A molecular map of long non-coding RNA expression, isoform switching and alternative splicing in osteoarthritis

Abstract

Osteoarthritis is a prevalent joint disease and a major cause of disability worldwide with no curative therapy. Development of disease-modifying therapies requires a better understanding of the molecular mechanisms underpinning disease. A hallmark of osteoarthritis is cartilage degradation. To define molecular events characterising osteoarthritis at the whole transcriptome level, we performed deep RNA sequencing in paired samples of low- and high-osteoarthritis grade knee cartilage derived from 124 patients undergoing total joint replacement. We detected differential expression between low- and high-osteoarthritis grade articular cartilage for 365 genes and identified a 38-gene signature in osteoarthritis cartilage by replicating our findings in an independent dataset. We also found differential expression for 25 novel long non-coding RNA genes (lncRNAs) and identified potential lncRNA interactions with RNA-binding proteins in osteoarthritis. We assessed alterations in the relative usage of individual gene transcripts and identified differential transcript usage for 82 genes, including ABI3BP, coding for an extracellular matrix protein, AKT1S1, a negative regulator of the mTOR pathway, and TPRM4, coding for a transient receptor potential channel. We further assessed genome-wide differential splicing, for the first time in osteoarthritis, and detected differential splicing for 209 genes, which were enriched for extracellular matrix, proteoglycans and integrin surface interactions terms. In the largest study of its kind in osteoarthritis, we find that isoform and splicing changes, in addition to extensive differences in both coding and non-coding sequence expression, are associated with disease and demonstrate a novel layer of genomic complexity to osteoarthritis pathogenesis.

Insights into the comorbidity between type 2 diabetes and osteoarthritis

“…Results of the causal inference analysis mirror the output of differential expression analyses conducted in pancreatic islets and osteoarthritic cartilage [38], [39]. While TMEM176A is more highly expressed in diabetes compared to healthy pancreatic islets, an increase of its expression in the same tissue has a causal effect on increased risk of type 2 diabetes.…”

“…We explored if the analysed genes show differential expression for type 2 diabetes and osteoarthritis using published summary statistics from RNA-seq datasets. For osteoarthritis, differential expression was assessed by comparing paired intact and degraded osteoarthritis cartilage from 124 patients [38]. Since the samples were collected within patients, the data is automatically robust against cofactors such as age and population structure.…”

RNA binding proteins in osteoarthritis

“…In recent times, Katsoula et al performed deep RNA sequencing and genome-wide differential splicing analysis of cartilage tissues of 124 OA patients, and they reported differential splicing for 209 genes, which consists of extracellular matrix proteins, proteoglycans, and integrin surface interactions terms ( Katsoula et al, 2022 ). For example, periostin (POSTN) is a secretory matricellular matrix protein.…”

Organic solvents enhance polyvinyl alcohol/polyethylene glycol self‐healing hydrogels for artificial cartilage

“…1,2 Around the world, more than 25% of adults suffer from osteoarthritis. 3 Osteoarthritis is the most common degenerative disease associated with synovial joints and is usually associated with wear and tear of cartilage and bone, loss and deterioration of bone volume, formation of bone fragments and inflammation. 4 Articular cartilage is a smooth, viscoelastic connective tissue with a unique two-phase structure that provides adequate mechanical support for the tissue and reduces and transfers stress and lubricating properties.…”

“…But with this comes the aging of the body and various diseases of advanced age that come with increased longevity 1,2 . Around the world, more than 25% of adults suffer from osteoarthritis 3 . Osteoarthritis is the most common degenerative disease associated with synovial joints and is usually associated with wear and tear of cartilage and bone, loss and deterioration of bone volume, formation of bone fragments and inflammation 4 .…”