Long non-coding RNA expression profiling of subchondral bone reveals AC005165.1 modifying FRZB expression during osteoarthritis

Abstract

Objective To gain insight in the expression profile of long non-coding RNAs (lncRNAs) in OA subchondral bone. Methods RNA sequencing data of macroscopically preserved and lesioned OA subchondral bone of patients that underwent joint replacement surgery due to OA (N = 22 pairs; 5 hips, 17 knees, Research osteoArthrits Articular Tissue (RAAK study) was run through an in-house pipeline to detect expression of lncRNAs. Differential expression analysis between preserved and lesioned bone was performed. Spearman correlations were calculated between differentially expressed lncRNAs and differentially expressed mRNAs identified previously in the same samples. Primary osteogenic cells were transfected with locked nucleic acid (LNA) GapmeRs targeting AC005165.1 lncRNA, to functionally investigate its potential mRNA targets. Results In total, 2816 lncRNAs were well-expressed in subchondral bone and we identified 233 lncRNAs exclusively expressed in knee and 307 lncRNAs exclusively in hip. Differential expression analysis, using all samples (N = 22 pairs; 5 hips, 17 knees), resulted in 21 differentially expressed lncRNAs [false discovery rate (FDR) < 0.05, fold change (FC) range 1.19–7.39], including long intergenic non-protein coding RNA (LINC) 1411 (LINC01411, FC = 7.39, FDR = 2.20 × 10−8), AC005165.1 (FC = 0.44, FDR = 2.37 × 10−6) and empty spiracles homeobox 2 opposite strand RNA (EMX2OS, FC = 0.41, FDR = 7.64 × 10−3). Among the differentially expressed lncRNAs, five were also differentially expressed in articular cartilage, including AC005165.1, showing similar direction of effect. Downregulation of AC005165.1 in primary osteogenic cells resulted in consistent downregulation of highly correlated frizzled related protein (FRZB). Conclusion The current study identified a novel lncRNA, AC005165.1, being dysregulated in OA articular cartilage and subchondral bone. Downregulation of AC005165.1 caused a decreased expression of OA risk gene FRZB, an important member of the wnt pathway, suggesting that AC005165.1 could be an attractive potential therapeutic target with effects in articular cartilage and subchondral bone.

Long Non-Coding RNA PVT1 and Its Target miRNA-146a as Potential Prognostic Biomarkers in Rheumatoid Arthritis Patients

“…Many reports have revealed interactions between lncRNA and miRNA, as well as their conurbations, in the pathogenesis of rheumatoid arthritis (RA) [27,36,[40][41][42][43]. In addition, the biological significance of lncRNA in OA, as well as the mechanisms that underpin it, has also been extensively studied [44][45][46][47]. For the first time, we studied the relationship between the expression of lnc-PVT1 and its target miRNA (miR-146a) and the pathogenesis of RA compared to OA.…”

Allelic expression imbalance in articular cartilage and subchondral bone refined genome-wide association signals in osteoarthritis

“…MALAT1 was identified as as sponges for miR-150-5p and it was found up-regulated in OA chondrocytes compared with normal chondrocytes(18). Nevertheless, MALAT1 was not significant differentially expressed between lesioned and preserved cartilage(19) or in subchondral bone(20) in our dataset. We found allelic imbalance of the allele C (in LD with the risk allele G) with an upregulated effect ( Figure 2B ).…”

Comprehensive analysis on subchondral bone marrow lesions of human osteoarthritis by integrating bulk and single-cell transcriptomes

“…Previous GWAS analyses exhibited the correlation between IL11 and hip OA, rather than knee OA (23,24). IL11 was detected upregulating in both OA subchondral bone (knee and hip) and cartilage (10), as well as in synovial uid (40). Interestingly, IL11 was reported to facilitate brosis and in ammation in cardiovascular brosis (41) and rheumatoid arthritis (42).…”

“…Though several researches have reported the pathologic and genetic changes of subchondral BMLs in OA (9)(10)(11)(12)(13), there are still large uncharted territory. First, although the differentially expressed genes (DEGs) between OA-BML tissue and non-OA tissue were identi ed, the differences in gene expression between OA non-BMLs (OA-NBML) tissue and OA-BML tissue have yet to be described.…”