Circular RNA MELK Promotes Chondrocyte Apoptosis and Inhibits Autophagy in Osteoarthritis by Regulating MYD88/NF-κB Signaling Axis through MicroRNA-497-5p

Abstract

Osteoarthritis (OA) is a rheumatic disease and its pathogenesis involves the dysregulation of noncoding RNAs. Therefore, the regulatory mechanism of circular RNA MELK (circMELK) was specified in this work. OA human cartilage tissue was collected, and circMELK, miR-497-5p, and myeloid differentiation factor 88 (MYD88) expression were examined. Human chondrocytes were stimulated with interleukin- (IL-) 1β and interfered with vectors altering circMELK, miR-497-5p, and MyD88 expression to observe their effects on cell viability, cell cycle and apoptosis, autophagy, and inflammation. The binding relationship between RNAs was verified. The data presented that OA cartilage tissues presented raised circMELK and MYD88 and inhibited miR-497-5p expression. IL-1β suppressed cell viability, prevented cell cycle, and induced apoptosis, autophagy, and inflammation of chondrocytes. Functionally, IL-1β-induced changes of chondrocytes could be attenuated by suppressing circMELK or overexpressing miR-497-5p. circMELK acted as a sponge of miR-497-5p while miR-497-5p was a regulator of MYD88. MYD88 restricted the effect of overexpressing miR-497-5p on IL-1β-stimulated chondrocytes. MYD88 triggered nuclear factor-kappaB (NF-κB) pathway activation. Shortly, CircMELK promotes chondrocyte apoptosis and inhibits autophagy in OA by regulating MYD88/NF-κB signaling axis through miR-497-5p. Our study proposes a new molecular mechanism for the development of OA.

Physalin A alleviates intervertebral disc degeneration via anti-inflammatory and anti-fibrotic effects

“…The inflammatory landscape is composed of the activation of multiple inflammatory pathways and the secretion of multiple inflammatory factors as the main facilitator to accelerate IVDD progression [ 50 ]. Based on extensive research, NF-κB and MAPK pathways are crucial inflammatory pathways involved in progression of degeneration diseases, such as IVDD and osteoarthritis, and its activation may lead to secretion of inflammatory cytokines and dysfunction of ECM synthesis [ [51] , [52] , [53] ]. In this study, IL-1β was used to stimulate NP cells to mimic inflammatory and degenerative disc environments in vitro .…”

Mulberroside A alleviates osteoarthritis via restoring impaired autophagy and suppressing MAPK/NF-κB/PI3K-AKT-mTOR signaling pathways

“…The MAPK and NF-κB signaling pathways are crucial factors in the regulation of inflammatory response and are closely related to many diseases, including OA. 47 , 48 Studies have revealed that the activation of the two signaling pathways could upregulate the expression of inflammatory proteins (iNOS, COX-2, and IL-6) and catabolic proteins (MMP1, MMP3, MMP13, and ADAMTS5), as well as downregulate the expression of anabolic proteins (Aggrecan, Collagen II, and SOX9), which in turn facilitate the degradation of ECM and cartilage destruction. 18 , 49 , 50 , 51 Measurements of the inhibition of the MAPK and NF-κB signal transduction could prevent or slow the development of OA.…”

Regulatory mechanism of circular RNA involvement in osteoarthritis

“…So, in cases where both autophagy and apoptosis may occur, autophagy should be given more importance For example, circFOXO3 overexpression alleviates OA by activating the forkhead box O3 (FOXO3) parental gene and thus the autophagy pathway, which in turn impairs chondrocyte apoptosis and promote ECM anabolism (40). Conversely, CircMELK exacerbated OA by regulating the miR-497-5p/MYD88/nuclear factor-kappa B (NF-κB) signaling axis, promoting chondrocyte apoptosis and inhibiting autophagy (41). Although circMELK and circFOXO3 are expressed at different levels in OA, their effects promote apoptosis and inhibit autophagy through ceRNA mechanisms, ultimately leading to OA progression.…”