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MiR-7 has been recognized as an osteoarthritis (OA-)-promoting factor, but the specific downstream pathway of miR-7 still remains unknown. Further investigation of the molecular regulatory mechanism of miR-7 might help develop a novel therapeutic method for OA. In this study, we revealed that Semaphorin 6D (SEMA6D) was a direct target gene of miR-7 and presented a negative regulatory relation with SEMA6D in vitro and in vivo . SEMA6D could improve OA in rat OA models, as indicated by H&E and Safranin O-Fast green staining, and also μ CT analysis. Further evaluation of SEMA6D suggested that SEMA6D promotes the anabolism and reduces the catabolism of C28/I2 chondrocytes via inhibiting the activation of the p38 pathway. The present research illustrated that SEMA6D is a negatively regulatory factor of miR-7 and a pivotal mediator of catabolism and anabolism in C28/I2 chondrocytes. SEMA6D exerts its function via inhibiting the activation of the p38 pathway., Competing Interests: There are no competing interests between authors., (Copyright © 2022 Haoyu Yang et al.)

Osteoarthritis (OA) is a chronic degenerative disease which seriously affects the patients' daily activities and quality of life. In our previous findings, we demonstrated that overexpression of miR-7 was found in OA and promoted OA development. Its exact mechanism remains unclear. Herein, we confirmed that KLF4 was the target gene of miR-7 and KLF4 was down-regulated in human OA tissues and OA chondrocyte. KLF4 was negatively modulated by miR-7 via dual luciferase reporter assay. Cartilage-specific genes (SOX9, COL2A1, RUNX2, MMP13) are crucial regulators in cartilage degeneration. Through qRT-PCR and western blot, we observed that KLF4 overexpression could increase the expression of SOX9 and COL2A1, decrease RUNX2 and MMP13. In the meanwhile, miR-7 was proven to regulate the expression of the above cartilage-specific genes by targeting KLF4, which demonstrated KLF4 could prevent OA development. Subsequently, KLF4 also activated TGF-β1 signaling pathway, thereby affecting OA progression. Excessive KLF4 could up-regulate TGF-β1 and p-Smad2/3 level, and Smad4 level was prevented in OA chondrocytes, while adding TGF-β1 inhibitor SB525334 could rescue this impact, along with reduced TGF-β1 and p-Smad2/3 level, enriched Smad4 level. KLF4 could also reverse the effect of miR-7 on TGF-β1 signaling. Besides, it was confirmed that KLF4 could improve OA in rat OA models by HE and Safranin O-Fast green staining, and immunohistochemistry. Collectively, our findings will give more detailed evidence about miR-7 and KLF4 in OA diagnosis and treatment., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Osteoarthritis (OA) is a common degenerative disease in middle-aged and elderly people. Our previous study has proved that microRNA-7 (miR-7) exacerbated the OA process. This study was aimed to explore the downstream genes and mechanism regulated by miR-7 to affect OA. Multiple EGF-like-domains 9 (MEGF9) was the predicted target of miR-7 by databases. Luciferase report experiment results confirmed that MEGF9 could bind to miR-7. Among the 10 collected pairs of OA and healthy samples, the expression levels of miR-7 and MEGF9 were both up-regulated when compared with healthy subjects by qRT-PCR and immunohistochemistry (IHC). The increased MEGF9 levels were due to the interaction with epidermal growth factor receptor (EGFR) by co-immunoprecipitation. Evaluations found that upregulation of miR-7 or MEGF9 can increase the expression of EGFR, matrix metalloproteinase-13 (MMP-13) and a disintegrin like and metallopeptidase with thrombospondin type 1 motif 5 (ADAMTS-5), so as to aggravate cartilage degradation. In addition, this effect induced by miR-7/EGFR/MEGF9 axis was by activation of PI3K/AKT signaling. The IHC and western blot assay results on OA model mice also demonstrated that miR-7/EGFR/MEGF9 axis regulated cartilage degradation in vivo. In summary, miR-7/EGFR/MEGF9 axis may perform a crucial function in the regulation of OA, providing potential for OA treatment.

Osteoarthritis (OA) is one of the most painful and widespread chronic degenerative joint diseases and is characterized by destructed articular cartilage and inflamed joints. Previously, our findings indicated that circular RNA ciRS-7 (ciRS-7)/microRNA 7 (miR-7) axis is abnormally expressed in OA, and regulates proliferation, inflammatory responses, and apoptosis of interleukin-1β (IL-1β)-stimulated chondrocytes. However, its underlying role in OA remains unknown. In this study, we first validated cartilage degradation and defection of autophagy in samples of OA patients. IL-1β initially stimulated autophagy of chondrocytes, and ultimately significantly suppressed autophagy. Upregulated ciRS-7/down-regulated miR-7 aggravated IL-1β-induced cartilage degradation, and restrained autophagy in vitro . Gene sequencing and bioinformatics analysis performed on a control group, IL-1β group, and IL-1β+miR-7-mimics group demonstrated that seven of the most significant mRNA candidates were enriched in the interleukin-17 (IL-17) signaling pathway. Increased IL-17A levels were also observed by qRT-PCR and ELISA. In addition, it was revealed that the ciRS-7/miR-7 axis ameliorated cartilage degradation and defection of autophagy by PI3K/AKT/mTOR activation in IL-1β-induced chondrocytes. Furthermore, an OA model was established in rats with medial meniscus destabilization. miR-7-siRNA-expressing lentiviruses alleviated surgical resection-induced cartilage destruction of OA mice, whereas miR-7 mimics worsened the effects. Thus, these findings revealed that the mechanism of the ciRS-7/miR-7 axis involved regulating OA progression and provided valuable directions for OA treatment.

Osteoarthritis (OA) is a degenerative joint disease caused by articular cartilage degradation and joint inflammation, with considerable involvement of microRNAs and circular RNAs. However, the precise role of the ciRS-7/miR-7 axis within OA still requires further elucidation. In this study, quantitative reverse-transcription PCR (qRT-PCR) was utilized to determine the relative expression of ciRS-7 and miR-7 in blood samples from OA patients compared with those from healthy individuals. Human OA chondrocytes (C28/12 cell line) were transfected with ciRS-7-siRNA, ciRS-7-cDNA, inhibitor or miR-7 mimic to investigate the influence of ciRS-7/miR-7 expression on chondrocyte apoptosis, inflammation and related signaling pathways. Decreased ciRS-7 expression and increased miR-7 expression were observed in OA blood samples. IL-1β exposure of chondrocytes significantly inhibited proliferation and promoted inflammatory cytokine release. ciRS-7 was down-regulated but miR-7 was up-regulated in IL-1β-induced chondrocytes. Transfection of ciRS-7 siRNA and miR-7 mimic enhanced the impact of IL-1β on inflammatory cytokine release and cell apoptosis as quantified using ELISA and flow cytometry. Conversely, ciRS-7 cDNA and miR-7 inhibitor induced the reverse effect. These findings demonstrate that the ciRS-7/miR-7 axis can possibly serve as a regulator in mediating proliferation, apoptosis and inflammation in chondrocytes in the process of OA development., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: To investigate a possible effect of a gene mutation on rheumatoid arthritis (RA), we performed genotyping, in a hospital-based, case-control study in a Chinese cohort, relating the single nucleotide polymorphism (SNP) of microRNA (miRNA)-146a (rs2910164) to RA and undertook a meta-analysis using the available literature., Methods: Six hundred and fifteen RA patients and 839 controls were enrolled in our study. A polymorphism of the miRNA-146a (rs2910164) gene was detected using a custom-by-design 48-Plex SNPscan TM Kit. In addition, we performed a systematic literature research and identified an additional 7 studies with 1066 cases and 1513 controls., Results: We did not find a significant association of miRNA-146a polymorphism with an RA risk in our data. And the results of the meta-analyses suggested no significant association between miRNA-146a polymorphism and RA in any genetic model. However, when the subgroup analyses were performed, genotype GG was observed to be significantly associated with RA in females. And the DAS28 score may also be significantly influenced by CC genotype., Conclusions: Our study suggested that miRNA-146a polymorphism might not be associated with RA susceptibility. However, the miRNA-146 GG genotype might increase the risk of RA in females, and CC genotype may influence disease activity when evaluated with DAS28 score., (Copyright © 2015 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.)