Pain-Associated Transcriptome Changes in Synovium of Knee Osteoarthritis Patients

Abstract

Joint pain causes significant morbidity in osteoarthritis (OA). The aetiology of joint pain in OA is not well understood. The synovial membrane as an innervated joint structure represents a potential source of peripheral pain in OA. Here we analyse, using a hypothesis-free next generation RNA sequencing, the differences in protein-coding and non-coding transcriptomes in knee synovial tissues from OA patients with high knee pain (n = 5) compared with OA patients with low knee pain (n = 5), as evaluated by visual analogue scale (VAS). We conduct Gene Ontology and pathway analyses on differentially expressed mRNA genes. We identify new protein-coding, long non-coding RNA and microRNA candidates that can be associated with OA joint pain. Top enriched genes in painful OA knees encode neuronal proteins that are known to promote neuronal survival under cellular stress or participate in calcium-dependent synaptic exocytosis and modulation of GABA(γ-aminobutyric acid)ergic activity. Our study uncovers transcriptome changes associated with pain in synovial microenvironment of OA knees. This sets a firm ground for future mechanistic studies and drug discovery to alleviate joint pain in OA.

Identification of key biomarkers and immune infiltration in the synovial tissue of osteoarthritis by bioinformatics analysis

“…Leukocyte infiltration and cellulose deposition (mainly in the stage of chronic inflammation) occur in the synovium of OA at different stages, suggesting the existence of synovitis since the initial stage of OA (Deligne et al, 2015;Young et al, 2001;Mapp & Walsh, 2012). Despite the controversy, arthroscopic debridement of the joint cavity and synovium can effectively alleviate the pain symptoms of some OA patients, suggesting that there may be some specific stimuli that trigger synovial lesions and eventually lead to the pathophysiological changes of the whole joint into a vicious circle (Bratus-neuenschwander et al, 2018;Sellam & Berenbaum, 2010). However, there is little research on the molecular mechanism of why synovitis is able to promote the development of OA.…”

A Long Noncoding RNA (lncRNA)-Associated Competing Endogenous RNA (ceRNA) Network Identifies Eight lncRNA Biomarkers in Patients with Osteoarthritis of the Knee

“…Primary osteoarthritis (OA) of the knee is a common chronic disease with increasing incidence and prevalence [1–3]. Effective therapies remain to be discovered to prevent the progression of OA and reduce its severity, and OA is predicted to become an increasing economic burden as the population ages [1,4,5]. Chronic pain from OA is a common public health problem that has a detrimental impact on patient health and function [6].…”

“…Dudek et al reported that lncRNA H19 was overexpressed in chondrocytes and was regulated by SOX9 [17]. Large-scale RNA sequencing studies in patients with OA of the knee with severe pain and mild pain showed that several lncRNAs were differentially expressed, which indicates that these dysregulated lncRNAs may be involved in the progression of OA [1,18]. However, the molecular mechanisms of the role of dysregulated lncRNAs in the progression of OA remain poorly understood and further functional studies are needed to determine these roles.…”

Of mice and men: converging on a common molecular understanding of osteoarthritis

“… 146 Although this observation might be surprising in view of broadly held views that osteoarthritis pain originates from inflammatory processes in the synovium or subchondral bone, emerging molecular data from human tissue also support the notion that cartilage is the principal source of NGF in the osteoarthritis joint. Using agnostic approaches, NGF was not regulated in the synovium of individuals with painful compared with non-painful osteoarthritis, 27 , 79 and it was not found in bone marrow lesions from samples taken at the time of arthroplasty. 147 NGF was found to be regulated in damaged articular cartilage in early microarray studies of osteoarthritis cartilage, 148 and it defines one of seven subsets of chondrocytes identified by single-cell sequencing of human osteoarthritis cartilage.…”

“…Two mRNA studies of human synovium have been done in individuals stratified by having painful or non-painful osteoarthritis. 27 , 79 One of these studies 27 identified CCL2 as being significantly up-regulated in painful disease. CCR2 antagonism in osteoarthritis pain has been explored clinically (registered with ClinicalTrials.gov , NCT00689273 ), although the results of the study do not appear to have been reported.…”