circPDE4B prevents articular cartilage degeneration and promotes repair by acting as a scaffold for RIC8A and MID1

Abstract

ObjectivesCircular RNAs (circRNAs) have emerged as significant biological regulators. Herein, we aimed to elucidate the role of an unidentified circRNA (circPDE4B) that is reportedly downregulated in osteoarthritis (OA) tissues.MethodsThe effects of circPDE4B were explored in human and mouse chondrocytes in vitro. Specifically, RNA pull-down (RPD)-mass spectrometry analysis (MS), immunoprecipitation, glutathione-S-transferase (GST) pull-down, RNA immunoprecipitation and RPD assays were performed to verify the interactions between circPDE4B and the RIC8 guanine nucleotide exchange factor A (RIC8A)/midline 1 (MID1) complex. A mouse model of OA was also employed to confirm the role of circPDE4B in OA pathogenesis in vivo.ResultscircPDE4B regulates chondrocyte cell viability and extracellular matrix metabolism. Mechanistically, FUS RNA binding protein (FUS) was found to promote the splicing of circPDE4B, while downregulation of circPDE4B in OA is partially caused by upstream inhibition of FUS. Moreover, circPDE4B facilitates the association between RIC8A and MID1 by acting as a scaffold to promote RIC8A degradation through proteasomal degradation. Furthermore, ubiquitination of RIC8A at K415 abrogates RIC8A degradation. The circPDE4B–RIC8A axis was observed to play an important role in regulating downstream p38 mitogen-activated protein kinase (MAPK) signalling. Furthermore, delivery of a circPDE4B adeno-associated virus (AAV) abrogates the breakdown of cartilage matrix by medial meniscus destabilisation in mice, whereas a RIC8A AAV induces the opposite effect.ConclusionThis work highlights the function of the circPDE4B–RIC8A axis in OA joints, as well as its regulation of MAPK-p38, suggesting this axis as a potential therapeutic target for OA.

EIF4A3-regulated circ_0087429 can reverse EMT and inhibit the progression of cervical cancer via miR-5003-3p-dependent upregulation of OGN expression

“…The mechanism of action of circRNA is also complex and diverse. CircRNAs can be used as scaffolds for the assembly of protein complexes [ 7 ]; circRNAs can regulate gene transcription and RNA splicing [ 8 ]; circRNAs containing internal ribosome entry site elements and open reading frames can also be translated into proteins or polypeptides [ 9 ]. However, the most common mechanism of action of circRNA in cancer is the competitive endogenous RNA (ceRNA) mechanism.…”

Circular RNA circ0007360 Attenuates Gastric Cancer Progression by Altering the miR-762/IRF7 Axis

“…Recently, several research groups have shown that circRNAs are capable of encoding polypeptides that serve as scaffolds for certain proteins to exert their regulatory effects ( Li et al, 2021 ; Liu et al, 2021 ; Shen et al, 2021 ). We examined the protein coding potential of the bone fide polypeptides of circ0007360 and found that the coding probabilities of them are rather low (data not shown).…”

Arctiin-reinforced antioxidant microcarrier antagonizes osteoarthritis progression

“…MAPK and phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT) were identified by the bioinformatic analysis as the key pathways involved in the crosstalk between arctiin and OA. Cumulative evidence indicates that abnormal activation of p38-MAPK accelerates articular cartilage degeneration [ 36 ]. Due to the thorough inhibition of arctiin on MAPK or PI3K/AKT [ 33 ], the robust cartilage protection observed in vivo may be mediated in part by these signaling pathways.…”