Low-intensity pulsed ultrasound delays the progression of osteoarthritis by regulating the YAP-RIPK1-NF-κB axis and influencing autophagy.

BACKGROUND: Osteoarthritis (OA) is a degenerative disease characterized by chronic inflammation of the joint. As the disease progresses, patients will gradually develop symptoms such as pain, physical limitations and even disability. The risk factors for OA include genetics, gender, trauma, obesity, and age. Unfortunately, due to limited understanding of its pathological mechanism, there are currently no effective drugs or treatments to suspend the progression of osteoarthritis. In recent years, some studies found that low-intensity pulsed ultrasound (LIPUS) may have a positive effect on osteoarthritis. Nonetheless, the exact mechanism by which LIPUS affects osteoarthritis remains unknown. It is valuable to explore the specific mechanism of LIPUS in the treatment of OA. METHODS: In this study, we validated the potential therapeutic effect of LIPUS on osteoarthritis by regulating the YAP-RIPK1-NF-κB axis at both cellular and animal levels. To verify the effect of YAP on OA, the expression of YAP was knocked down or overexpressed by siRNA and plasmid in chondrocytes and adeno-associated virus was injected into the knee joint of rats. The effect of LIPUS was investigated in inflammation chondrocytes induced by IL-1ß and in the post-traumatic OA model. RESULTS: In this study, we observed that YAP plays an important role in the development of osteoarthritis and knocking down of YAP significantly inhibited the inflammation and alleviated cartilage degeneration. We also demonstrated that the expression of YAP was increased in osteoarthritis chondrocytes and YAP could interact with RIPK1, thereby regulating the NF-κB signal pathway and influencing inflammation. Moreover, we also discovered that LIPUS decreased the expression of YAP by restoring the impaired autophagy capacity and inhibiting the binding between YAP and RIPK1, thereby delaying the progression of osteoarthritis. Animal experiment showed that LIPUS could inhibit cartilage degeneration and alleviate the progression of OA. CONCLUSIONS: These results showed that LIPUS is effective in inhibiting inflammation and cartilage degeneration and alleviate the progression of OA. As a result, our results provide new insight of mechanism by which LIPUS delays the development of osteoarthritis, offering a novel therapeutic regimen for osteoarthritis.

Incidence and risk factors of urinary tract infection in hospitalized patients with spinal cord injury in a hospital of China.

Urinary tract infection (UTI) caused by spinal cord injury (SCI) can have significant morbidity. There is currently a lack of relevant data in China. This study explores incidence and risk factors of UTI in hospitalized patients with SCI in China, and will help healthcare professionals to make informed clinical decisions to reduce the incidence of UTI. This retrospective study analyzed the medical records of patients with SCI who were hospitalized at three campuses of a hospital in central China between August 2014 and August 2023. The files of patients with SCI were reviewed for demographics and clinical characteristics. Logistic regression analysis was performed to identify risk factors associated with UTI. A total of 538 patients were included in this study. The incidence of UTI was 49.8%. Sex, hypoproteinemia, urinary incontinence, bladder irrigation, timing of rehabilitation, duration of indwelling urinary catheter were risk factors of UTI. The implementation of specific preventive measures is anticipated to result in a decrease in the occurrence of UTI among individuals with SCI, consequently enhancing their overall quality of life and prognosis.

Exercise-induced modulation of myokine irisin on muscle-bone unit in the rat model of post-traumatic osteoarthritis.

BACKGROUND AND AIM: Post-traumatic osteoarthritis (PTOA) is a subtype of osteoarthritis (OA). Exercise may produce and release the myokine irisin through muscle fiber contraction. However, the effect of exercise-promoted irisin production on the internal interactions of the muscle-bone unit in PTOA studies remains unclear. METHODS: Eighteen 8-week-old Sprague-Dawley (SD) rats were randomly divided into three groups: Sham/sedentary (Sham/Sed), PTOA/sedentary (PTOA/Sed), and PTOA/treadmill-walking (PTOA/TW). The PTOA model was established by transection of anterior cruciate ligament (ACLT) and destabilization of medial meniscus (DMM). After 4 weeks of modeling, the PTOA/TW group underwent treadmill exercise (15 m/min, 30 min/d, 5 d/ week, 8 weeks), and the other two groups were free to move in the cage. Evaluation and correlation analysis of muscle, cartilage, subchondral bone and serological indexes were performed after euthanasia. RESULTS: Eight weeks of treadmill exercise effectively alleviated the trauma-induced OA phenotype, thereby maintaining cartilage and subchondral bone integrity in PTOA, and reducing quadriceps atrophy and myofibril degradation. Exercise reversed the down-regulated expression of peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) and fibronectin type III structural domain protein 5 (FNDC5) in muscle tissue of PTOA rats, and increased the blood irisin level, and the irisin level was positively correlated with the expression of PGC-1α and FNDC5. In addition, correlation analysis showed that irisin metabolism level was strongly negatively correlated with Osteoarthritis Research Society International (OARSI) and subchondral bone loss, indicating that irisin may be involved in cartilage biology and PTOA-related changes in cartilage and subchondral bone. Moreover, the metabolic level of irisin was strongly negatively correlated with muscle fiber cross-sectional area (CSA), Atrogin-1 and muscle ring-finger protein-1(MuRF-1) expression, suggesting that irisin may alleviate muscle atrophy through autocrine action. CONCLUSION: Treadmill exercise can alleviate the atrophy and degeneration of muscle fibers in PTOA rats, reduce the degradation of muscle fibrin, promote the expression of serum irisin, and alleviate the degeneration of articular cartilage and subchondral bone loss in PTOA rats. These results indicate that treadmill exercise can affect the process of PTOA by promoting the expression of myokine irisin in rat muscle-bone unit.

P21 resists ferroptosis in osteoarthritic chondrocytes by regulating GPX4 protein stability.

Ferroptosis is involved in the pathogenesis of osteoarthritis (OA) while suppression of chondrocyte ferroptosis has a beneficial effect on OA. However, the molecular mechanism of ferroptosis in OA remains to be elucidated. P21, an indicator of aging, has been reported to inhibit ferroptosis, but the relationship between P21 and ferroptosis in OA remains unclear. Here, we aimed to investigate the expression and function of P21 in OA chondrocytes, and the involvement of P21 in the regulation of ferroptosis in chondrocytes. First, we demonstrated that high P21 expression was observed in the cartilage from OA patients and destabilized medial meniscus (DMM) mice, and in osteoarthritic chondrocytes induced by IL-1ß, FAC and erastin. P21 knockdown exacerbated the reduction of Col2a1 and promoted the upregulation of MMP13 in osteoarthritic chondrocytes. Meanwhile, P21 knockdown exacerbated cartilage degradation in DMM-induced OA mouse models and decreased GPX4 expression in vivo. Furthermore, P21 knockdown sensitized chondrocytes to ferroptosis induced by erastin, which was closely associated with the accumulation of lipid peroxides. In mechanism, we demonstrated that P21 regulated the stability of GPX4 protein, and the regulation was independent of NRF2. Meanwhile, we found that P21 significantly affected the recruitment of GPX4 to linear ubiquitin chain assembly complex (LUBAC) and regulated the level of M1-linked ubiquitination of GPX4. Overall, our results suggest that P21 plays an essential anti-ferroptosis role in OA by regulating the stability of GPX4.

The Pivotal Role of Nrf2 Signal Axis in Intervertebral Disc Degeneration.

Intervertebral disc degeneration (IDD) is considered as a dominant contributor to low back pain (LBP), causing severe pain, limited range of lumbar motion, physical dysfunction, and restriction of social activity. However, the specific pathological mechanisms underlying IDD remain elusive, and effective strategies to delay the pathogenesis of IDD are still unclear and limited. In recent years, some studies have found that nuclear factor erythroid 2-related factor 2 (Nrf2), an important antioxidant transcription factor, may play crucial roles in the pathogenesis and progression of age-related diseases including IDD. Nrf2 can maintain redox homeostasis and protecting nucleus pulposus (NP) cells against oxidative stress, inflammatory response, extracellular matrix (ECM) catabolism, cell senescence and cell death involving in the progression of IDD. In this review, we aim to systematically describe the vital roles and pathological mechanism of Nrf2 signaling axis in the pathogenesis of IDD, which may put forward potential therapeutic strategies for the prevention and treatment of IDD by targeting Nrf2.

Moderate mechanical strain and exercise reduce inflammation and excessive autophagy in osteoarthritis by downregulating mitofusin 2.

AIMS: The major pathological mechanisms of osteoarthritis (OA) progression include inflammation, autophagy, and apoptosis, etc. Moderate mechanical strain and exercise effectively improve chondrocyte degeneration by reducing these adverse factors. Mitofusin 2 (MFN2) is a crucial regulatory factor associated with inflammation, autophagy and apoptosis, and its expression is regulated by exercise. This study aims to elucidate the effects of moderate mechanical strain and exercise on MFN2 expression and its influence on OA progression. MAIN METHODS: Destabilization of the medial meniscus (DMM) surgery was performed on rats to induce an OA rat model. Subsequently, adeno-associated virus (overexpression/knockdown) intra-articular injection or moderate treadmill exercise was administered to evaluate the effects of these treatments on MFN2 expression and OA progression. Overexpressed plasmids and siRNA vectors were used to regulate MFN2 expression in chondrocytes. An inflammatory degeneration cell model was generated by IL-1ß stimulation. Moderate mechanical strain was applied to MFN2-overexpressing cells to explore their interactions. KEY FINDINGS: MFN2 overexpression aggravated inflammation by activating the NF-κB and P38 pathways and induced excessive autophagy by inhibiting the PI3K/AKT/mTOR pathway, thereby causing chondrocyte apoptosis and metabolic disorder. Moderate mechanical strain partially reversed these adverse effects. In the DMM rat model, MFN2 overexpression in articular cartilage exacerbated OA progression, whereas MFN2 knockdown and treadmill exercise alleviated cartilage degeneration, inflammation, and mechanical pain. SIGNIFICANCE: MFN2 is a critical factor mediating the association between inflammation and excessive autophagy in OA progression. Moderate mechanical strain and treadmill exercise may improve OA through downregulating MFN2 expression. This study may provide a theoretical basis for exercise therapy in OA treatment.

Effect of moderate exercise on osteoarthritis.

Osteoarthritis (OA) is a chronic degenerative disease, which can cause a series of symptoms including pain and functional limitation, thus severely decreasing quality of life. OA pathogenesis can be categorized into four levels, including risk factors, potential mechanisms, intraarticular degeneration phenotype, and substantive histological changes. Moderate exercise can alleviate OA at all levels of pathogenesis, while excessive exercise may have adverse effects. Based on rat-related original research, the parameters of moderate exercise and the effect of improving osteoarthritis have been comprehensively summarized. Based on the extensive randomized controlled trial studies, results show various moderate exercises can improve the symptom and prognosis of OA in clinical settings. This review gives an overview of the pathogenesis of OA and the mechanisms as well as clinical examples of moderate exercise treatment, aimed at providing rationale and evidence for moderate exercise in the treatment of OA to facilitate the provision of appropriate exercise therapy for OA patients.

Exercise modifies the disease-relevant gut microbial shifts in post-traumatic osteoarthritis rats.

AIMS: Post-traumatic osteoarthritis (PTOA) is a subset of osteoarthritis (OA). The gut microbiome is shown to be involved in OA. However, the effect of exercise on gut microbiome in PTOA remains elusive. METHODS: A total of 18 eight-week Sprague-Dawley rats were assigned into three groups: Sham/sedentary (Sham/Sed), PTOA/sedentary (PTOA/Sed), and PTOA/treadmill-walking (PTOA/TW). PTOA model was induced by transection of the anterior cruciate ligament (ACLT) and the destabilization of the medial meniscus (DMM). Treadmill-walking (15 m/min, 30 min/d, five days/week for eight weeks) was employed in the PTOA/TW group. The response of cartilage, subchondral bone, serology, and gut microbiome and their correlations were assessed. RESULTS: Eight-week treadmill-walking was effective at maintaining the integrity of cartilage-subchondral bone unit and reducing the elevated systematic inflammation factors and microbiome-derived metabolites. Furthermore, 16S ribosomal ribonucleic acid (rRNA) sequencing showed disease-relevant microbial shifts in PTOA animals, characterized by the decreased abundance of phylum TM7 and the increase of phylum Fusobacteria. At the genus level, the abundance of Lactobacillus, Turicibacter, Adlercreutzia, and Cetobacterium were increased in the PTOA animals, while the increase of Adlercreutzia and Cetobacterium was weakened as a response to exercise. The correlation analysis showed that genus Lactobacillus and Adlercreutzia were correlated to the structural OA phenotypes, while phylum Fusobacteria and genus Cetobacterium may contribute to the effects of exercise on the diminishment of serological inflammatory factors. CONCLUSION: Exercise is effective at maintaining the integrity of cartilage-subchondral bone unit, and the exercise-induced modification of disease-relevant microbial shifts is potentially involved in the mechanisms of exercise-induced amelioration of PTOA. Cite this article: Bone Joint Res 2022;11(4):214-225.

Whole Transcriptome Mapping Identifies an Immune- and Metabolism-Related Non-coding RNA Landscape Remodeled by Mechanical Stress in IL-1ß-Induced Rat OA-like Chondrocytes.

Background: Osteoarthritis (OA) is a common degenerative joint disease. The aims of this study are to explore the effects of mechanical stress on whole transcriptome landscape and to identify a non-coding transcriptome signature of mechanical stress. Methods: Next-generation RNA sequencing (RNA-seq) was performed on IL-1ß-induced OA-like chondrocytes stimulated by mechanical stress. Integrated bioinformatics analysis was performed and further verified by experimental validations. Results: A total of 5,022 differentially expressed mRNAs (DEMs), 88 differentially expressed miRNAs (DEMIs), 1,259 differentially expressed lncRNAs (DELs), and 393 differentially expressed circRNAs (DECs) were identified as the transcriptome response to mechanical stress. The functional annotation of the DEMs revealed the effects of mechanical stress on chondrocyte biology, ranging from cell fate, metabolism, and motility to endocrine, immune response, and signaling transduction. Among the DELs, ∼92.6% were identified as the novel lncRNAs. According to the co-expressing DEMs potentially regulated by the responsive DELs, we found that these DELs were involved in the modification of immune and metabolism. Moreover, immune- and metabolism-relevant DELs exhibited a notable involvement in the competing endogenous RNA (ceRNA) regulation networks. Silencing lncRNA TCONS_00029778 attenuated cellular senescence induced by mechanical stress. Moreover, the expression of Cd80 was elevated by mechanical stress, which was rescued by silencing TCONS_00029778. Conclusion: The transcriptome landscape of IL-1ß-induced OA-like chondrocytes was remarkably remodeled by mechanical stress. This study identified an immune- and metabolism-related ncRNA transcriptome signature responsive to mechanical stress and provides an insight of ncRNAs into chondrocyte biology and OA.

The gut microbiota in osteoarthritis: where do we stand and what can we do?

Osteoarthritis (OA) is one of the most frequent musculoskeletal diseases characterized by degeneration of articular cartilage, subchondral bone remodeling, and synovial membrane inflammation, which is a leading cause of global disability, morbidity, and decreased quality of life. Interpreting the potential mechanisms of OA pathogenesis is essential for developing novel prevention and disease-modifying therapeutic interventions. Gut microbiota is responsible for a series of metabolic, immunological, and structural and neurological functions, potentially elucidating the heterogeneity of OA phenotypes and individual features. In this narrative review, we summarized research evidence supporting the hypothesis of a "gut-joint axis" and the interaction between gut microbiota and the OA-relevant factors, including age, gender, genetics, metabolism, central nervous system, and joint injury, elucidating the underlying mechanisms of this intricate interaction. In the context, we also speculated the promising manipulation of gut microbiota in OA management, such as exercise and fecal microbiota transplantation (FMT), highlighting the clinical values of gut microbiota. Additionally, future research directions, such as more convincing studies by the interventions of gut microbiota, the gene regulation of host contributing to or attributed to the specific phenotypes of gut microbiota related to OA, and the relevance of distinct cell subgroups to gut microbiota, are expected. Moreover, gut microbiota is also the potential biomarker related to inflammation and gut dysbiosis that is able to predict OA progression and monitor the efficacy of therapeutic intervention.