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

Chiara Pastrello,Shabana Amanda Ali,Michelle J Ormseth,Navdeep Kaur,Mandy J Peffers,Igor Jurisica

doi:10.3389/fendo.2021.744747

Abstract

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 We highlight some challenges to data integration, including non-existent naming conventions and out-of-date databases for non-coding RNAs, and some successes exemplified by the International Molecular Exchange Consortium for protein interactions.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.

Highlights

Noncoding RNAs are key regulators of gene expression in the musculoskeletal system
We present two examples that integrate the recent literature on non-coding RNAs in OA and rheumatoid arthritis (RA), focusing on chondrocytes and fibroblast-like synoviocytes (FLS), respectively
We hold the perspective that non-coding RNAs function in tissuespecific networks that can be elucidated using curation and computational biology to integrate experimentally validated data from individual studies

Summary

INTRODUCTION

Noncoding RNAs are key regulators of gene expression in the musculoskeletal system. These RNA molecules are transcribed from DNA but not translated into protein [1]. For highly prevalent musculoskeletal diseases like osteoarthritis (OA) and rheumatoid arthritis (RA), multiple tissues in the joint compartment can show pathology that is driven by tissue-specific miRNA patterns This multi-level regulation of miRNA expression presents a challenge when attempting to elucidate the function of a particular miRNA in disease. Studies to date have tended to focus on elucidating a single axis involving one or two non-coding RNAs, often a lncRNA or circRNA, and its effects on a miRNA and one or two downstream gene targets. While these studies are necessary to demonstrate direct interactions, they may be missing the broader biological context. These challenges are discussed along with our perspectives on future directions needed to advance the non-coding RNA field

METHODS

Findings

DISCUSSION