Objectives N6‐methyladenosine (m6A) is one of the most abundant internal RNA modifications. We investigated the role of m6A‐modified circRERE in osteoarthritis (OA) and its mechanism. Materials and Methods CircRERE and IRF2BPL were screened by microarrays. The role of m6A‐modification in circRERE was examined by methylated RNA precipitation and morpholino oligo (MOs) treatment. The axis of circRERE/miR‐195‐5p/IRF2BPL/β‐catenin was determined using flow cytometry, western blotting and immunofluorescence in human chondrocytes (HCs) and corroborated using a mouse model of destabilization of medial meniscus (DMM) with intra‐articular (IA) injection of adeno‐associated viruses (AAV). Results CircRERE was decreased in OA cartilage and chondrocytes compared with control. CircRERE downregulation was likely attributed to its increased m6A modification prone to endoribonucleolytic cleavage by YTHDF2‐HRSP12‐RNase P/MRP in OA chondrocytes. MOs transfection targeting HRSP12 binding motifs in circRERE partially reversed decreased circRERE expression and increased apoptosis in HCs treated with IL‐1β for 6 h. CircRERE exerted chondroprotective effects by targeting miR‐195‐5p/IRF2BPL, thus regulating the ubiquitination and degradation of β‐catenin. CircRere (mouse homologue) overexpression by IA‐injection of AAV‐circRere into mice attenuated the severity of DMM‐induced OA, whereas AAV‐miR‐195a‐5p or AAV‐sh‐Irf2bpl reduced the protective effects. The detrimental effects of AAV‐sh‐Irf2bpl on DMM‐induced OA were substantially counteracted by ICG‐001, an inhibitor of β‐catenin. Conclusions Our study is a proof‐of‐concept demonstration for targeting m6A‐modified circRERE and its target miR‐195‐5p/IRF2BPL/β‐catenin as potential therapeutic strategies for OA treatment.

Osteoarthritis (OA) is the most common joint disease globally, and its progression is irreversible. The mechanism of osteoarthritis is not fully understood. Research on the molecular biological mechanism of OA is deepening, among which epigenetics, especially noncoding RNA, is an emerging hotspot. CircRNA is a unique circular noncoding RNA not degraded by RNase R, so it is a possible clinical target and biomarker. Many studies have found that circRNAs play an essential role in the progression of OA, including extracellular matrix metabolism, autophagy, apoptosis, the proliferation of chondrocytes, inflammation, oxidative stress, cartilage development, and chondrogenic differentiation. Differential expression of circRNAs was also observed in the synovium and subchondral bone in the OA joint. In terms of mechanism, existing studies have mainly found that circRNA adsorbs miRNA through the ceRNA mechanism, and a few studies have found that circRNA can serve as a scaffold for protein reactions. In terms of clinical transformation, circRNAs are considered promising biomarkers, but no large cohort has tested their diagnostic value. Meanwhile, some studies have used circRNAs loaded in extracellular vesicles for OA precision medicine. However, there are still many problems to be solved in the research, such as the role of circRNA in different OA stages or OA subtypes, the construction of animal models of circRNA knockout, and more research on the mechanism of circRNA. In general, circRNAs have a regulatory role in OA and have particular clinical potential, but further studies are needed in the future.

Trial design: This study prospectively analyzes the effect of EPO combined with Iron sucrose on postoperative anemia prevention and prognosis of patients with TKA. Methods: Participants in this study will be randomly assigned to a treatment group or control group. Patients in the treatment group will receive EPO for ten days combined with iron sucrose injection for three days preoperative. The general data, hematological indexes, transfusion rate, total blood loss, and knee joint function score will be analyzed. Results: 92 patients met the inclusion criteria, including 46 patients in the treatment group and 46 in the control group. There were no significant statistical differences in descriptive characteristics of the population between the two groups. The results indicated that the anemic rate of the treatment group was significantly lower than the control group after treatment (67.4%vs93.5%, P=0.001). The hematological index also has a significant difference in the two groups, such as Postoperative Hb, RBC count, Hct. The treatment group, perioperative blood loss, was significantly lower than the control group (587.69±340.81ml vs. 812.72±329.7ml, P=0.002). The treatment group showed a better HSS score and WOMAC score (HSS score: P=0.007; WOMAC score: P=0.001), HSS score improved 3.37 points, and WOMAC scores improved 12.08 points after the operation than the control group. No postoperative blood transfusion and postoperative complications occurred in the study period. Conclusions: According to our study, we found that perioperative treatment of erythrocyte mobilization in patients with TKA can improve postoperative hemoglobin level, reduce postoperative total blood loss, and reduce postoperative anemic rate without increased drug costs on the hospitalization expenses. Patients who receive erythrocyte mobilization treatment can significantly accelerate erythropoiesis after surgery and promote the hemoglobin level to normal more quickly. The patients after treatment show an advantage in HSS score and WOMAC score.