Progression Of Osteoarthritis Research Articles

Deep Learning for Predicting Progression of Patellofemoral Osteoarthritis Based on Lateral Knee Radiographs, Demographic Data, and Symptomatic Assessments.

In this study, we propose a novel framework that utilizes deep learning and attention mechanisms to predict the radiographic progression of patellofemoral osteoarthritis (PFOA) over a period of 7 years. This study included subjects (1,832 subjects, 3,276 knees) from the baseline of the Multicenter Osteoarthritis Study (MOST). Patellofemoral joint regions of interest were identified using an automated landmark detection tool (BoneFinder) on lateral knee X-rays. An end-to-end deep learning method was developed for predicting PFOA progression based on imaging data in a five-fold cross-validation setting. To evaluate the performance of the models, a set of baselines based on known risk factors were developed and analyzed using gradient boosting machine (GBM). Risk factors included age, sex, body mass index, and Western Ontario and McMaster Universities Arthritis Index score, and the radiographic osteoarthritis stage of the tibiofemoral joint (Kellgren and Lawrence [KL] score). Finally, to increase predictive power, we trained an ensemble model using both imaging and clinical data. Among the individual models, the performance of our deep convolutional neural network attention model achieved the best performance with an area under the receiver operating characteristic curve (AUC) of 0.856 and average precision (AP) of 0.431, slightly outperforming the deep learning approach without attention (AUC = 0.832, AP = 0.4) and the best performing reference GBM model (AUC = 0.767, AP = 0.334). The inclusion of imaging data and clinical variables in an ensemble model allowed statistically more powerful prediction of PFOA progression (AUC = 0.865, AP = 0.447), although the clinical significance of this minor performance gain remains unknown. The spatial attention module improved the predictive performance of the backbone model, and the visual interpretation of attention maps focused on the joint space and the regions where osteophytes typically occur. This study demonstrated the potential of machine learning models to predict the progression of PFOA using imaging and clinical variables. These models could be used to identify patients who are at high risk of progression and prioritize them for new treatments. However, even though the accuracy of the models were excellent in this study using the MOST dataset, they should be still validated using external patient cohorts in the future.

Long-term functional success and robust implant survival in lateral unicompartmental knee arthroplasty: A case series with a mean follow-up of twenty two and a halfyears.

Lateral unicompartmental knee arthroplasty (UKA) is an accepted treatment option in cases of end-stage lateral osteoarthritis. While lateral UKA has many proposed advantages compared to total knee arthroplasty, its technical challenges and relatively small number of cases make this an uncommon procedure. The aim of this study was to report the survivorship and functional outcomes beyond 20years of follow-up of isolated UKA. Between January 1988 and October 2003, 54 lateral UKAs were performed in a single center. The fitted prosthesis was a fixed plate and cemented polyethylene (PE). All patients had isolated lateral tibiofemoral osteoarthritis, including five open meniscectomies, three arthroscopies, and three open reductions of lateral tibial plateau fractures. Patients with a minimum of 20years of follow-up were included in the final analysis. Of the 54 UKA, 22 died before reaching the minimum follow-up period and four were lost to follow-up. Twenty-eight were included in the final analysis. Among them, 21 patients remained alive and an additional seven were deceased after 20years. The mean age at the last follow-up was 84.8 ± 11.9years with a mean follow-up duration of 22.5 ± 2.1years. Of the 28 knees, eight underwent revision surgery (5 for the progression of osteoarthritis; 2 for aseptic loosening; 1 for PE wear). Kaplan-Meier survival analysis revealed a survival rate at 20 and 25years of 72.3% (CI 59.1; 88.6). The average time to revision was 14.9 ± 4.9years. At the last follow-up, the mean function Knee Society Score (KSS) was 41.5 ± 32.9 and the mean objective KSS score was 79.4 ± 9.7. In the unrevised population, 94.7% of patients (n = 18) reported being satisfied or very satisfied with the surgery. Lateral UKA remains a viable treatment option for patients with isolated lateral tibiofemoral osteoarthritis, providing satisfactory 20-year implant survivorship and high patient satisfaction.

Robotic-arm-assisted lateral unicompartmental knee arthroplasty leads to high implant survival and patient satisfaction at mean 10-year follow-up.

There is a lack of literature reporting on long-term outcomes following robotic-arm-assisted lateral unicompartmental knee arthroplasty (UKA). This study assessed the long-term survivorship, patient-reported satisfaction and pain scores following robotic-arm-assisted lateral UKA for lateral compartment osteoarthritis (OA). A single surgeon's database was reviewed to identify all patients who underwent robotic-arm-assisted lateral UKA with a cemented, fixed-bearing prosthesis prior to May 2015. Patients were contacted to determine implant survivorship, satisfaction and pain. Kaplan-Meier models were applied to analyse survival. A total of 77 knees (70 patients) with a mean follow-up of 10.2 ± 1.5 years (range: 8.1-13.3) were included. Five knees were revised, corresponding to a 10-year survivorship of 96.1% and estimated survival time of 12.7 ± 0.3 years (95% confidence interval: 12.2-13.2) with all-cause revision as the endpoint. Unexplained pain (40.0%) and progression of OA (40.0%) in contralateral compartments were the most reported reasons for revision. Among patients without revision, 94.4% were either satisfied or very satisfied with their lateral UKA and the average pain score was 1.1. Robotic-arm-assisted lateral UKA led to high implant survivorship and patient satisfaction, and low pain scores at long-term follow-up. Progression of OA in contralateral compartments and unexplained pain were the most frequent reasons for revision. These findings support the continued use of robotic-arm-assisted lateral UKA for lateral compartment OA; however, its clinical value over conventional techniques remains to be established in prospective comparative studies. Therapeutic Level IV.

Accuracy and completeness of registry-reported unicompartmental knee arthroplasty revision.

The key outcome of joint registries is revision events, which inform clinical practice and identify poor-performing implants. Registries record revision events and reasons, but accuracy may be limited by a lack of standardized definitions of revision. Our study aims to assess the accuracy and completeness of unicompartmental knee arthroplasty (UKA) revision and indications reported to the New Zealand Joint Registry (NZJR) with independent clinical review. Case record review of 2272 patients undergoing primary UKA at four large tertiary hospitals between 2000 and 2017 was performed, identifying 158 patients who underwent revision. Detailed review of clinical findings, radiographs and operative data was performed to identify revision cases and the reasons for revision using a standardized protocol. These were compared to NZJR data using chi-squared and Fisher exact tests. The NZJR recorded 150 (95%) of all UKA revisions. Osteoarthritis progression was the most common reason on the systematic clinical review (35%), however, this was underreported to the registry (8%, P < 0.001). A larger proportion of revisions reported to the registry were for 'pain' (30% of cases vs. 5% on clinical review, P < 0.001). A reason for revision was not reported to the registry for 10% of cases. The NZJR had good capture of UKA revisions, but had significant differences in registry-reported revision reasons compared to our independent systematic clinical review. These included over-reporting of 'pain', under-reporting of osteoarthritis progression, and failing to identify a revision reason. Efforts to improve registry capture of revision reasons for UKA could be addressed through more standardized definitions of revision and tailored revision options for UKA on registry forms.

Potential Stem Cell Treatment for Common Hip Conditions: Osteoarthritis, Osteonecrosis and Gluteal Tendinopathy

Hip pathology, encompassing common conditions such as Osteoarthritis (OA), Osteonecrosis (ONFH) and gluteal tendinopathy, presents significant challenges in clinical management which often necessitate innovative treatment modalities. Stem cell therapy has emerged as a promising approach for addressing these complex hip conditions by promoting tissue regeneration and modifying disease progression. This paper aims to review the current literature on stem cell therapy for hip pathology, focusing on its application in OA, ONFH and gluteal tendinopathy. A comprehensive review of relevant studies and clinical trials was conducted by examining the safety, efficacy and potential mechanisms of action of stem cell therapy in hip conditions. Studies investigating the use of Bone Marrow-Derived Mesenchymal Stem Cells (BMMSCs), Adipose-Derived Mesenchymal Stem Cells (ADMSCs) and Tendon-Derived Stem Cells (TDSCs) were included in the analysis. The reviewed studies demonstrate promising outcomes of stem cell therapy in improving pain, functionality and halting disease progression in patients with hip OA. Intra-articular injections of MSCs have shown sustained benefits and arrested the progression of osteoarthritis. Stem cell therapy has also shown effectiveness in delaying the progression of ONFH, reducing femoral head collapse and decreasing the need for total hip replacement. Furthermore, in cases of gluteal tendinopathy, stem cell therapy has exhibited significant improvements in pain and functionality in a limited number of studies on the topic and also offers sustained relief in patients unresponsive to conventional treatments. Stem cell therapy holds immense potential as a safe and effective intervention for hip pathology and offers disease-modifying effects and sustained clinical benefits in these prevalent conditions. Further research is warranted to optimize treatment protocols, clarify mechanisms of action and validate long-term efficacy in larger cohorts.

Identification and Verification of Endoplasmic Reticulum Stress-Related Genes as Novel Signatures for Osteoarthritis Diagnosis and Therapy: A Bioinformatics Analysis-Oriented Pilot Study.

Endoplasmic reticulum stress (ERS) has been reported to be closely associated with the development of osteoarthritis (OA), but the underlying mechanisms are not fully delineated. The present study was designed to investigate the involvement of ERS-related genes in regulating OA progression. The expression profiles of OA patients and normal people were downloaded from the gene expression omnibus (GEO) database. The differentially expressed genes (DEGs) in datasets GSE55457 and GSE55235 were screened and identified by R software with the construction of the protein-protein interaction (PPI) networks. Through the STRING and Venn diagram analysis, hub ERS-related genes were obtained. Gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses were performed. Biomarkers with high diagnostic values of osteoarthritis (OA) were studied. The hematoxylin and eosin (H&E) staining and micro-CT were applied to evaluate the establishment of the OA model. The expression levels of biomarkers were validated with the use of reverse transcription‑quantitative polymerase chain reaction (RT-qPCR) and western blot. Finally, we evaluated the correlations of hub ERS-related genes with the immune infiltration cells via the CIBERSORT algorithm. A total of 60 downregulated and 52 upregulated DEGs were identified, and the following GO and KEGG pathway analyses verified that those DEGs were mainly enriched in biological process (BP), cellular component (CC), molecular function (MF), and inflammation-associated signal pathways. Interestingly, among all the DEGs, six ER stress-associated genes, including activating transcription factor 3 (ATF3), DEAD-Box Helicase 3 X-Linked (DDX3X), AP-1 transcription factor subunit (JUN), eukaryotic initiation factor 4 (EIF4A1), KDEL endoplasmic reticulum protein retention receptor 3 (KDELR3), and vascular endothelial growth factor A (VEGFA), were found to be closely associated with OA progression, and the following RT-qPCR and Western Blot analysis confirmed that DDX3X, JUN, and VEGFA were upregulated, whereas KDELR3, EIF4A1, and ATF3 were downregulated in OA rats tissues compared to the normal tissues, which were in accordance with our bioinformatics findings. Furthermore, our receiver operating characteristic (ROC) curve analysis verified that the above six ER stress-associated genes could be used as ideal biomarkers for OA diagnosis and those genes also potentially regulated immune responses by influencing the biological functions of mast cells and macrophages. Collectively, the present study firstly identified six ER stress-associated genes (ATF3, DDX3X, JUN, EIF4A1, KDELR3, and VEGFA) that may play critical role in regulating the progression of OA.

PUM2 promoted osteoarthritis progression through PTEN-mediated chondrocyte ferroptosis by facilitating NEDD4 mRNA degradation.

Osteoarthritis (OA) is a prevalent degenerative joint disease with a lack of effective therapeutic. Chondrocyte ferroptosis contributes to the progression of OA. PUM2 is shown to exacerbate ischemia-reperfusion-induced neuroinflammation by promoting ferroptosis, but its role in OA remains unexplored. Here, primary mouse chondrocytes were stimulated with IL-1β to mimic OA chondrocyte injury in vitro. And PUM2 was upregulated in OA cartilage tissues and IL-1β-induced chondrocytes. Silencing PUM2 alleviated IL-1β-induced chondrocyte inflammation and ECM degradation. Mechanistically, PUM2 facilitated the degradation of NEDD4 mRNA by binding to the 3'UTR of NEDD4 mRNA, which in turn inhibited NEDD4 induced PTEN ubiquitination and degradation. Consistently, NEDD4 silencing reversed the ameliorative effect of PUM2 knockdown on chondrocyte injury, and overexpression of PTEN abolished the improved role of NEDD4 in chondrocyte injury. Moreover, PTEN aggravated IL-1β-induced ferroptosis in chondrocytes through the Nrf2/HO-1 pathway by increasing the levels of Fe2+, ROS, MDA, and ACSL4 protein, decreasing the activity of SOD and the levels of GSH and GPX4 protein, and aggravating mitochondrial damage. Additionally, destabilized medial meniscus (DMM) were conducted to establish the OA mouse model, and adenovirus-mediated PUM2 shRNA was administered intra-articularly. Silencing PUM2 attenuated OA-induced cartilage damage in vivo. In conclusion, PUM2 promoted OA progression through PTEN-mediated chondrocyte ferroptosis by facilitating NEDD4 mRNA degradation.

Cartilage Collagen Neoepitope C2C Expression in the Articular Cartilage and Its Relation to Joint Tissue Damage in Patients with Knee Osteoarthritis

Pathological cleavage of type II collagen (Col2) and generation of Col2 neoepitopes can serve as useful molecular markers of the progression of osteoarthritis (OA). One of such potential biomarkers is type II collagen neoepitope C2C. The aim of this study was to correlate the degree of articular cartilage damage in OA patients with C2C expression in histological samples of tissues removed during total knee replacement. Cartilage samples were obtained from 27 patients ranging in age from 55 to 66 years. In each patient, medial and lateral tibia plateau samples were analyzed according to the OARSI histopathology grading system. The C2C expression was evaluated on histological slides by semi-quantitative analysis using ImageJ Fiji 2.14.0 software. Spearman’s rank correlation analysis revealed a positive weak correlation (rho = 0.289, p = 0.0356) between the histological grade of tissue damage and the percentage of C2C staining. In addition, a highly significant positive correlation (rho = 0.388, p = 0.0041) was discovered between the osteoarthritis score (combining the histological grade of damage with the OA macroscopic stage) and the percentage of C2C staining in the samples. The C2C expression was detected in all the regions of the articular cartilage (i.e., the superficial zone, mid zone, deep zone and tidemark area, and the zone of calcified cartilage). Our findings imply that local expression of C2C correlates with the articular cartilage damage in OA-affected knees. This confirms that C2C can be used as a prospective marker for assessing pathological changes in the OA course and OA clinical trials.

ACCURACY OF REGISTRY-REPORTED REASONS FOR UNICOMPARTMENTAL KNEE ARTHROPLASTY REVISION

IntroductionA key outcome measured by national joint registries are revision events. This informs best practice and identifies poor-performing surgical devices. Although registry data often record reasons for revision arthroplasty, interpretation is limited by lack of standardised definitions of revision reasons and objective assessment of radiologic and laboratory parameters. Our study aim was to compare reasons for unicompartmental knee arthroplasty (UKA) revision reported to the New Zealand Joint Registry (NZJR) with reasons identified by independent clinical review.MethodsA total of 2,272 patients undergoing primary medial and lateral UKA at four large tertiary hospitals between 2000 and 2017 were included. A total of 158 patients underwent subsequent revision with mean follow-up of 8 years. A systematic review of clinical findings, radiographs and operative data was performed to identify revision cases and to determine the reasons for revision using a standardised protocol. These were compared to reasons reported to the NZJR using Chi-squared and Fisher exact tests.ResultsOsteoarthritis progression was the most common reason for revision on systematic clinical review (30%), however this was underreported to the registry (4%, p&lt;0.001). A larger proportion of revisions reported to the registry were for ‘unexplained pain’ (30% of cases vs. 4% on clinical review, p&lt;0.001). A reason for revision was not reported to the registry for 24 (15%) of cases.Discussion and ConclusionWe found significant inaccuracies in registry-reported reasons for revision following UKA. These included over-reporting of ‘unexplained pain’, under-reporting of osteoarthritis progression, and failure to identify a reason for revision. Efforts to improve registry capture of revision reasons for UKA should focus on increasing accuracy in these three areas. This could be addressed through standardised recording methods and tailored revision reason options for UKA for surgeons to select when recording the reasons.

Novel biomimetic macromolecules system for highly efficient lubrication, ROS scavenging and osteoarthritis treatment

The early stages of osteoarthritis (OA) in the joints are typically characterized by two key factors: the dysfunction of articular cartilage lubrication and inflammation resulting from the excessive production of reactive oxygen species (ROS). Synthetic injectable macromolecular materials present great potential for preventing the progression of early OA. In this study, to mimic the excellent lubricity of brush-like aggregates found in natural synovial fluid, we develop a novel macromolecular biolubricant (CS-PS-DA) by integrating adhesion and hydration groups onto backbone of natural biomacromolecules. CS-PS-DA exhibits a strong affinity for cartilage surfaces, enabling the formation of a stable lubrication layer at the sliding interface of degraded cartilages to restore joint lubrication performance. In vitro results from ROS scavenging and anti-inflammatory experiments indicate the great advantage of CS-PS-DA to decrease the levels of proinflammatory cytokines by inhibiting ROS overproduction. Finally, in vivo rats OA model demonstrates that intra-cavitary injection of CS-PS-DA could effectively resist cartilage wear and mitigated inflammation in the joints. This novel biolubricant provides a new and timely strategy for the treatment of OA.

Identification of mitophagy-related biomarkers in osteoarthritis.

Osteoarthritis (OA) is a common joint disease, and existing drugs cannot cure OA, so there is an urgent need to identify new targets. Mitophagy plays an important role in OA; however, the role of mitophagy in the OA immune system is not yet clear. In this study, differential analysis and enrichment analysis were used to identify mitophagy-related genes (MRGs) with differential expression in OA and the functional pathways involved in OA. Subsequently, two machine learning methods, RF and LASSO, were used to screen MRGs with diagnostic value and construct nomograms. At the same time, the relationship between mitophagy and OA immune response was explored by immunoinfiltration analysis. Forty-three differentially MRGs were identified in OA, of which six MRGs (GABARAPL2, PARL, GABARAPL1, JUN, RRAS, and SNX7) were associated with the diagnosis of OA. The ROC analysis results show that these 6 MRGs have high predictive accuracy in the diagnosis of OA. In immune infiltration analysis, we found that the abundance of significantly different immune cells in OA was mostly upregulated. In addition, the expression of diagnostic-related MRGs is correlated with changes in the abundance of immune cells in OA. This study demonstrates that six MRGs can be used as diagnostic biomarkers. The expression of diagnostic-related MRGs is correlated with changes in the abundance of immune cells in OA. At the same time, mitophagy may affect the immune microenvironment of OA by regulating immune cells, ultimately leading to the progression of OA.

Macrophage-derived ectosomal miR-350-3p promotes osteoarthritis progression through downregulating chondrocyte H3K36 methyltransferase NSD1

Mechanical overloading can promote cartilage senescence and osteoarthritis (OA) development, but its impact on synovial macrophages and the interaction between macrophages and chondrocytes remain unknown. Here, we found that macrophages exhibited M1 polarization under mechanical overloading and secreted ectosomes that induced cartilage degradation and senescence. By performing miRNA sequencing on ectosomes, we identified highly expressed miR-350-3p as a key factor mediating the homeostatic imbalance of chondrocytes caused by M1-polarized macrophages, this result being confirmed by altering the miR-350-3p level in chondrocytes with mimics and inhibitor. In experimental OA mice, miR-350-3p was increased in synovium and cartilage, while intra-articular injection of antagomir-350-3p inhibited the increase of miR-350-3p and alleviated cartilage degeneration and senescence. Further studies showed that macrophage-derived ectosomal miR-350-3p promoted OA progression by inhibiting nuclear receptor binding SET domain protein 1(NSD1) in chondrocytes and regulating histone H3 lysine 36(H3K36) methylation. This study demonstrated that the targeting of macrophage-derived ectosomal miRNAs was a potential therapeutic method for mechanical overload-induced OA.

Mume Fructus reduces interleukin-1 beta-induced cartilage degradation via MAPK downregulation in rat articular chondrocytes.

Osteoarthritis is the most prevalent type of degenerative arthritis. It is characterized by persistent pain, joint dysfunction, and physical disability. Pain relief and inflammation control are prioritised during osteoarthritis treatment Mume Fructus (Omae), a fumigated product of the Prunus mume fruit, is used as a traditional medicine in several Asian countries. However, its therapeutic mechanism of action and effects on osteoarthritis and articular chondrocytes remain unknown. In this study, we analyzed the anti-osteoarthritis and articular regenerative effects of Mume Fructus extract on rat chondrocytes. Mume Fructus treatment reduced the interleukin-1β-induced expression of matrix metalloproteinase 3, matrix metalloproteinase 13, and a disintegrin and metalloproteinase with thrombospondin type 1 motifs 5. Additionally, it enhanced collagen type II alpha 1 chain and aggrecan accumulation in rat chondrocytes. Furthermore, Mume Fructus treatment regulated the inflammatory cytokine levels, mitogen-activated protein kinase phosphorylation, and nuclear factor-kappa B activation. Overall, our results demonstrated that Mume Fructus inhibits osteoarthritis progression by inhibiting the nuclear factor-kappa B and mitogen-activated protein kinase pathways to reduce the levels of inflammatory cytokines and prevent cartilage degeneration. Therefore, Mume Fructus may be a potential therapeutic option for osteoarthritis.

Efficacy of Mulligan joint mobilizations and trunk stabilization exercises versus isometric knee strengthening in the management of knee osteoarthritis: a randomized controlled trial

BackgroundKnee osteoarthritis (KOA) progression is often influenced by biomechanical factors. Biomechanical interventions, such as Trunk stabilization exercise (TSE) and Mulligan joint mobilization (MWM), may offer relief from KOA symptoms and potentially slow disease progression. However, the comparative efficacy of these therapies remains uncertain. This study aimed to compare the efficacy of TSE, Mulligan joint mobilization, and isometric knee strengthening (KSE) on disability, pain severity, and aerobic exercise capacity in patients with KOA.MethodologyA randomized controlled trial (RCT) with three intervention groups was conducted between September 2020 to February 2021. The study enrolled adults aged between 40 and 60 years with a confirmed KOA diagnosis recruited from the physical therapy clinic of the Sindh Institute of Physical Medicine and Rehabilitation, Pakistan. Participants were randomly assigned to receive 24 sessions of either TSE, MWM, or KSE. The knee’s functionality was assessed using the Knee Injury and Osteoarthritis Outcome Score (KOOS), pain on a visual analogue scale (VAS), and two objective functional tests—the 6-minute walk test (6MWT) and the 11-stair climb test (SCT). These assessments were conducted at baseline, the third week, and the sixth week. Changes in outcome measures were analyzed using a mixed-design ANOVA with Bonferroni post-hoc analysis, with statistical significance set at a p-value < 0.05.ResultOf the 60 participants, 22 (36.7%) were females, and 38 (63.3%) were males. Within-group analysis revealed a significant improvement in all outcome measures at the third week (p < 0.05) and sixth week (p < 0.05). Notably, the TSE group exhibited a greater reduction in mean difference (M.D) in VAS scores than the MWM and KSE groups across various measures in the third week. At rest, during stair ascent, and descent, the TSE group showed significant improvements in VAS scores: MWM (-2.05; -1.94; -1.94), TSE (-2.38; -2.5; -2.5), KSE (-1.05; -0.63; -0.63). Additionally, during sub-maximal exercise capacity assessment, the TSE group showed greater improvement (MWM 12.89; TSE 22.68; KSE 7.89), as well as in Knee Injury and Osteoarthritis Outcome Score for activities of daily living (KOOS-ADL) (MWM 20.84; TSE 28.84; KSE 12.68), and KOOS-pain (MWM 24.84; TSE 27.77; KSE 5.77) at the third-week assessment (p < 0.05). The TSE group demonstrated significant improvements (p < 0.05) across various measures in the sixth week. Specifically, improvements were observed in VAS scores at rest (MWM − 4.15; TSE − 4.42; KSE − 3.78), during stair ascent (MWM − 3.89; TSE − 4.88; KSE − 3.56) and descent (MWM − 3.78; TSE − 4.05; KSE − 2.94). Furthermore, significant improvements were noted in the stair climb test (MWM − 7.05; TSE − 7.16; KSE − 4.21), 6-minute walk test (6MWT) (MWM 22.42; TSE 37.6; KSE 13.84), KOOS-pain (MWM 41.47; TSE 49.11; KSE 28.73), and KOOS-ADL (MWM 40.31; TSE 50.57; KSE 26.05).ConclusionIn this study in patients with KOA, TSE had greater efficacy compared to MWM and KSE in enhancing functional levels, reducing pain, improving sub-maximal exercise capacity, and performance on the stair climb test. Importantly, mean scores between the groups, particularly in the TSE group, reached the minimally important level, particularly in key areas such as pain, functional levels, sub-maximal exercise capacity, and stair climb performance. Clinicians should consider the significant pain reduction, improved functionality, and enhanced exercise capacity demonstrated by TSE, indicating its potential as a valuable therapeutic choice for individuals with KOA.Trial noClinicalTrials.gov = NCT04099017 23/9/2019.

Cathelicidin-BF regulates the AMPK/SIRT1/NF-κB pathway to ameliorate murine osteoarthritis: In vitro and in vivo studie

Osteoarthritis (OA) is a chronic degenerative disease with a significant prevalence that causes cartilage damage and can lead to disability. The main factors contributing to the onset and progression of OA include inflammation and degeneration of the extracellular matrix. Cathelicidin-BF (BF-30), a natural peptide derived from Bungarus fasciatus venom, has shown multiple important pharmacological effects. However, the action mechanism of BF-30 in OA treatment remains to be elucidated. In this research, X-ray and Safranin O staining were employed to evaluate the imageology and histomorphology differences in the knee joints of mice in vivo. Techniques such as Western blot analysis, RT-qPCR, ELISA, and immunofluorescence staining were applied to examine gene and protein level changes in in vitro experiments. It was found that BF-30 significantly decreased inflammation and enhanced extracellular matrix metabolism. For the first time, it was demonstrated that the positive effects of BF-30 are mediated through the activation of the AMPK/SIRT1/NF-κB pathway. Moreover, when BF-30 was co-administered with Compound C, an AMPK inhibitor, the therapeutic benefits of BF-30 were reversed in both in vivo and in vitro settings. In conclusion, the findings suggest that BF-30 could be a novel therapeutic agent for OA improvement.

Clinical validation of C12FDG as a marker associated with senescence and osteoarthritic phenotypes.

Chronic conditions associated with aging have proven difficult to prevent or treat. Senescence is a cell fate defined by loss of proliferative capacity and the development of a pro-inflammatory senescence-associated secretory phenotype comprised of cytokines/chemokines, proteases, and other factors that promotes age-related diseases. Specifically, an increase in senescent peripheral blood mononuclear cells (PBMCs), including T cells, is associated with conditions like frailty, rheumatoid arthritis, and bone loss. However, it is unknown if the percentage of senescent PBMCs associated with age-associated orthopedic decline could be used for potential diagnostic or prognostic use in orthopedics. Here, we report senescent cell detection using the fluorescent compound C12FDG to quantify PBMCs senescence across a large cohort of healthy and osteoarthritic patients. There is an increase in the percent of circulating C12FDG+ PBMCs that is commensurate with increases in age and senescence-related serum biomarkers. Interestingly, C12FDG+ PBMCs and T cells also were found to be elevated in patients with mild to moderate osteoarthritis, a progressive joint disease that is strongly associated with inflammation. The percent of C12FDG+ PBMCs and age-related serum biomarkers were decreased in a small subgroup of study participants taking the senolytic drug fisetin. These results demonstrate quantifiable measurements in a large group of participants that could create a composite score of healthy aging sensitive enough to detect changes following senolytic therapy and may predict age-related orthopedic decline. Detection of peripheral senescence in PBMCs and subsets using C12FDG may be clinically useful for quantifying cellular senescence and determining how and if it plays a pathological role in osteoarthritic progression.

Protective Effects of an Oligo-Fucoidan-Based Formula against Osteoarthritis Development via iNOS and COX-2 Suppression following Monosodium Iodoacetate Injection

Osteoarthritis (OA) is a debilitating joint disorder characterized by cartilage degradation and chronic inflammation, accompanied by high oxidative stress. In this study, we utilized the monosodium iodoacetate (MIA)-induced OA model to investigate the efficacy of oligo-fucoidan-based formula (FF) intervention in mitigating OA progression. Through its capacity to alleviate joint bearing function and inflammation, improvements in cartilage integrity following oligo-fucoidan-based formula intervention were observed, highlighting its protective effects against cartilage degeneration and structural damage. Furthermore, the oligo-fucoidan-based formula modulated the p38 signaling pathway, along with downregulating cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression, contributing to its beneficial effects. Our study provides valuable insights into targeted interventions for OA management and calls for further clinical investigations to validate these preclinical findings and to explore the translational potential of an oligo-fucoidan-based formula in human OA patients.

Transcriptomics and metabolomics: Challenges of studying obesity in osteoarthritis

ObjectiveObesity is a leading risk factor for both the incidence and progression of osteoarthritis (OA). Omic technologies, including transcriptomics and metabolomics are capable of identifying RNA and metabolite profiles in tissues and biofluids of OA patients. The objective of this review is to highlight studies using transcriptomics and metabolomics that contribute to our understanding of OA pathology in relation to obesity. DesignWe conducted a targeted search of PUBMED for articles, and GEO for datasets, published up to February 13, 2024, screening for those using high-throughput transcriptomic and metabolomic techniques to study human or pre-clinical animal model tissues or biofluids related to obesity-associated OA. We describe relevant studies and discuss challenges studying obesity as a disease-related factor in OA. ResultsOf the 107 publications identified by our search criteria, only 15 specifically used transcriptomics or metabolomics to study joint tissues or biofluids in obesity-related OA. Specific transcriptomic and metabolomic signatures associated with obesity-related OA have been defined in select local joint tissues, biofluids and other biological material. However, considerable challenges exist in understanding contributions of obesity-associated modifications of transcriptomes and metabolomes related to OA, including sociodemographic, anthropometric, dietary and molecular redundancy-related factors. ConclusionsA number of additional transcriptomic and metabolomic studies are needed to comprehensively understand how obesity affects OA incidence, progression and outcomes. Integration of transcriptome and metabolome signatures from multiple tissues and biofluids, using network-based approaches will likely help to better define putative therapeutic targets that could enable precision medicine approaches to obese OA patients.

Periostin Is a Biomarker for Anterior Shoulder Instability: Proteomic Analysis of Synovial Fluid.

The incremental biological changes in the synovial microenvironment of the shoulder in acute and chronic instability that may contribute to joint degeneration are poorly understood. Proteomic analysis of synovial fluid in patients with shoulder instability may improve our understanding of proteins that are shed into shoulder synovial fluid after an injury. Injury-specific factors such as the direction of instability and the severity of glenoid and humeral bone loss are associated with the proteome of synovial fluid in patients with shoulder instability. Descriptive laboratory study. Synovial fluid lavage samples were compared between patients with anterior (n = 12) and posterior (n = 8) instability and those without instability (n = 5). Synovial proteins were identified with liquid chromatography-tandem mass spectrometry. Orthogonal validation of protein targets found to be significant on tandem mass spectrometry was performed in a separate set of prospective patients with Western blotting. Data were processed and analyzed, and P values were adjusted with the Benjamini-Hochberg method for multiple comparisons. A total of 25 patients were included. Tandem mass spectrometry identified 720 protein groups in synovial fluid of patients with shoulder instability. There were 4 synovial proteins that were significantly expressed in patients with anterior instability relative to posterior instability: periostin (POSTN) (adjusted P value = .03; log fold change [logFc] = 4.7), transforming growth factor beta-induced protein ig-h3 (adjusted P value = .05; logFc = 1.7), collagen type VI alpha-3 chain (adjusted P value = .04; logFc = 2.6), and coagulation factor V (adjusted P value = .04; logFc = -3.3). Among these targets, POSTN showed a moderate correlation with the Hill-Sachs lesion size (r = 0.7). Prospective validation with Western blotting confirmed a significantly higher level of POSTN in synovial fluid of patients with anterior instability (P = .00025; logFc = 5.1). Proteomic analysis enriched our understanding of proteins that were secreted into shoulder synovial fluid of patients with shoulder instability. The identification of POSTN, a proinflammatory catabolic protein involved with tissue remodeling and repair, as a significant target in anterior shoulder instability is a novel finding. Therefore, further study is warranted to determine the role that POSTN may play in the progression of bone loss and posttraumatic osteoarthritis. Proteomic analysis of synovial fluid in patients with shoulder instability improved our understanding of this abnormality after an injury.

No genetic causal association between circulating alpha-tocopherol levels and osteoarthritis, a two-sample Mendelian randomization analysis

The causal association between vitamin E status and osteoarthritis (OA) remains controversial in previous epidemiological studies. We employed a Mendelian randomization (MR) analysis to explore the causal relationship between circulating alpha-tocopherol levels (main forms of vitamin E in our body) and OA. The instrumental variables (IVs) of circulating alpha-tocopherol levels were obtained from a Genome-wide association study (GWAS) dataset of 7781 individuals of European descent. The outcome of OA was derived from the UK biobank. Two-sample MR analysis was used to estimate the causal relationship between circulating alpha-tocopherol levels and OA. The inverse-variance weighted (IVW) method was the primary analysis in this analysis. We used the MR-Egger method to determine horizontal pleiotropic in this work. The heterogeneity effect of instrumental IVs was detected by MR-Egger and IVW analyses. Sensitivity analysis was performed by removing single nucleotide polymorphism (SNP) one by one. Three SNPs (rs964184, rs2108622, and rs11057830) (P < 5E−8) strongly associated with circulating alpha-tocopherol levels were used in this analysis. The IVW-random effect indicated no causal relationship between circulating alpha-tocopherol levels and clinically diagnosed OA (OR = 0.880, 95% CI 0.626, 1.236, P = 0.461). Similarly, IVW analysis showed no causal association between circulating alpha-tocopherol levels and self-reported OA (OR = 0.980, 95% CI 0.954, 1.006, P = 0.139). Other methods of MR analyses and sensitivity analyses revealed consistent findings. MR-Egger and IVW methods indicated no significant heterogeneity between IVs. The MR–Egger intercept showed no horizontal pleiotropic. The results of this linear Mendelian randomization study indicate no causal association between genetically predicted alpha-tocopherol levels and the progression of OA. Alpha-tocopherol may not provide beneficial and more favorable outcomes for the progression of OA. Further MR analysis based on updated GWASs with more IVs is required to verify the results of our study.