Dataset Information

Identify CRNDE and LINC00152 as the key lncRNAs in age-related degeneration of articular cartilage through comprehensive and integrative analysis.

ABSTRACT: Background:Osteoarthritis (OA) is one of the most important age-related degenerative diseases, and the leading cause of disability and chronic pain in the aging population. Recent studies have identified several lncRNA-associated functions involved in the development of OA. Because age is a key risk factor for OA, we investigated the differential expression of age-related lncRNAs in each stage of OA. Methods:Two gene expression profiles were downloaded from the GEO database and differentially expressed genes (DEGs) were identified across each of the different developmental stages of OA. Next, gene ontology (GO) functional and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to annotate the function of the DEGs. Finally, a lncRNA-targeted DEG network was used to identify hub-lncRNAs. Results:A total of 174 age-related DEGs were identified. GO analyses confirmed that age-related degradation was strongly associated with cell adhesion, endodermal cell differentiation and collagen fibril organization. Significantly enriched KEGG pathways associated with these DEGs included the PI3K-Akt signaling pathway, focal adhesion, and ECM-receptor interaction. Further analyses via a protein-protein interaction (PPI) network identified two hub lncRNAs, CRNDE and LINC00152, involved in the process of age-related degeneration of articular cartilage. Our findings suggest that lncRNAs may play active roles in the development of OA. Investigation of the gene expression profiles in different development stages may supply a new target for OA treatment.

SUBMITTER: Hu P

PROVIDER: S-EPMC6544125 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Identify CRNDE and LINC00152 as the key lncRNAs in age-related degeneration of articular cartilage through comprehensive and integrative analysis.

Hu Pengfei P Sun Fangfang F Ran Jisheng J Wu Lidong L

PeerJ 20190528

<h4>Background</h4>Osteoarthritis (OA) is one of the most important age-related degenerative diseases, and the leading cause of disability and chronic pain in the aging population. Recent studies have identified several lncRNA-associated functions involved in the development of OA. Because age is a key risk factor for OA, we investigated the differential expression of age-related lncRNAs in each stage of OA.<h4>Methods</h4>Two gene expression profiles were downloaded from the GEO database and di ...[more]

PMID: 31179196

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Project description:Osteoarthritis (OA), the most common form of arthritis, is characterized by inflammation of joints and cartilage degradation leading to disability, discomfort, severe pain, inflammation, and stiffness of the joint. It has been shown that adenosine, a purine nucleoside composed of adenine attached to ribofuranose, is enzymatically produced by the human synovium. However, the functional significance of adenosine signaling in homeostasis and pathology of synovial joints remains unclear. Adenosine acts through four cell surface receptors, i.e., A1, A2A, A2B, and A3, and here, we have systematically analyzed mice with a deficiency for A3 receptor as well as pharmacological modulations of this receptor with specific analogs. The data show that adenosine receptor signaling plays an essential role in downregulating catabolic mechanisms resulting in prevention of cartilage degeneration. Ablation of A3 resulted in development of OA in aged mice. Mechanistically, A3 signaling inhibited cellular catabolic processes in chondrocytes including downregulation of Ca2+/calmodulin-dependent protein kinase (CaMKII), an enzyme that promotes matrix degradation and inflammation, as well as Runt-related transcription factor 2 (RUNX2). Additionally, selective A3 agonists protected chondrocytes from cell apoptosis caused by pro-inflammatory cytokines or hypo-osmotic stress. These novel data illuminate the protective role of A3, which is mediated via inhibition of intracellular CaMKII kinase and RUNX2 transcription factor, the two major pro-catabolic regulators in articular cartilage.Key messagesAdenosine receptor A3 (A3) knockout results in progressive loss of articular cartilage in vivo. Ablation of A3 results in activation of matrix degradation and cartilage hypertrophy. A3 agonists downregulate RUNX2 and CaMKII expression in osteoarthritic human articular chondrocytes. A3 prevents articular cartilage matrix degradation induced by inflammation and osmotic fluctuations. A3 agonist inhibits proteolytic activity of cartilage-degrading enzymes.

Project description:An exact understanding of the interplay between the articulating tissues of the knee joint in relation to the osteoarthritis (OA)-related degeneration process is of considerable interest. Therefore, the aim of the present study was to characterize the biomechanical properties of mildly and severely degenerated human knee joints, including their menisci and tibial and femoral articular cartilage (AC) surfaces. A spatial biomechanical mapping of the articulating knee joint surfaces of 12 mildly and 12 severely degenerated human cadaveric knee joints was assessed using a multiaxial mechanical testing machine. To do so, indentation stress relaxation tests were combined with thickness and water content measurements at the lateral and medial menisci and the AC of the tibial plateau and femoral condyles to calculate the instantaneous modulus (IM), relaxation modulus, relaxation percentage, maximum applied force during the indentation, and the water content. With progressing joint degeneration, we found an increase in the lateral and the medial meniscal instantaneous moduli (p < 0.02), relaxation moduli (p < 0.01), and maximum applied forces (p < 0.01), while for the underlying tibial AC, the IM (p = 0.01) and maximum applied force (p < 0.01) decreased only at the medial compartment. Degeneration had no influence on the relaxation percentage of the soft tissues. While the water content of the menisci did not change with progressing degeneration, the severely degenerated tibial AC contained more water (p < 0.04) compared to the mildly degenerated tibial cartilage. The results of this study indicate that degeneration-related (bio-)mechanical changes seem likely to be first detectable in the menisci before the articular knee joint cartilage is affected. Should these findings be further reinforced by structural and imaging analyses, the treatment and diagnostic paradigms of OA might be modified, focusing on the early detection of meniscal degeneration and its respective treatment, with the final aim to delay osteoarthritis onset.

Dataset Information

Identify CRNDE and LINC00152 as the key lncRNAs in age-related degeneration of articular cartilage through comprehensive and integrative analysis.

Publications

Identify CRNDE and LINC00152 as the key lncRNAs in age-related degeneration of articular cartilage through comprehensive and integrative analysis.

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