Progression Of Osteoarthritis Research Articles

Biomechanical impact of progressive meniscal extrusion on the knee joint: a finite element analysis.

While measuring meniscal extrusion quantitatively is an early risk factor for knee osteoarthritis (KOA), the biomechanics involved in this process are not well understood. This study aimed to investigate the effects of varying degrees of medial and lateral meniscal extrusion and their material softening on knee osteoarthritis progression. Finite element analysis (FEA) was utilized to simulate varying degrees of meniscal extrusion (1-5mm) in 72 knee joint models, representing progressive meniscal degeneration and material softening due to injury. Changes in von Mises stress of the cartilage and menisci and the load distribution on the tibial plateau's meniscus and cartilage were studied under balanced standing posture in both healthy and injured knees, and statistical analysis was performed using Spearman correlation. Compared to healthy knees, peak stress in medial compartment tissues increased by over 40% with 4mm of medial meniscus extrusion, and in lateral compartment tissues with 2mm of lateral meniscus extrusion. Meniscus extrusion reduced the contact load between the meniscus and femoral cartilage but increased it between the tibial and femoral cartilages, with a maximum increase up to fivefold. Spearman correlation analysis indicated that meniscal extrusion significantly affected peak stress and contact loads in the respective knee compartment (p < 0.001), with a lesser impact on the opposite compartment. Notably, medial meniscal extrusion also significantly increased peak stress in the lateral tibial cartilage (p < 0.05). The quantitative analysis revealed that meniscal extrusion significantly affected the biomechanics of soft tissues within the same compartment, with limited impact on the opposite side. Specifically, Medial extrusion beyond 4mm significantly affected the biomechanics of the medial compartment, while lateral extrusion over 2mm had a similar impact on the lateral compartment. Meniscal softening, without altering joint contact characteristics, primarily affected the biomechanics of the meniscus itself, with minimal impact on other soft tissues.

Investigation of GPM6B as a novel therapeutic target in Osteoarthritis.

Osteoarthritis (OA) is the most common motor system disease in older people, characterized by a high incidence and significant social and economic burden. Women have a higher risk of OA, more severe clinical symptoms, and a higher rate of disabilities than men. However, the pathogenesis of OA remains unclear. Therefore, we screened for differentially expressed genes (DEGs) in OA patients of different sex and searched for new targets that may be involved in regulating the development of OA. The study compared the expression of DEGs in synovial fluid exosomes between male and female patients with OA through RNA sequencing combined with bioinformatics analysis using public data. To evaluate the screened DEGs, synovial tissue and fluid samples were obtained from patients with OA who underwent joint replacement surgery. SiRNA-mediated knockdown in vitro experiments were performed to investigate the role of glycoprotein membrane 6B (GPM6B). Meanwhile, GPM6B gene knockout mice were used to assess the in vivo pathological roles of GPM6B in OA. The results revealed that GPM6B is a potential target associated with OA. Immunofluorescence staining demonstrated that GPM6B was expressed in fibroblast-like synoviocytes (FLS) and macrophage-like synoviocytes in patients with OA. In vitro experiments confirmed that GPM6B knockdown can reduce the expression of inflammatory factors in primary FLS from patients with OA. Under inflammatory conditions, GPM6B knockdown can reduce the expression of matrix metalloproteinases as well as proliferation of FLS. In addition, using a destabilization of the medial meniscus-induced OA model, we revealed that GPM6B is associated with OA progression in mice. Thus, we provided evidence that GPM6B act as a new target associated with OA.

MiR203a-3p as a potential biomarker for synovial pathology associated with osteoarthritis: a pilot study.

Osteoarthritis (OA) is a degenerative musculoskeletal disease that significantly impacts the quality of life. Currently, no validated biomarkers for early detection of OA are defined. The possibility of discovering OA biomarkers is the focus of this study. Human primary OA synovial cells (SVs), isolated from discarded joint tissue of patients with Kellgren & Lawrence score (KL) < 3, (mild/moderate) and KL ≥ 3 (severe), were characterized by FACS analysis. Through qRT-PCR and ELISA assays the inflammation, fibrosis status and the different miRNAs expression has been investigated. The role of miR-203a-3p and its precursors were evaluated through gain and loss of function study, IL-1β synoviocytes treatments and methylation analysis of miR203a promoter. The qRT-PCR analysis of miR203a-3p and pre-miR203a on plasma (isolated 24h before surgery, 3days and 1month after surgery) and synovial fluid (recovered during the surgery) were done to support our in vitro data. MiR203a-3p expression is inversely correlated with the aggressiveness of OA, modulating the expression of epithelial to mesenchymal transition (EMT) and pro-inflammatory factors, as well as regulating the expression of secreted protein acidic and rich in cysteine (SPARC) mRNA. Methylation analysis of the miR203a promoter and SVs IL-1β treatment's highlighted the impact of inflammation on miR203a-3p and pre-miR203a expression; as confirmed by both miRNAs detection in biological fluids derived from patients with severe OA. Our preliminary results suggest that miR-203a-3p might be a potential candidate for staging OA progression and a new protective/predictive biomarker for synovial OA degeneration. Further studies are needed to validate its potential impact on OA.

Effects of iron overload in human joint tissue explant cultures and animal models.

Osteoarthritis (OA) is a prevalent degenerative joint disease affecting over 530 million individuals worldwide. Recent studies suggest a potential link between iron overload, a condition characterised by the excessive accumulation of iron in the body, and the onset of OA. Iron is essential for various biological processes, and any disruption in its homeostasis can trigger significant health effects, including OA. This study aimed to elucidate the effects of excess iron on joint tissue and the underlying mechanisms associated with excess iron and OA development. Human articular cartilage (n = 6) and synovium (n = 4) were collected from patients who underwent total knee arthroplasty. Cartilage and synovium explants were incubated with a gradually increasing concentration of ferric ammonium citrate for 3days respectively. The effects of iron homeostasis in tissue explants were analysed using a Laser Ablation Inductively Coupled Plasma Mass Spectrometry (LA-ICP-MS). To further study the effects of iron excess on OA initiation and development, male 3-week-old Hfe-/- and 5-week-old Tfr2-/- mice, animal models of hereditary haemochromatosis were established. Littermate wild-type mice were fed a high-iron diet to induce dietary overload. All animals were sacrificed at 8weeks of age, and knee joints were harvested for histological analysis. The LA-ICP-MS analysis unveiled changes in the elemental composition related to iron metabolism, which included alterations in FTH1, FPN1, and HAMP within iron(III)-treated cartilage explants. While chondrocyte viability remained stable under different iron concentrations, ex vivo treatment with a high concentration of Fe3+ increased the catabolic gene expression of MMP13. Similar alterations were observed in the synovium, with added increases in GAG content and inflammation markers. In vivo studies further supported the role of iron overload in OA development as evidenced by spontaneous OA symptoms, proteoglycan loss, increased Mankin scores, synovial thickening, and enhanced immunohistochemical expression of MMP13, ADAMTS5, and P21 in Hfe-/-, Tfr2-/-, and diet-induced iron overload mouse models. Our findings elucidate the specific pathways through which excess iron accelerates OA progression and highlights potential targets for therapeutic intervention aimed at modulating iron levels to mitigate OA symptoms. KEY MESSAGES: Iron overload alters joint iron metabolism, increasing OA markers in cartilage and synovium. High iron levels in mice accelerate OA, highlighting genetic and dietary impacts. Excess iron prompts chondrocyte iron storage response, signalling potential OA pathways. Iron dysregulation linked to increased cartilage degradation and synovial inflammation. Our findings support targeted therapies for OA based on iron modulation strategies.

Innate Immunity and Synovitis: Key Players in Osteoarthritis Progression

Osteoarthritis (OA) is a chronic progressive disease of the joint. Although representing the most frequent cause of disability in the elderly, OA remains partly obscure in its pathogenic mechanisms and is still the orphan of resolutive therapies. The concept of what was once considered a “wear and tear” of articular cartilage is now that of an inflammation-related disease that affects over time the whole joint. The attention is increasingly focused on the synovium. Even from the earliest clinical stages, synovial inflammation (or synovitis) is a crucial factor involved in OA progression and a major player in pain onset. The release of inflammatory molecules in the synovium mediates disease progression and worsening of clinical features. The activation of synovial tissue-resident cells recalls innate immunity cells from the bloodstream, creating a proinflammatory milieu that fuels and maintains a damaging condition of low-grade inflammation in the joint. In such a context, cellular and molecular inflammatory behaviors in the synovium could be the primum movens of the structural and functional alterations of the whole joint. This paper focuses on and discusses the involvement of innate immunity cells in synovitis and their role in the progression of OA.

Development and accuracy of an artificial intelligence model for predicting the progression of hip osteoarthritis using plain radiographs and clinical data: a retrospective study

BackgroundPredicting the progression of hip osteoarthritis (OA) remains challenging, and no reliable predictive method has been established. This study aimed to develop an artificial intelligence (AI) model to predict hip OA progression via plain radiographs and patient data and to determine its accuracy.MethodsThis retrospective study utilized anteroposterior pelvic radiographs of consecutive patients with hip OA who underwent primary unilateral total hip arthroplasty. Radiographs diagnosed with Kellgren–Lawrence (KL) grade 0–2 were extracted from 361 patients and 1697 images. This AI model was developed to predict whether OA would progress from KL grade 0–2 to KL grade ≥ 3 within n years (n = 3, 4, 5). A gradient-boosting decision tree approach was utilized according to feature extractions obtained by a convolutional neural network from radiographs and patient data (height, body weight, sex, age, and KL grade given by an orthopedic surgeon) with five-fold cross-validation. The model performance was assessed using accuracy, specificity, sensitivity, and the area under the receiver operating characteristic curve (AUC).ResultsThe mean accuracy, specificity, sensitivity, and AUC of our prediction model were, respectively, 81.8%, 88.0%, 66.7%, and 0.836 for 3 years; 79.8%, 85.0%, 71.6%, and 0.836 for 4 years; and 78.5%, 80.4%, 76.9%, and 0.846 for 5 years.ConclusionsThe proposed AI model performed adequately in predicting hip OA progression and may be clinically applicable with additional datasets and validation.

RIP1 inhibition reduces chondrocyte apoptosis through downregulating nuclear factor-kappa B signaling in a mouse osteoarthritis model.

Excessive chondrocyte death is a critical player in the process of osteoarthritis (OA). The present study was aimed to study the role of receptor-interacting serine/threonine kinase (RIP) 1-mediated signaling for programmed cell death in OA. In the present study, RIP1 protein expression was evaluated in mouse OA cartilage and cultured primary murine chondrocytes exposed to tumor necrosis factor-alpha (TNF-α). Protein expression involved in necroptosis and apoptosis and chondrocyte-derived extracellular matrix were examined. Inhibition of RIP1 was conducted using the RNAi technique and pharmacological inhibition. Western blot, immunohistochemistry, and immunofluorescence examination were applied. The protein presence of RIP1, but not RIP3, was increased in the mouse OA tissue and cultured chondrocytes exposed to TNF-α. Knockdown of RIP1 increased protein expression of collagen II and sex-determining region Y-box transcription factor 9, and reduced protein expression of matrix metallopeptidases 13 and a disintegrin and metalloproteinase with thrombospondin motifs 5. Inhibition of RIP1 reduced the phosphorylated NF-κB signals, decreased cell apoptosis, and restored extracellular matrix expression in cultured chondrocytes. Both RNAi and pharmacological inhibition of RIP1 decelerated the progress of OA in mice. RIP1 regulates chondrocyte apoptosis through NF-κB signaling. Inhibition of RIP1 provides a novel therapeutic approach for OA therapy.

Inhibition of Slit3/Robo1 signaling alleviates osteoarthritis in mice by reducing abnormal H-type vessel formation in subchondral bone

Background The aberrant H-type vessel formation was found to be intimately linked to subchondral bone remodeling during osteoarthritis (OA) development. Herein, we investigated the role and mechanism of osteoblast-secreted slit guidance ligand 3 (Slit3) in H-type vessel formation during OA progression. Methods Slit3 protein levels in subchondral bone samples of OA patients were detected. The isolated osteoblasts were transfected with Slit3 overexpression or knockdown plasmids, and their conditioned medium was cultured with endothelial progenitor cells (EPCs). The migration, tube formation, VEGF, and H-type vessel marker protein CD31 and endomucin (EMCN) levels in EPCs were accessed. The interactions between Slit3 and roundabout (Robo) family members were validated by Co-IP assay. Besides, whether the Slit3/Robo signaling affects the transforming growth factor β1 (TGF-β1)/SMADs pathway was determined. Additionally, sh-Slit3 was injected into OA mice, followed by the detection of articular cartilage degradation, subchondral bone remodeling, and H-type vessel formation. Results Slit3 was upregulated in subchondral bone tissues of OA patients. Slit3 overexpression in osteoblasts intensified the migration and H-type vessel formation of EPCs, while Slit3 knockdown showed the opposite results. Slit3 overexpression enhanced Robo1 protein level. Robo1 knockdown abrogated Slit3-mediated migration and H-type vessel formation in EPCs. Slit3 activated the TGF-β1/SMADs pathway in EPCs, which might be associated with H-type vessel formation in EPCs. Additionally, Slit3 silencing restrained articular cartilage degradation, aberrant subchondral bone formation, and H-type vessel formation in OA mice. Conclusion Inhibition of Slit3/Robo1 signaling alleviates osteoarthritis in mice by reducing abnormal H-type vessel formation in the subchondral bone.

Potential of diacerein in combination with aerobic exercise in comprehensive treatment of knee osteoarthritis

BACKGROUND: Knee osteoarthritis is a common degenerative disease characterized by cartilage destruction and inflammatory changes in the synovial membrane. Obesity and metabolic syndrome are significant risk factors that exacerbate inflammatory processes and contribute to the progression of osteoarthritis. Modern treatment methods include both pharmacological agents and non-pharmacological approaches such as aerobic exercise. AIM: To evaluate and compare the effectiveness of diacerein combined with aerobic physical activity (Nordic walking) in the comprehensive treatment of knee osteoarthritis. MATERIALS AND METHODS: The study involved 65 patients aged 45 to 70 years with knee osteoarthritis and metabolic syndrome. The participants were divided into three groups. The first group received diacerein (Artrocare); the second group was engaged in Nordic walking; the third group – a combination of these methods. The visual analog scale of pain, Western Ontario and McMaster University Osteoarthritis (WOMAC) index, quality of life (Short Form-36), glycated hemoglobin levels, and other biochemical parameters were assessed over 16 weeks of observation. RESULTS: The study demonstrated statistically significant reductions in pain levels and improvements in functional parameters in all the groups. The greatest improvements were observed in the group receiving combined therapy. The method showed a significantly positive impact on quality of life and reduced the need for analgesics in comorbid patients. Additionally, the patients with metabolic syndrome showed improved biochemical parameters with the combination of diacerein and Nordic walking. CONCLUSIONS: The combined use of diacerein and Nordic walking is an effective and safe method for treating knee osteoarthritis, particularly in patients with metabolic syndrome. This approach significantly reduces pain, improves joint function, and enhances overall quality patient’s life.

The Conversion of Unicompartmental Knee Arthroplasty to Total Knee Arthroplasty with Non-CT-Based Robotic Assistance: A Novel Surgical Technique and Case Series.

Robotic-assisted devices help provide precise component positioning in conversion of unicompartmental knee arthroplasty (UKA) to total knee arthroplasty (TKA). A few studies offer surgical techniques for computed tomography (CT) based robotic-assisted conversion of UKA to TKA; however, no studies to date detail this procedure utilizing a non-CT-based robotic-assisted device. This article introduces a novel technique employing a non-CT-based robotic-assisted device (ROSA Knee System, Zimmer Biomet, Warsaw, IN) for converting UKA to TKA with a focus on its efficacy in gap balancing. We present three patients (ages 46-66 years) who were evaluated for conversion of UKA to TKA for aseptic loosening, stress fracture, and progressive osteoarthritis. Each patient underwent robotic-assisted conversion to TKA. Postoperative assessments at 6 months revealed improved pain, function, and radiographic stability. Preoperative planning included biplanar long leg radiographs to determine the anatomic and mechanical axis of the leg. After arthrotomy with a standard medial parapatellar approach, infrared reflectors were pinned into the femur and tibia, followed by topographical mapping of the knee with the UKA in situ. The intraoperative software was utilized to evaluate flexion and extension balancing and plan bony resections. Then, the robotic arm guided placement of the femoral and tibial guide pins and the UKA components were removed. After bony resection of the distal femur and proximal tibia, the intraoperative software was used to reassess the extension gap, and plan posterior condylar resection to have the flexion gap match the extension gap. The use of a non-CT-based robotic-assisted device in conversion of UKA to TKA is a novel technique and a good option for surgeons familiar with robotic-assisted arthroplasty, resulting in excellent outcomes at 6 months.

Therapeutic Controlled Release Strategies for Human Osteoarthritis.

Osteoarthritis is a progressive, irreversible debilitating whole joint disease that affects millions of people worldwide. Despite the availability of various options (non-pharmacological and pharmacological treatments and therapy, orthobiologics, and surgical interventions), none of them can definitively cure osteoarthritis in patients. Strategies based on the controlled release of therapeutic compounds via biocompatible materials may provide powerful tools to enhance the spatiotemporal delivery, expression, and activities of the candidate agents as a means to durably manage the pathological progression of osteoarthritis in the affected joints upon convenient intra-articular (injectable) delivery while reducing their clearance, dissemination, or side effects. The goal of this review is to describe the current knowledge and advancements of controlled release to treat osteoarthritis, from basic principles to applications in vivo using therapeutic recombinant molecules and drugs and more innovatively gene sequences, providing a degree of confidence to manage the disease in patients in a close future.

Association between thyroid function and osteoarthritis: a population-based cohort study

ObjectivesPrevious genetic and animal studies indicated a causal role of thyroid hormones in osteoarthritis (OA), which has not been observed in the general population. We aimed to investigate whether thyroid-stimulating hormone (TSH) and free thyroxine (FT4) were associated with hand, hip, or knee OA. MethodsParticipants from the Rotterdam Study with baseline TSH, FT4, and joint radiographs were included. We used multivariable regression models to investigate the association of thyroid function with the prevalence, severity, incidence, and progression of OA. We conducted stratified analyses by sex, age, body mass index (BMI) and weight-bearing physical activity. ResultsAmong 9054 participants included (mean age 65 years, 56.3% women), higher FT4 concentrations were associated with an increased risk of prevalent knee OA (OR 1.04 per pmol/L, 95% CI 1.01-1.06, corresponding to an OR of 1.62 across the reference range [i.e., 14pmol/L changes] of FT4) and more severe knee OA. There was a positive association between FT4 and overall progression of knee OA (OR 1.03 per pmol/L, 1.00-1.07). No association of TSH with hand, hip, or knee OA was identified. Stratified analysis revealed an association between FT4 and prevalent knee OA among individuals with BMI≥30 kg/m2 (OR 1.05 per pmol/L, 1.01-1.08) and those with high levels of weight-bearing physical activity (OR 1.05 per pmol/L, 1.01-1.10). ConclusionsOur study indicated that higher FT4 concentrations may increase the risk of knee OA. This association might be greater in individuals with extra joint loading, such as those with obesity.

Clinical efficacy of arthroscopic single-bundle versus double-bundle reconstruction of the posterior cruciate ligament: a retrospective study.

To compare the functional and clinical outcomes of knee joints in patients over a 10-year period following posterior cruciate ligament (PCL) reconstruction with single-bundle versus double-bundle. Patients who underwent PCL reconstruction were retrospectively analyzed. Based on the surgical approach, they were divided into the single-bundle reconstruction group and the double-bundle reconstruction group. Preoperative and postoperative Lysholm score, International Knee Documentation Committee (IKCD) score, and Tegner activity score were evaluated, and the stability of the joints was assessed using KT-2000 arthrometer. Radiographs were taken at the final follow-up to evaluate the progression of osteoarthritis. A total of 61 patients were included in the analysis: 26 in the double-bundle group and 35 in the single-bundle group. Baseline data were comparable between the two groups (P > 0.05). There were no significant differences between the two groups in preoperative Lysholm, IKDC score, and Tegner activity score. Postoperatively, these scores were significantly higher at two and ten years follow-up (P < 0.05), with no significant difference between the groups (P > 0.05). There was no significant difference in side-to-side differences (SSD) at 30° and 90° of knee flexion preoperatively between the groups (P > 0.05). Postoperatively, SSD decreased significantly at the two year and ten year follow-up (P < 0.05), with no significant difference between the groups (P > 0.05). For osteoarthritis progression, there were four cases of Kellgren-Lawrence grade ≥ II in the single-bundle group and three cases in the double-bundle group, with no significant difference in the progression of osteoarthritis between the groups (P > 0.05). Both single-bundle and double-bundle reconstructions for PCL result in good joint stability and mobility, with similar progression of osteoarthritis in long-term follow-up. Level III.

Understanding the role of machine learning in predicting progression of osteoarthritis.

Machine learning (ML), a branch of artificial intelligence that uses algorithms to learn from data and make predictions, offers a pathway towards more personalized and tailored surgical treatments. This approach is particularly relevant to prevalent joint diseases such as osteoarthritis (OA). In contrast to end-stage disease, where joint arthroplasty provides excellent results, early stages of OA currently lack effective therapies to halt or reverse progression. Accurate prediction of OA progression is crucial if timely interventions are to be developed, to enhance patient care and optimize the design of clinical trials. A systematic review was conducted in accordance with PRISMA guidelines. We searched MEDLINE and Embase on 5 May 2024 for studies utilizing ML to predict OA progression. Titles and abstracts were independently screened, followed by full-text reviews for studies that met the eligibility criteria. Key information was extracted and synthesized for analysis, including types of data (such as clinical, radiological, or biochemical), definitions of OA progression, ML algorithms, validation methods, and outcome measures. Out of 1,160 studies initially identified, 39 were included. Most studies (85%) were published between 2020 and 2024, with 82% using publicly available datasets, primarily the Osteoarthritis Initiative. ML methods were predominantly supervised, with significant variability in the definitions of OA progression: most studies focused on structural changes (59%), while fewer addressed pain progression or both. Deep learning was used in 44% of studies, while automated ML was used in 5%. There was a lack of standardization in evaluation metrics and limited external validation. Interpretability was explored in 54% of studies, primarily using SHapley Additive exPlanations. Our systematic review demonstrates the feasibility of ML models in predicting OA progression, but also uncovers critical limitations that currently restrict their clinical applicability. Future priorities should include diversifying data sources, standardizing outcome measures, enforcing rigorous validation, and integrating more sophisticated algorithms. This paradigm shift from predictive modelling to actionable clinical tools has the potential to transform patient care and disease management in orthopaedic practice.

TRPM2-mediated feed-forward loop promotes chondrocyte damage in osteoarthritis via calcium-cGAS-STING-NF-κB pathway

IntroductionsOsteoarthritis (OA) is a significant contributor to disability in the elderly population. However, current therapeutic options are limited. The transient receptor potential melastatin 2 (TRPM2) is involved in a range of disease processes, yet its role in OA remains unclear. ObjectivesTo investigate the role of TRPM2 in OA. MethodsCartilage samples were collected from patients with osteoarthritis (OA) and mice with OA to examine TRPM2 expression levels. To investigate the effects of TRPM2 modulation on the destabilization of the medial meniscus (DMM) induced knee OA in mice, we utilized TRPM2 knockout mice and employed adenovirus-mediated overexpression of TRPM2. Furthermore, siRNA-mediated TRPM2 knockdown or plasmid-mediated TRPM2 overexpression was conducted to explore the role of TRPM2 in IL-1β-induced chondrocytes. The regulatory mechanism of IL-1β on TRPM2 expression was screened by signaling pathway inhibitors, and the transcription factors and binding sites of TRPM2 were predicted using the database. The binding of RELA (NF-κB-p65) to the Trpm2 promoter was verified by chip-PCR and ChIP-qPCR. The therapeutic potential of Ca2+ chelation with BAPTA-AM for the treatment of osteoarthritis (OA) was investigated. ResultsAn increased expression of TRPM2 was observed in the cartilage of OA patients and OA mice. Furthermore, mice deficient in Trpm2 exhibited a protective effect against DMM-induced OA progression. In contrast, TRPM2 overexpression resulted in exacerbation of DMM-induced OA and thepromotion of an OA-like phenotype of chondrocytes. TRPM2 was upregulated by IL-1β in an NF-κB-p65-dependent manner. Subsequently, the TRPM2-Ca2+-mtDNA-cGAS-STING-NF-κB axis in the progression of OA was validated. Furthermore, inhibition of the TRPM2-Ca2+ axis with BAPTA-AM effectively attenuated established OA. ConclusionsOur data collectively revealed a pathological feedback loop involving TRPM2, Ca2+, mtDNA, cGAS, STING, and NF-κB in OA chondrocytes. This suggests that disrupting this loop could be a viable therapeutic approach for OA.

Increased Rab1a accelerates osteoarthritis by inhibiting autophagy via activation of the mTORC1-S6K pathway

IntroductionCartilage degradation is a critical alteration in the progression of osteoarthritis (OA) due to the disorder of chondrocyte metabolic homeostasis. Autophagy plays an important role in maintaining intracellular homeostasis. Recent investigations have increasingly underscored the importance of autophagy in modulating the pathological mechanisms underlying OA. Ras-related protein Rab-1a (Rab1a) has been illustrated to regulate autophagy in many diseases but not in OA. ObjectivesThis study aims to elucidate whether Rab1a could regulate the development of OA through modulation of chondrocyte autophagy and apoptosis. MethodsProteomic sequencing, Western blotting, and immunohistochemistry were applied to detect the expression level of Rab1a in vitro and in vivo. Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways were rigorously identified. The effects of Rab1a and the interaction between Rab1a, mTORC1, autophagy and apoptosis were explored by qPCR, Western blotting, and immunofluorescence. An experimental mouse OA model was also performed to confirm the role of Rab1a in OA pathogenesis in vivo. Histological analysis was employed to demonstrate cartilage damage. ResultsRab1a expression was significantly upregulated in inflamed chondrocytes and knee OA cartilage. Inhibition of Rab1a partially attenuated the degradation of the extracellular matrix and cell apoptosis both in vitro and in vivo, whereas overexpression of Rab1a intensified cartilage matrix degradation and cellular apoptosis. Additionally, elevated Rab1a levels were observed to suppress autophagy and activate the mTORC1-S6K signaling pathway, thereby aggravating OA pathogenesis. ConclusionThe augmentation of Rab1a expression impairs autophagy and promotes apoptosis through the activation of the mTORC1-S6K signaling pathway, further exacerbating OA pathogenesis. This finding suggests that Rab1a serves as a promising and innovative therapeutic target for the prevention and treatment of OA.

Circ_0104873 promotes osteoarthritis progression via miR-875-5p/NOTCH3/Notch signaling pathway

Osteoarthritis (OA) is the most common joint disease with high prevalence and incidence. Increasing reports has indicated that circular RNAs (circRNAs) are implicated in OA progression. Nevertheless, the roles and functions of most circRNAs in OA remain to be elucidated. In this study, we emphatically discussed circ-IQGAP1 (circ_0104873) in OA. Firstly, we discovered that circ_0104873 was dramatically overexpressed during osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Several functional assays demonstrated that circ_0104873 inhibition repressed BMSCs proliferation and osteogenic differentiation. Moreover, mechanism assays also revealed that circ_0104873 sponged microRNA-875-5p (miR-875-5p) to up-regulate notch receptor 3 (NOTCH3), thereby activating the Notch signaling pathway. Rescue assays disclosed that circ_0104873 contributed to the development of OA via targeting miR-875-5p/NOTCH3 axis. In conclusion, circ_0104873 promoted the progression of OA by miR-875-5p/NOTCH3/Notch signaling pathway, which might provide a promising target for OA treatment.

Semiautomated Three-Dimensional Landmark Placement on Knee Models Is a Reliable Method to Describe Bone Shape and Alignment

PurposeThe purpose of this study was to assess the inter- and intra-rater reliability of 21 anatomical landmarks initially placed with an AI-algorithm and then manually verified with human input. Methods30 knee CT scans of participants from the Multicenter Osteoarthritis Study (MOST) ages 45-55 years were included. Approximately one-half experienced progression of patellofemoral osteoarthritis, defined as an increased cartilage score in the patellofemoral compartment on MRI over 2 years. The algorithm automatically placed 19 anatomic landmarks on the femur, tibia, and patella. An additional 2 landmarks were added manually. Two landmark reviewers separately reviewed all 30 scans and verified all landmarks. After 2 weeks, one reviewer repeated the process for the same dataset. The mean Euclidean distance of manual landmark displacement, mean absolute disagreement between and within raters, and intraclass correlation coefficients for inter- and intra-rater reliability were calculated. ResultsAll landmarks had excellent inter-rater reliability. The tibial and femoral shaft centers had ICCs of 1, indicating their positions did not differ. Seventeen landmarks had ICCs between 0.90-0.99 and the tibial tuberosity had an ICC of 0.87. Intra-rater reliability scores were 1 for 16 landmarks and between 0.90-0.99 for the remaining five. ConclusionThere was excellent agreement on the locations of all 21 landmarks evaluated in this study. Clinical RelevanceThe potential role of artificial intelligence in medical imaging and orthopedic research is a growing area of interest. The excellent reliability demonstrated across multiple landmarks in our study reveals the potential for semi-automated 3D methods to enhance precision of anatomical measurements of the knee over 2D methods.

KLF2 Inhibits Ferroptosis and Improves Mitochondrial Dysfunction in Chondrocyte Through SIRT1/GPX4 Signaling to Improve Osteoarthritis.

Osteoarthritis (OA), a disease of articular joints, is the leading cause of disability in the elderly. Repressing ferroptosis and improving mitochondrial function can delay the progression of OA. Kruppel-like factor 2 (KLF2) exerts a protective effect on OA. However, whether KLF2 affects ferroptosis and mitochondrial function during OA remains unknown. The OA in vivo and in vitro models were constructed in this work. The structural damage of knee joint in OA mice was evaluated through Micro-CT scanning. H&E, SOFG, TB, and TUNEL staining were applied for pathological examination of cartilage tissues. ELISA was employed to examine the contents of inflammatory factors. Additionally, iron deposition in cartilage tissues was measured by Prussian blue staining, and the levels of proteins related to ferroptosis were assessed by immunoblotting. Besides, mitochondrial morphology and function were estimated using a transmission electron microscope and JC-1 staining. In interleukin (IL)-1β-treated C28/I2 cells, the levels of inflammatory factors, intracellular ROS, mitochondrial ROS, lipid ROS, and Fe2+ were measured. Mitochondrial function was evaluated by detecting the levels of mitochondrial membrane potential (MMP), ATP, mPTP, and OCR. KLF2 overexpression ameliorated the structural damage of knee cartilage in OA mice. KLF2 upregulation inhibited ferroptosis and alleviated mitochondrial damage in knee cartilage of OA mice and IL-1β-treated C28/I2 cells. Moreover, KLF2 overexpression activated SIRT1/GPX4 signaling in vivo and in vitro. EX527 addition blocked the influences of KLF2 upregulation on ferroptosis and mitochondrial dysfunction in IL-1β-treated C28/I2 cells. Altogether KLF2 inhibits ferroptosis and improves mitochondrial dysfunction in chondrocytes through SIRT1/GPX4 signaling to improve OA.

Regulation of chondrocyte apoptosis in osteoarthritis by endoplasmic reticulum stress.

Osteoarthritis(OA), a common degenerative joint disease, is characterized by the apoptosis of chondrocytes as a primary pathophysiological change, with endoplasmic reticulum stress(ERS) playing a crucial role. It has been demonstrated that an imbalance in endoplasmic reticulum(ER) homeostasis can lead to ERS, activating three cellular adaptive response pathways through the unfolded protein response(UPR) to restore ER homeostasis. Mild ERS exerts a protective effect on cells, while prolonged ERS that disrupts the self-regulatory balance of the endoplasmic reticulum activates apoptotic signaling pathways, leading to chondrocyte apoptosis and hastening OA progression. Hence, controlling the ERS signaling pathway and its apoptotic factors has become a critical focus for preventing and treating OA. This review aims to elucidate the key mechanisms of ERS pathway-induced apoptosis, associated targets, and regulatory pathways, offering valuable insights to enhance the mechanistic understanding of OA. And it also reviews the mechanisms studied for ERS-related drugs or compounds for the treatment of OA.