CircSERPINE2 weakens IL-1β-caused apoptosis and extracellular matrix degradation of chondrocytes by regulating miR-495/TGFBR2 axis

Abstract

The dysregulated circular RNAs (circRNAs) are relevant to the development of osteoarthritis (OA). The circRNA serpin family E member 2 (circSERPINE2) is dysregulated in OA, while the role and mechanism of circSERPINE2 in OA are largely unknown. The aim of our research is to explore how and whether circSERPINE2 regulates interleukin-1β (IL-1β)-caused chondrocyte damage in OA. In present study, the chondrocytes (CHON-001 cells) were exposed to IL-1β to mimic the injury in OA. CircSERPINE2, microRNA-495 (miR-495) and transforming growth factor-β receptor 2 (TGFBR2) abundances were detected via quantitative reverse transcription polymerase chain reaction or western blot. Cell apoptosis was assessed via viability, apoptotic rate and caspase-3 activity. Extracellular matrix was investigated by levels of Sry-type high-mobility-group box 9 (SOX9), collagen type II alpha 1 (COL2A1) and Aggrecan using western blot. The interaction among circSERPINE2, miR-495 and TGFBR2 was assessed via dual-luciferase reporter analysis and RNA immunoprecipitation. The results showed that circSERPINE2 expression was reduced in OA patients and IL-1β-treated chondrocytes. CircSERPINE2 overexpression mitigated IL-1β-caused apoptosis and extracellular matrix degradation. miR-495 was targeted by circSERPINE2 and up-regulated in OA patients and IL-1β-treated chondrocytes. miR-495 up-regulation reversed overexpression of circSERPINE2-mediated inhibition of apoptosis and extracellular matrix degradation. TGFBR2 was targeted by miR-495 and lowly expressed in OA patients and IL-1β-treated chondrocytes. CircSERPINE2 could mediate TGFBR2 expression by binding with miR-495. As a conclusion, CircSERPINE2 attenuated IL-1β-caused apoptosis and extracellular matrix degradation of chondrocytes by regulating miR-495/TGFBR2 axis, indicating a new target for OA treatment.

Biological roles and therapeutic potential of circular RNAs in osteoarthritis

“…As noted earlier in this review, circSERPINE2 protects ECM metabolism and regulates the apoptosis of OA chondrocytes. Xia and colleagues 83 found that the overexpression of circSERPINE2 mitigated IL-1b-induced chondrocyte apoptosis by decreasing caspase-3. OAassociated miR-495 has been confirmed as a target of circSERPINE2, and TGF-b receptor 2 (TGFBR2) is targeted by miR-495.…”

Studies on the Role of circRNAs in Osteoarthritis

“…In addition, circRNA TMBIM6 promotes ECM degradation of OA-induced chondrocytes via the miR-27a/matrix metalloproteinase-13 (MMP-13) axis, according to Bai et al [ 21 ]. circRNA SERPINE2 reduces IL-1 β -induced apoptosis and ECM degradation of chondrocytes by regulating the miR-495/transforming growth factor-beta receptor 2 (TGFBR2) axis [ 32 ]. Furthermore, the functions of circRNAs also include protein kinase activity, glycosaminoglycan binding, endoplasmic reticulum membrane, and peptidyl-serine phosphorylation, which can be the focus of future studies on the mechanism of OA.…”

“…Xiang et al [54] revealed the expression profile of circRNAs in OA through RNA sequencing and identified 122 cir-cRNAs of differential expression. Based on these studies, NT5C2 [8], DUSP5 [9], UBE2G1 [10], GCN1L1 [11], HIPK3 [12], VCAN [13], ASH2L [15], SEC24A [18], PRKCH [19,20], TMBIM6 [21], VWF [23], PLOD1 [23], COL6A3 [23], hsa_circ_7 [24,25], ATP9B [26], PSM3 [27], MSR [28], CDR1 [29], CDH13 [30], RNF121 [31], CSNK1G1 [33], DHRS3 [35], PTPRA [38], IQGAP1 [39], SCAPER [39], RP11-909M7.3 [39] , RSU1 [40] SERPINE2 [7,32], CDK14 [14], PDE4D [16], ANKRD36 [17], hsa_circ_9119 [22], EPS15 [26,34], ADAMTS6 [36], UNK [37,41] BioMed Research International VWF (hsa_circ_0025119) had the highest value (Figure 3, Tables 3 and 4), indicating a significant interaction between VWF and other circRNAs; also, additional functions and signaling pathways were detected in the BP. Therefore, we speculated that VWF (hsa_circ_0025119) is more feasible to be used as a...…”

Experimental Therapeutics for the Treatment of Osteoarthritis

“…As a conclusion, CircSERPINE2 attenuated IL-1β-caused apoptosis and ECM degradation of chondrocytes by regulating miR-495/TGFBR2 axis → new target for OA treatment. [ 232 ] miR-17-5p OA cartilage and IL-1β-induced chondrocytes: miR-17-5p↓ Fucosyltransferase (FUT)1↑ [ 233 ] miR-296-3p CircCDH13 contributes to OA pathogenesis by acting as a sponge of miR-296-3p and regulating the miR-296-3p-PTEN pathway. Silencing of CircCDH13: chondrocyte apoptosis↓, ECM catabolism↓, anabolism↑, in vivo: alleviated OA.…”