Abstract
BackgroundOsteoarthritis (OA) is characterized by joint pain and joint function limitation. Hsa_circ_0045714 (circ_0045714) is a novel OA-related circular RNA. However, its repertoire remains to be further clarified in joint chondrocytes.MethodsRNA and protein expression levels and inflammatory factor levels were detected by real-time quantitative polymerase chain reaction, western blotting and enzyme-linked immunosorbent assay. Cell proliferation and apoptosis were determined by colony formation assay, cell counting kit-8 assay and apoptosis assay. Direct interaction was predicted by bioinformatics method and confirmed by dual-luciferase reporter assay.ResultsExpression of circ_0045714 and phosphoinositide-3-kinase (PI3K) regulatory subunit 3 (PIK3R3) was declined, and microRNA (miR)-331-3p was promoted in knee articular cartilages and cells from OA patients, as well as interleukin (IL)-1β-challenged human articular chondrocytes (HAC) cell line. In stimulation of IL-1β, HAC cells showed a loss of colony formation ability, cell viability and expression of Bcl-2 and Collagen II, allied with an increase in apoptosis rate and levels of IL-6, IL-8 and tumor necrosis factor-α, Bcl-2-associated X protein, cleaved caspase-3, and ADAM with thrombospondin motif-5. Noticeably, overexpressing circ_0045714 and inhibiting miR-331-3p could suppress IL-1β-evoked these effects, and both were through up-regulating PIK3R3, a key gene in PI3K/AKT signaling pathway. Mechanically, circ_0045714 functioned as competing endogenous RNA (ceRNA) for miR-331-3p and further regulated expression of the downstream target gene PIK3R3.ConclusionThere was a novel circ_0045714/miR-331-3p/PIK3R3 ceRNA axis in HAC, and its inhibition might be one mechanism of HAC injury in OA.
Highlights
Osteoarthritis (OA) is a complex multifactorial disease, and its pathology has been advanced in genetics, genomics and epigenetics [1]
Down‐regulation of circ_0045714 was one molecular event in OA patients and IL‐1β‐insulted human articular chondrocytes (HAC) cells Circ_0045714 was derived from unk zinc finger (UNK) via back-splicing event (Fig. 1A), and its expression was abundantly decreased in the knee articular cartilages and chondrocytes from OA patients than normal ones (Fig. 1B, C)
MiR‐331‐3p was up‐regulated in OA and functioned as a target for circ_0045714 in HAC cells According to the prediction result, miR-331-3p response elements in circ_0045714 were mutated for further confirmation (Fig. 3A)
Summary
Osteoarthritis (OA) is a complex multifactorial disease, and its pathology has been advanced in genetics, genomics and epigenetics [1]. Inflammation has been shown to be associated with the complex etiology of joint pain in OA [4]. Ding et al J Orthop Surg Res (2021) 16:595 inflammation-related genes, tumor necrosis factor (TNF)-α and interleukin (IL)-1β are independent predictors for postoperative pain development in OA patients [5]. IL-1β plays versatile roles in different cell types involved in OA pathology, and IL-1β-insulted chondrocytes are suitable OA cell models [9]. Circular RNAs (circRNAs), a novel type of noncoding RNAs, are ubiquitous, structure-stable, tissue-specific and multifunctional. Hsa_ circ_0045714 (circ_0045714) is a novel circRNA that is differently expressed in fracture and OA [13, 14], and it might be a therapeutic target for fracture healing and functional recovery of OA-affected chondrocytes [15, 16]. Hsa_circ_0045714 (circ_0045714) is a novel OA-related circular RNA. Its repertoire remains to be further clarified in joint chondrocytes
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