MiR-653-5p drives osteoarthritis pathogenesis by modulating chondrocyte senescence.

BACKGROUND: Due to the unclear pathogenesis of osteoarthritis (OA), effective treatment for this ailment is presently unavailable. Accumulating evidence points to chondrocyte senescence as a key driver in OA development. This study aims to identify OA-specific microRNAs (miRNAs) targeting chondrocyte senescence to alleviate OA progression. METHODS: We screened and identified miRNAs differentially expressed in OA and normal cartilage, then confirmed the impact of miR-653-5p on chondrocyte functions and senescence phenotypes through in vitro experiments with overexpression/silencing. We identified interleukin 6 (IL-6) as the target gene of miR-653-5p and confirmed the regulatory influence of miR-653-5p on the IL-6/JAK/STAT3 signaling pathway through gain/loss-of-function studies. Finally, we assessed the therapeutic efficacy of miR-653-5p on OA using a mouse model with destabilization of the medial meniscus. RESULTS: MiR-653-5p was significantly downregulated in cartilage tissues and chondrocytes from OA patients. Overexpression of miR-653-5p promoted chondrocyte matrix synthesis and proliferation while inhibiting chondrocyte senescence. Furthermore, bioinformatics target prediction and the luciferase reporter assays identified IL-6 as a target of miR-653-5p. Western blot assays demonstrated that miR-653-5p overexpression inhibited the protein expression of IL-6, the phosphorylation of JAK1 and STAT3, and the expression of chondrocyte senescence phenotypes by regulating the IL-6/JAK/STAT3 signaling pathway. More importantly, the cartilage destruction was significantly alleviated and chondrocyte senescence phenotypes were remarkably decreased in the OA mouse model treated by agomiR-653-5p compared to the control mice. CONCLUSIONS: MiR-653-5p showed a significant decrease in cartilage tissues of individuals with OA, leading to an upregulation of chondrocyte senescence phenotypes in the articular cartilage. AgomiR-653-5p emerges as a potential treatment approach for OA. These findings provide further insight into the role of miR-653-5p in chondrocyte senescence and the pathogenesis of OA.

No Difference in Bone Tunnel Enlargement and Clinical Outcome between Cortical Suspension and Hybrid Femoral Fixation in Hamstring Anterior Cruciate Ligament Reconstruction.

OBJECTIVE: The best method for femoral fixation in anterior cruciate ligament reconstruction (ACLR) remains controversial. The study assesses the bone tunnel enlargement and clinical outcome in hamstring ACLR using cortical suspension or hybrid (cortical suspension and compression) femoral fixation. METHODS: From January 2010 to December 2021, 102 patients who underwent quadruple hamstring ACLR using cortical suspension (39 patients) or hybrid (63 patients) fixation on the femoral side were retrospectively analyzed. Clinical evaluation was conducted using the international knee documentation committee score, the Lysholm score, the Tegner activity level scale, the knee injury and osteoarthritis outcome score (quality of life score), the Lachman test, and the side-to-side difference by the KT-1000 arthrometer. The complications after the surgery were also evaluated. These data were compared at baseline and last follow-up. The diameters of the femoral tunnel were calculated at three sites: the width of the entrance of the femoral tunnel, 1 cm proximal to the entrance of the femoral tunnel and the largest diameter of the femoral tunnel on magnetic resonance imaging (MRI) coronal images. Bone tunnel widening data were contrasted between MRI images conducted at least 2 years and within 2 weeks after surgery. The morphology of bone tunnel enlargement was also observed and recorded. The categorical parameters were analyzed using the χ2-test and Fisher's exact test. The continuous variables conforming to a normal distribution were analyzed using Student's t-test, and the Mann-Whitney U-test was undertaken between the two groups without normal distribution. RESULTS: Both cortical suspension and hybrid femoral fixation in quadruple hamstring ACLR achieved significantly improved patient-reported outcome scores and knee stability compared to preoperative data. However, no significant differences were found between these two methods in clinical evaluations, postoperative complications, and patient-reported outcome scores. Although the mean diameter of the enlarged bone tunnel was lowered by an additional bioabsorbable interference screw fixation near the joint line, a statistically insignificant difference was found between the hybrid and cortical suspension fixation on the femoral side. There was no statistical difference in the distribution of enlarged bone tunnel morphology between groups. CONCLUSIONS: No significant difference was found in the bone tunnel enlargement and clinical outcome between cortical suspension and hybrid femoral fixation in ACLR using hamstring autograft.

Stress Response and Hearing Loss Differentially Contribute to Dynamic Alterations in Hippocampal Neurogenesis and Microglial Reactivity in Mice Exposed to Acute Noise Exposure.

Noise-induced hearing loss (NIHL) is one of the most prevalent forms of acquired hearing loss, and it is associated with aberrant microglial status and reduced hippocampal neurogenesis; however, the nature of these associations is far from being elucidated. Beyond its direct effects on the auditory system, exposure to intense noise has previously been shown to acutely activate the stress response, which has increasingly been linked to both microglial activity and adult hippocampal neurogenesis in recent years. Given the pervasiveness of noise pollution in modern society and the important implications of either microglial activity or hippocampal neurogenesis for cognitive and emotional function, this study was designed to investigate how microglial status and hippocampal neurogenesis change over time following acoustic exposure and to analyze the possible roles of the noise exposure-induced stress response and hearing loss in these changes. To accomplish this, adult male C57BL/6J mice were randomly assigned to either a control or noise exposure (NE) group. Auditory function was assessed by measuring ABR thresholds at 20 days post noise exposure. The time-course profile of serum corticosterone levels, microglial status, and hippocampal neurogenesis during the 28 days following noise exposure were quantified by ELISA or immunofluorescence staining. Our results illustrated a permanent moderate-to-severe degree of hearing loss, an early but transient increase in serum corticosterone levels, and time-dependent dynamic alterations in microglial activation status and hippocampal neurogenesis, which both present an early but transient change and a late but enduring change. These findings provide evidence that both the stress response and hearing loss contribute to the dynamic alterations of microglia and hippocampal neurogenesis following noise exposure; moreover, noise-induced permanent hearing loss rather than noise-induced transient stress is more likely to be responsible for perpetuating the neurodegenerative process associated with many neurological diseases.