Abstract
Background: Osteoarthritis (OA) is a common degenerative joint disease. The aims of this study are to explore the effects of mechanical stress on whole transcriptome landscape and to identify a non-coding transcriptome signature of mechanical stress. Methods: Next-generation RNA sequencing (RNA-seq) was performed on IL-1β-induced OA-like chondrocytes stimulated by mechanical stress. Integrated bioinformatics analysis was performed and further verified by experimental validations. Results: A total of 5,022 differentially expressed mRNAs (DEMs), 88 differentially expressed miRNAs (DEMIs), 1,259 differentially expressed lncRNAs (DELs), and 393 differentially expressed circRNAs (DECs) were identified as the transcriptome response to mechanical stress. The functional annotation of the DEMs revealed the effects of mechanical stress on chondrocyte biology, ranging from cell fate, metabolism, and motility to endocrine, immune response, and signaling transduction. Among the DELs, ∼92.6% were identified as the novel lncRNAs. According to the co-expressing DEMs potentially regulated by the responsive DELs, we found that these DELs were involved in the modification of immune and metabolism. Moreover, immune- and metabolism-relevant DELs exhibited a notable involvement in the competing endogenous RNA (ceRNA) regulation networks. Silencing lncRNA TCONS_00029778 attenuated cellular senescence induced by mechanical stress. Moreover, the expression of Cd80 was elevated by mechanical stress, which was rescued by silencing TCONS_00029778. Conclusion: The transcriptome landscape of IL-1β-induced OA-like chondrocytes was remarkably remodeled by mechanical stress. This study identified an immune- and metabolism-related ncRNA transcriptome signature responsive to mechanical stress and provides an insight of ncRNAs into chondrocyte biology and OA.
Highlights
Osteoarthritis (OA) is a common degenerative joint disease characterized by degradation of articular cartilage and subchondral bone, which causes a significant socioeconomic burden (Felson, 2010; Glyn-Jones et al, 2015)
Given that the mechanical stimulation employed in this study induced the genes relevant to OA-like phenotypes, including Mmp9 and Mmp13, we found that this stimulation promoted chondrocyte catabolic metabolism (Supplementary Figure S1A)
Principal component analysis based on mRNA or longnoncoding RNAs (lncRNA) profiles showed the high relevance of lncRNA transcriptome with mRNA in IL-1βinduced rat OA-like chondrocytes (Figure 1C)
Summary
Osteoarthritis (OA) is a common degenerative joint disease characterized by degradation of articular cartilage and subchondral bone, which causes a significant socioeconomic burden (Felson, 2010; Glyn-Jones et al, 2015). As a key component of cartilage, chondrocytes are mechanosensitive, perceiving and responding to mechanical stress throughout life in a magnitude-dependent manner (Liu et al, 2016b). It is still a puzzle how the mechanical stimulation favors the cartilage and chondrocytes and how this process is attenuated and the outcome is turned over by excessive loading. Moderate mechanical stress favors chondrocytes by regulating multiple signaling pathways and cellular functions, such as cytoskeleton and primary cilia (Yang et al, 2016; Xiang et al, 2018; Fu et al, 2019), while excessive mechanical stimulation always triggers the unfavorable changes and outcomes of chondrocytes, for instance, enhanced catabolic effects, compromised respiratory function, and apoptosis (Sun, 2010; Coleman et al, 2016). The aims of this study are to explore the effects of mechanical stress on whole transcriptome landscape and to identify a non-coding transcriptome signature of mechanical stress
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