LncRNA MEG3 Inhibits the Degradation of the Extracellular Matrix of Chondrocytes in Osteoarthritis via Targeting miR-93/TGFBR2 Axis

Abstract

Background As a degenerative joint disease, osteoarthritis (OA) is characterized by articular cartilage degradation. Long noncoding RNAs (lncRNAs) act critical roles in the regulation of OA development, including affecting the proliferation, apoptosis, extracellular matrix (ECM) degradation, and inflammatory response of chondrocytes. The current study’s aim was to investigate the regulatory function and the underlying molecular mechanism of lncRNA MEG3 in ECM degradation of chondrocytes in OA. Methods In the current study, chondrocytes were induced by interleukin-1β (IL-1β) to simulate OA condition, and further assessed cell viability, lncRNA MEG3 and miR-93 expression levels. Overexpression or knockdown of lncRNA MEG3 in chondrocytes treated with IL-1β were performed to investigate the function of MEG3 in regulating cell proliferation, apoptosis and ECM degradation using EdU assay, flow cytometry, quantitative reverse transcription polymerase chain reaction (qRT-PCR), and Western blot. The interaction between MEG3 and miR-93 was assessed using qRT-PCR. Furthermore, overexpression of miR-93 was performed as recovery experiment to explore the functional mechanism of MEG3. Results MEG3 was significantly downregulated in chondrocytes treated with IL-1β, whereas miR-93 was upregulated concomitantly. Overexpression of MEG3 induced the proliferation, suppressed the apoptosis, and relieved the degradation of ECM in IL-1β-induced chondrocytes. By contrast, knockdown of MEG3 suppressed the proliferation, promoted the apoptosis, and aggravated ECM degradation in IL-1β induced chondrocytes. In addition, MEG3 was found to relieve the inhibitive expression of TGFBR2 as a competitive endogenous RNA (ceRNA) of miR-93, and then activated transforming growth factor-β (TGF-β) signaling pathway, regulated chondrocytes ECM degradation in IL-1β induced chondrocytes subsequently. Conclusion LncRNA MEG3 targeted miR-93/TGFBR2 axis, regulated the proliferation, apoptosis and ECM degradation of chondrocytes in OA.

Elucidating another level of epigenetic regulation in osteoarthritis by identifying functionalcis-acting long non-coding RNAs and their targets in articular cartilage

“…We showed a particular enrichment of lincRNAs in the differential expression analysis (17.8% to 34.6% figure 2), showing that lincRNAs indeed play an important role in the OA pathophysiology as seen in previous studies [8,16,28]. Nonetheless, in comparison to the fraction of FDR significant DE lncRNAs reported by Pearson et al [8], this fraction is still Of the 191 FDR significant DE lncRNAs between lesioned and preserved OA cartilage (figure 3), multiple lncRNAs were previously found, including MEG3, LINC01614, and PART1 [16,24]. Nonetheless, there were also examples of lncRNAs previously associated to OA, which were expressed but not FDR significantly different, such as MALAT1, HOTAIR, GAS5, and TUG1 [25][26][27].…”

Elucidating Epigenetic Regulation by Identifying Functional cis‐Acting Long Noncoding RNAs and Their Targets in Osteoarthritic Articular Cartilage

“…The 191 lncRNAs identified in this study included several previously found to be associated with OA, such as MEG3 (fold change 0.6, FDR 8.8 × 10 −3 ), PART1 (fold change 1.8, FDR 1.7 × 10 −4 ), and LINC01614 (fold change 2.6, FDR 9.5 × 10 −3 ) (16,26), as well as novel OA‐associated lncRNAs, including P3H2‐AS1 (fold change 2.7, FDR 4.1 × 10 −4 ) and AC090877.2 (fold change 0.3, FDR 6.2 × 10 −5 ). Notably, previously identified lncRNAs such as MALAT1 (fold change 1.3, FDR 0.4) (27), TUG1 (fold change 1.1, FDR 0.7) (28), HOTAIR (fold change 0.8, FDR 0.5), and GAS5 (fold change 1.1, FDR 0.8) (29) were not found to be significantly differentially expressed in the present study.…”

lncRNA IGHCγ1 Acts as a ceRNA to Regulate Macrophage Inflammation via the miR-6891-3p/TLR4 Axis in Osteoarthritis

“…As a kind of noncoding RNA, lncRNA can function as ceRNA and restrain miRNA by lncRNA-miRNA sponge in cancer, cardiovascular disease, and so on [25,26]. Several functional lncRNAs have been demonstrated to influence osteoblast differentiation and OA pathogenesis through lncRNA-miRNA-mRNA ceRNA mechanism [27][28][29][30]. Some lncRNAs can affect the degradation of the extracellular matrix of chondrocytes by functioning as ceRNAs of specific miRNAs and thus participate in the development and progression of OA, such as lncRNAs of HOTTIP, MEG3, and XIST [28,29,31].…”

“…Several functional lncRNAs have been demonstrated to influence osteoblast differentiation and OA pathogenesis through lncRNA-miRNA-mRNA ceRNA mechanism [27][28][29][30]. Some lncRNAs can affect the degradation of the extracellular matrix of chondrocytes by functioning as ceRNAs of specific miRNAs and thus participate in the development and progression of OA, such as lncRNAs of HOTTIP, MEG3, and XIST [28,29,31]. Some lncRNAs have been well documented to regulate the differentiation of osteoblasts via the lncRNA-miRNA ceRNA network [27].…”