MiR-34a Enhances Chondrocyte Apoptosis, Senescence and Facilitates Development of Osteoarthritis by Targeting DLL1 and Regulating PI3K/AKT Pathway

Abstract

Background/Aims: Osteoarthritis (OA) is the prevalent degenerative disease caused by various factors. MicroRNAs are important regulators in the inflammation and immune response. The aim of this study was to investigate the effect of microRNA-34a (MiR-34a) on the death of chondrocytes, senescence, as well as its role in OA progression. Methods: A series of experiments involving CCK-8, flow cytometry, β-galactosidase staining and wound healing assays were conducted to determine the cellular capabilities of proliferation, cell apoptosis, senescence and the ability of cells to recover from injury, respectively. Binding sites between miR-34a and delta-like protein 1 (DLL1) were identified using a luciferase reporter system, whereas mRNA and protein expression of target genes was determined by RT-PCR and immunoblot, respectively. OA model was generated via surgery. Results: We found that miR-34a expression was increased in the cartilage of OA patients. In rat chondrocytes and chondrosarcoma cells, miR-34a transfections noticeably inhibited the expression of DLL1, triggered cell death and senescence, suppressed proliferation, and prevented scratch assay wound closure. However, transfection of a miR-34a inhibitor displayed adverse effects. Additionally, secretion and expression of factors associated with cartilage degeneration were altered via miR-34a. Moreover, miR-34a directly inhibits DLL1 mRNA. Furthermore, concentrations of DLL1, total PI3K, and p-AKT declined in chondrocytes that overexpress miR-34a. DLL1 overexpression elevated PI3K and p-AKT levels, and eliminated cell death triggered by a miR-34a mimic. In vivo, miR-34a remarkably inhibited miR-34a up-regulation, while enhanced the level of DLL1 expression. In the knee joints of surgery-induced OA rats, articular chondrocyte death and loss of cartilage were attenuated via miR-34a antagomir injection. Conclusions: These findings indicate that miR-34a contributes to chondrocyte death, causing OA progression through DLL1 and modulation of the PI3K/AKT pathway.

Mechanism of Action of Acupotomy in Inhibiting Chondrocyte Apoptosis in Rabbits with KOA through the PI3K/Akt Signaling Pathway

“…We can increase the expression of Akt to promote the growth of chondrocytes while reducing the apoptosis of cartilage. Based on our findings and those from previous studies [ 22 , 23 ], we speculate that acupotomy can activate the PI3K/Akt signaling pathway, thus regulating downstream target proteins to inhibit chondrocyte apoptosis and delay chondrocyte aging and degeneration. These effects help protect and improve the morphology of articular cartilage and are valuable for preventing and treating KOA.…”

Comparison of rheumatoid arthritis (RA) and osteoarthritis (OA) based on microarray profiles of human joint fibroblast‐like synoviocytes

“…44 These above signalling pathways also play a similar role in the development of OA. [45][46][47] Although the pathology of FLSs in OA and RA is somewhat similar, the distinctive pathogenesis and roles of FLSs in OA and RA are still not clear.…”

LINC00623/miR-101/HRAS axis modulates IL-1β-mediated ECM degradation, apoptosis and senescence of osteoarthritis chondrocytes

“…miR-199a-3p and miR-193b expression is upregulated with age and may be involved in chondrocyte senescence by downregulating anabolic factors such as type 2 collagen, aggrecan, and SOX9 [45]. Another miRNA, miR-34a, has been reported to noticeably inhibit the expression of DLL1, trigger cell death and senescence, suppress proliferation, and prevent scratch assay wound closure in rat chondrocytes and chondrosarcoma cells, therefore facilitating the development of OA [46]. Therefore, we further investigated miRNAs that might modulate OA chondrocyte senescence and apoptosis in a LINC00623 and HRAS-related way.…”