Circ0083429 Regulates Osteoarthritis Progression via the Mir-346/SMAD3 Axis

Abstract

Osteoarthritis (OA) is a degenerative joint disease. Currently, apart from symptomatic treatment or joint replacement, no other effective treatments for OA exist. The mechanisms underlying OA remain elusive and require further research. Circular RNAs (circRNAs) are known to be involved in many diseases; however, their function in OA is not yet fully understood. Here, we identified a novel circRNA, Circ0083429. The role of Circ0083429 in OA was confirmed via western blot (WB), quantitative real-time PCR (qRT-PCR), and immunofluorescence (IF) through knockdown and overexpression experiments. The binding of Circ0083429 to downstream miR-346 and its target gene SMAD3 was predicted via bioinformatics analysis and verified using a luciferase reporter assay and RNA pulldown experiments. Finally, the function of Circ0083429 was evaluated in mouse OA models. In our study, we found that Circ0083429 regulates the homeostasis of the extracellular matrix (ECM) in human chondrocytes. Mechanistically, Circ0083429 affects OA by regulating the mRNA level of SMAD3 through the sponging of microRNA (miRNA)-346. Injecting adeno-associated virus Circ0083429 into the intra-junction of the mouse knee alleviated OA. In conclusion, Circ0083429 regulates the ECM via the regulation of the downstream miRNA-346/SMAD3 in human chondrocytes, which provides a new therapeutic strategy for OA.

miR‐193b‐3p and miR‐346 Exert Antihypertensive Effects in the Rostral Ventrolateral Medulla

“… 45 The interaction between circ0083429 and miR‐346 can regulate osteoarthritis progression. 46 For the first time, the present study reported a decrease in miR‐346 expression in the RVLM of SHRs when compared with healthy controls. The enhancement of miR‐346 expression in RVLM can effectively inhibit neuronal excitability, sympathetic outflow, and lower BP, offering improvements in hypertension symptoms.…”

Circular RNA CREBBP modulates cartilage degradation by activating the Smad1/5 pathway through the TGFβ2/ALK1 axis

“…Recently, the regulatory potential of circRNAs in OA has attracted increased attention 35 . For example, studies have shown that circSERPINE2 alleviates chondrocyte apoptosis and promotes anabolism of the ECM through the mir1271-5p/ERG pathway 36 ; the ciRS-7/miR-7 axis ameliorates cartilage degradation and inhibits autophagy via PI3K/AKT/mTOR activation 37 ; circPDE4D regulates glycosaminoglycan composition and inhibits matrix degeneration enzymes 38 ; and circ0083429 regulates the ECM by downregulating miR-346/Smad3 in chondrocytes 39 . According to our previous study, the chondrogenic differentiation of MSCs started 7 days after induction, with cartilage matrix gradually synthesized, reaching the peak of the expression of Collagen II and Aggrecan at days 14–21, while matrix metalloproteinases (MMPs) and indicators of chondrocyte hypertrophy increased rapidly.…”

New perspectives on the roles of circular RNAs in osteoarthritis development and progression (Review)

“…CircRNA, circular RNA; FGF, fibroblast growth factor; FUT2, fucosyltransferase 2; GREM, gremlin; miR, microRNA; TRAF2, TNF receptor-associated factor 2 of circ_DHRS3 and circPDE4D may alleviate OA. circ0083429 regulates Smad3 by sponging miRNA-346, thereby alleviating OA through the miR-346/Smad3 axis (52). circCDH13 promotes OA by sponging miR-296-3p, contributing to OA pathogenesis via the circCDH13/miR-296-3p/PTEN axis (53).…”