Non-coding RNAs in disease: from mechanisms to therapeutics.

Background Inflammation may contribute to incident heart failure (HF). Rheumatoid arthritis (RA), a prototypic inflammatory condition, may serve as a model for understanding inflammation‐related HF...

Heart Failure Risk Associated With Rheumatoid Arthritis-Related Chronic Inflammation.

Abstract MicroRNAs (miRNAs), a class of endogenous single-stranded short noncoding RNAs, have emerged as vital epigenetic regulators of both pathological and physiological processes in animals. They direct fundamental cellular pathways and processes by fine-tuning the expression of multiple genes at the posttranscriptional level. Growing evidence suggests that miRNAs are implicated in the onset and development of rheumatoid arthritis (RA). RA is a chronic inflammatory disease that mainly affects synovial joints. This common autoimmune disorder is characterized by a complex and multifaceted pathogenesis, and its morbidity, disability and mortality rates remain consistently high. More in-depth insights into the underlying mechanisms of RA are required to address unmet clinical needs and optimize treatment. Herein, we comprehensively review the deregulated miRNAs and impaired cellular functions in RA to shed light on several aspects of RA pathogenesis, with a focus on excessive inflammation, synovial hyperplasia and progressive joint damage. This review also provides promising targets for innovative therapies of RA. In addition, we discuss the regulatory roles and clinical potential of extracellular miRNAs in RA, highlighting their prospective applications as diagnostic and predictive biomarkers. 

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Comprehensive overview of microRNA function in rheumatoid arthritis

Objective. MicroRNA (miRNA) are short noncoding RNA that regulate genes and are both biomarkers and mediators of disease. We used small RNA (sRNA) sequencing and machine learning methodology to develop an miRNA panel to reliably differentiate between rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) and control subjects. Methods. Plasma samples from 167 RA and 91 control subjects who frequency-matched for age, race, and sex were used for sRNA sequencing. TIGER was used to analyze miRNA. DESeq2 and random forest analyses were used to identify a prioritized list of miRNA differentially expressed in patients with RA. Prioritized miRNA were validated by quantitative PCR, and lasso and logistic regression were used to select the final panel of 6 miRNA that best differentiated RA from controls. The panel was validated in a separate cohort of 12 SLE, 32 RA, and 32 control subjects. Panel efficacy was assessed by area under the receiver operative characteristic curve (AUC) analyses. Results. The final panel included miR-22-3p, miR-24-3p, miR-96-5p, miR-134-5p, miR-140-3p, and miR-627-5p. The panel differentiated RA from control subjects in discovery (AUC = 0.81) and validation cohorts (AUC = 0.71), seronegative RA (AUC = 0.84), RA remission (AUC = 0.85), and patients with SLE (AUC = 0.80) versus controls. Pathway analysis showed upstream regulators and targets of panel miRNA are associated with pathways implicated in RA pathogenesis. Conclusion. An miRNA panel identified by a bioinformatic approach differentiated between RA or SLE patients and control subjects. The panel may represent an autoimmunity signature, perhaps related to inflammatory arthritis, which is not dependent on active disease or seropositivity.

https://www.jrheum.org/content/jrheum/early/2019/05/13/jrheum.181029.full.pdf

Development and Validation of a MicroRNA Panel to Differentiate Between Patients with Rheumatoid Arthritis or Systemic Lupus Erythematosus and Controls

Articular cartilage (AC), a bone-to-bone protective device made of up to 80% water and populated by only one cell type (i.e. chondrocyte), has limited capacity for regeneration and self-repair after being damaged because of its low cell density, alymphatic and avascular nature. Resulting repair of cartilage defects, such as osteoarthritis (OA), is highly challenging in clinical treatment. Fortunately, the development of tissue engineering provides a promising method for growing cells in cartilage regeneration and repair by using hydrogels or the porous scaffolds. In this paper, we review the therapeutic strategies for AC defects, including current treatment methods, engineering/regenerative strategies, recent advances in biomaterials, and present emphasize on the perspectives of gene regulation and therapy of noncoding RNAs (ncRNAs), such as circular RNA (circRNA) and microRNA (miRNA).

Regeneration of articular cartilage defects: Therapeutic strategies and perspectives

Non-coding RNAs have distinct regulatory roles in the pathogenesis of joint diseases including osteoarthritis (OA) and rheumatoid arthritis (RA). As the amount of high-throughput profiling studies and mechanistic investigations of microRNAs, long non-coding RNAs and circular RNAs in joint tissues and biofluids has increased, data have emerged that suggest complex interactions among non-coding RNAs that are often overlooked as critical regulators of gene expression. Identifying these non-coding RNAs and their interactions is useful for understanding both joint health and disease. Non-coding RNAs regulate signalling pathways and biological processes that are important for normal joint development but, when dysregulated, can contribute to disease. The specific expression profiles of non-coding RNAs in various disease states support their roles as promising candidate biomarkers, mediators of pathogenic mechanisms and potential therapeutic targets. This Review synthesizes literature published in the past 2 years on the role of non-coding RNAs in OA and RA with a focus on inflammation, cell death, cell proliferation and extracellular matrix dysregulation. Research to date makes it apparent that ‘non-coding’ does not mean ‘non-essential’ and that non-coding RNAs are important parts of a complex interactome that underlies OA and RA. Non-coding RNAs such as microRNAs, long non-coding RNAs and circular RNAs regulate signalling pathways that are important in joint development, homeostasis and disease. A better understanding of the non-coding RNA interactome could lead to new therapies for joint diseases.

The non-coding RNA interactome in joint health and disease

Objective The prevalence of heart failure is increased 2-fold in patients with rheumatoid arthritis (RA); this is not explained by ischemic heart disease or other risk factors for heart failure. We hypothesized that in patients with RA without known heart disease, cardiac magnetic resonance imaging (cMRI) would detect altered cardiac structure, function, and fibrosis. Methods We performed 1.5-T cMRI in 59 patients with RA and 56 controls frequency-matched for age, race, and sex, and compared cMRI indices of structure, function, and fibrosis [late gadolinium enhancement (LGE), native T1 mapping, and extracellular volume (ECV)] using Mann-Whitney U tests and linear regression, adjusting for age, race, and sex. Results Most patients with RA had low to moderate disease activity [28-joint count Disease Activity Score–C-reactive protein median 3.16, interquartile range (IQR) 2.03–4.05], and 49% were receiving anti-tumor necrosis factor agents. Left ventricular (LV) mass, LV end-diastolic and -systolic volumes indexed to body surface area, and LV ejection fraction and left atrial size were not altered in RA compared to controls (all p > 0.05). Measures of fibrosis were not increased in RA: LGE was present in 2 patients with RA and 1 control subject; native T1 mapping was similar comparing RA and control subjects, and ECV (median, IQR) was lower (26.6%, 24.7–28.5%) in patients with RA compared to control subjects (27.5%, 25.4–30.4%, p = 0.03). Conclusion cMRI measures of cardiac structure and function were not significantly altered, and measures of fibrosis were similar or lower in RA patients with low to moderate disease activity compared to a matched control group.

https://www.jrheum.org/content/jrheum/early/2018/04/09/jrheum.170770.full.pdf

Absence of Fibrosis and Inflammation by Cardiac Magnetic Resonance Imaging in Rheumatoid Arthritis Patients with Low to Moderate Disease Activity

Discovery of non-coding RNAs continues to provide new insights into some of the key molecular drivers of musculoskeletal diseases. Among these, microRNAs have received widespread attention for their roles in osteoarthritis and rheumatoid arthritis. With evidence to suggest that long non-coding RNAs and circular RNAs function as competing endogenous RNAs to sponge microRNAs, the net effect on gene expression in specific disease contexts can be elusive. Studies to date have focused on elucidating individual long non-coding-microRNA-gene target axes and circular RNA-microRNA-gene target axes, with a paucity of data integrating experimentally validated effects of non-coding RNAs. To address this gap, we curated recent studies reporting non-coding RNA axes in chondrocytes from human osteoarthritis and in fibroblast-like synoviocytes from human rheumatoid arthritis. Using an integrative computational biology approach, we then combined the findings into cell- and disease-specific networks for in-depth interpretation. We highlight some challenges to data integration, including non-existent naming conventions and out-of-date databases for non-coding RNAs, and some successes exemplified by the International Molecular Exchange Consortium for protein interactions. In this perspective article, we suggest that data integration is a useful in silico approach for creating non-coding RNA networks in arthritis and prioritizing interactions for further in vitro and in vivo experimentation in translational research.

A Network Biology Approach to Understanding the Tissue-Specific Roles of Non-Coding RNAs in Arthritis.

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Papers

The non-coding RNA interactome in joint health and disease

Absence of Fibrosis and Inflammation by Cardiac Magnetic Resonance Imaging in Rheumatoid Arthritis Patients with Low to Moderate Disease Activity

A Network Biology Approach to Understanding the Tissue-Specific Roles of Non-Coding RNAs in Arthritis.