Circular RNA CircCDH13 contributes to the pathogenesis of osteoarthritis via CircCDH13/miR‐296‐3p/PTEN axis

Abstract

Circular RNAs (circRNAs) are involved in a variety of human diseases; however, the function of circRNAs in osteoarthritis (OA) remains largely unknown. In this study, we investigated the role of CircCDH13 in OA and its underlying mechanisms. CircRNA expression profiles in OA and normal cartilage tissues were detected by microarray. The expression pattern, functional role, and mechanisms of CircCDH13 in OA were studied in vitro and in vivo. Gain‐of‐function and loss‐of‐function approaches were used to demonstrate the participation of CircCDH13 in OA. The regulatory relationship between CircCDH13 and miR‐296‐3p and miR‐296‐3p and phosphatase and tensin homolog (PTEN) was predicted by bioinformatics and verified by RNA pulldown and luciferase assay. Adeno‐associated virus was also used to reveal the role and mechanisms of CircCDH13 in destabilization of medial meniscus (DMM)‐induced OA mice. The upregulation of CircCDH13 in OA cartilage tissues significantly induces chondrocyte apoptosis, promotes extracellular matrix (ECM) catabolism, and inhibits ECM anabolism. Mechanistically, CircCDH13 contributes to OA pathogenesis by functioning as a sponge of miR‐296‐3p and regulating the miR‐296‐3p‐PTEN pathway. Silencing of CircCDH13 in vivo markedly alleviated DMM‐induced OA in mice. Our study revealed an important role of CircCDH13 in OA pathogenesis. Silencing of CircCDH13 could reduce chondrocyte apoptosis, inhibit ECM catabolism, and promote ECM anabolism through the miR‐296‐3p‐PTEN pathway. It provides a potential target for developing effective interventions in treating OA.

Biological roles and therapeutic potential of circular RNAs in osteoarthritis

“…Upregulated circCDH13 has been detected in OA chondrocytes and in HCs treated with IL-1b and TNF-a. 74 Knocking down circCDH13 downregulated MMP13 and ADAMTS5 and increased COL2A1 and aggrecan; all of these effects were reversed by the overexpression of circCDH13. circCDH13 can bind to miR-296-3p, acting as a sponge, and the downstream targets of circCDH13/miR-296-3p were investigated.…”

CircSLC7A2 protects against osteoarthritis through inhibition of the miR‐4498/TIMP3 axis

“…During previous study, some researchers identified the corresponding conservative sequences of circRNA between human and mouse and then used animal sequences to complete animal experiments instead of human. 58 However, a large number of circRNA do not exist conservative sequences in other species. In our study, the principium of in vivo experiments was to rely on the injected overexpressed human circSLC7A2 virus to bind to miR-4498 in mice, which in turn affected the expression of TIMP3 in mice.…”

Experimental Therapeutics for the Treatment of Osteoarthritis

“…Silencing of CircCDH13: chondrocyte apoptosis↓, ECM catabolism↓, anabolism↑, in vivo: alleviated OA. [ 234 ] Abbreviations: ASC, adipose tissue-derived mesenchymal stromal cells; FUT, Fucosyltransferase; HMGB1, High mobility group box 1; i.a., intraarticular; MAPK, MAP kinase; miR, microRNA; PARP, Poly(ADP-ribose)-Polymerase; TGFBR2, Transforming growth factor β receptor 2; Wnt, wingless and integration site-1. …”