assault survivors (β = −0.91, P = 0.013). Sex-dependent expression of miR-19b was also observed in blood and nervous tissue from 2 relevant animal models. Furthermore, in support of increasing evidence indicating a role for the circadian rhythm (CR) in PTWP and PTSS pathogenesis, miR-19b targets were enriched in CR gene transcripts. Human cohort and in vitro analyses assessing miR-19b regulation of key CR transcripts, CLOCK and RORA, supported the potential importance of miR-19b to regulating the CR pathway. Together, these results highlight the potential role that sex-dependent expression of miR-19b might play in PTWP and PTSS development after trauma/stress exposure.

Because the positioning and clustering of biomolecules within the extracellular matrix dictates cell behaviors, the engineering of biomaterials incorporating bioactive epitopes with spatial organization tunable at the nanoscale is of primary importance. Here we used a highly modular composite approach combining peptide amphiphile (PA) nanofibers and silica nanoparticles, which are both easily functionalized with one or several bioactive signals. We show that the surface of silica nanoparticles allows the clustering of RGDS bioactive signals leading to remix, or adapt this material for any purpose without crediting the original authors.