Small interfering RNAs in the management of human osteoporosis

Circular RNAs (circRNAs) are a newly appreciated type of endogenous noncoding RNAs that play vital roles in the development of various human cancers, including osteosarcoma (OS). In this study, we investigated three circRNAs (circ_0076684, circ_0003563, circ_0076691) from the RUNX Family Transcription Factor 2 (RUNX2) gene locus in OS. We found that the expression of circ_0076684, circ_0003563, circ_0076691, and RUNX2 mRNA is upregulated in OS, which is a consequence of CBX4-mediated transcriptional activation. Among these three RUNX2-circRNAs, only circ_0076684 is significantly associated with the clinical features and prognosis of OS patients. Functional experiments indicate that circ_0076684 promotes OS progression in vitro and in vivo. Circ_0076684 acts as a sponge for miR-370-3p, miR-140-3p, and miR-193a-5p, raising Cut Like Homeobox 1 (CUX1) expression by sponging these three miRNAs. Furthermore, we presented that circ_0076684 facilitates OS progression via CUX1. In conclusion, this study found that the expression of three circRNAs and RUNX2 mRNA from the RUNX2 gene locus is significantly upregulated in OS, as a result of CBX4-mediated transcriptional activation. Circ_0076684 raises CUX1 expression by sponging miR-370-3p, miR-140-3p, and miR-193a-5p, and facilitates OS progression via CUX1.

Section: Discussionmentioning

confidence: 99%

Upregulation of circ_0076684 in osteosarcoma facilitates malignant processes by mediating miRNAs/CUX1

Cai,

Fu,

et al. 2024

“…And circ_0044235 could regulate PIK3R3 through miR-375. Recently, siRNAs have been found to regulate tendon homeostasis, osteoporosis and arthritis progression [ 33 – 35 ]. Here, we found that PIK3R3 silencing abolished the role of anti-miR-375 on OA progression.…”

Section: Discussionmentioning

confidence: 99%

Circ_0044235 regulates the development of osteoarthritis by the modulation of miR-375/PIK3R3 axis

Qian,

Mei,

Zhu

et al. 2024

Background Circular RNAs (circRNAs) play an important role in osteoarthritis (OA). However, the role of circRNA in OA is still unclear. Here, we explored the role and mechanism of circ_0044235 in OA. Methods CHON-001 cells were treated with IL-1β to establish OA model in vitro. The levels of circ_0044235, miR-375 and phosphoinositide 3-kinase (PI3K) regulatory subunit 3 (PIK3R3) were detected by quantitative real-time PCR. Cell count kit-8 assay and flow cytometry assay were used to detect cell viability and apoptosis. The concentrations of inflammation factors were determined by enzyme-linked immunosorbent assay. Western blot was used to detect protein levels. The interaction between miR-375 and circ_0044235 or PIK3R3 was analyzed by dual-luciferase reporter assay and RNA immunoprecipitation assay. Results Circ_0044235 was significantly decreased in OA cartilage tissue and IL-1β-treated CHON-001 cells. Overexpression of circ_0044235 promoted IL-1β-stimulated CHON-001 cell viability and inhibited apoptosis, inflammation, and extracellular matrix (ECM) degradation. In mechanism analysis, circ_0044235 could act as a sponge for miR-375 and positively regulate PIK3R3 expression. In addition, miR-375 ameliorated the effect of circ_0044235 overexpression on IL-1β-mediated CHON-001 cells injury. In addition, miR-375 inhibition mitigated IL-1β-induced CHON-001 cell injury, while PIK3R3 silencing restored the effect. Conclusion Circ_0044235 knockdown alleviated IL-1β-induced chondrocytes injury by regulating miR-375/PIK3R3 axis, confirming that circ_0044235 might be a potential target for OA treatment.

“…MiRNA and siRNAs have been confirmed to play vital function in human diseases [ 23 – 27 ]. According to reported studies, circ_0000376 might be involved in regulating OS development through sponging miR-432-5p [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

Circ_0000376 regulates miR-577/HK2/LDHA signaling pathway to promote the growth, invasion and glycolysis of osteosarcoma

Dai,

Yi,

Jiang

et al. 2024

Background Many studies have confirmed that circular RNAs (circRNAs) mediate the malignant progression of various tumors including osteosarcoma (OS). Our study is to uncover novel molecular mechanisms by which circ_0000376 regulates OS progression. Methods The expression of circ_0000376, microRNA (miR)-577, hexokinase 2 (HK2) and lactate dehydrogenase-A (LDHA) was determined by quantitative real-time PCR. OS cell proliferation, apoptosis and invasion were measured using cell counting kit 8 assay, colony formation assay, EdU assay, flow cytometry and transwell assay. Besides, cell glycolysis was assessed by testing glucose consumption, lactate production, and ATP/ADP ratios. Protein expression was examined by western blot analysis. The interaction between miR-577 and circ_0000376 or HK2/LADA was verified by dual-luciferase reporter assay. The role of circ_0000376 on OS tumor growth was explored by constructing mice xenograft models. Results Circ_0000376 had been found to be upregulated in OS tissues and cells. Functional experiments revealed that circ_0000376 interference hindered OS cell growth, invasion and glycolysis. Circ_0000376 sponged miR-577 to reduce its expression. In rescue experiments, miR-577 inhibitor abolished the regulation of circ_0000376 knockdown on OS cell functions. MiR-577 could target HK2 and LDHA in OS cells. MiR-577 suppressed OS cell growth, invasion and glycolysis, and these effects were reversed by HK2 and LDHA overexpression. Also, HK2 and LDHA expression could be regulated by circ_0000376. In vivo experiments showed that circ_0000376 knockdown inhibited OS tumorigenesis. Conclusion Circ_0000376 contributed to OS growth, invasion and glycolysis depending on the regulation of miR-577/HK2/LDHA axis, providing a potential target for OS treatment. Graphical Abstract