End-stage Knee Osteoarthritis Patients Research Articles

Reliability of the Star Excursion Balance Test with End-Stage Knee Osteoarthritis Patients and Its Responsiveness Following Total Knee Arthroplasty.

Background/Objectives: The Star Excursion Balance Test (SEBT) is a simple and feasible tool for assessing dynamic balance in individuals with knee osteoarthritis (KOA). It has an advantage as it replicates dynamic balance better than other static balance tools. This study aims to determine how reliable SEBT is among people with end-stage KOA, as well as how responsive it is and how well it correlates with performance-based outcome measures after TKA. Methods: Patients on the waiting list for TKA performed SEBT in the anterior, posteromedial and posteriorlateral directions twice within 7 days. The measurements were repeated 6 and 12 months after TKA. The participants completed performance-based outcome measurements (PBOMs) and the Oxford Knee Score (OKS) before and after TKA to estimate correlation. Results: In all directions, the intraclass correlation coefficient range (ICC) was 0.998-0.993, and there were no significant differences between the test and re-test mean SEBT scores. The standard error of measurement (SEM) ranged from 0.37% to 0.68%, and the minimum detectable change (MDC) ranged from 1.02% to 1.89%. The post TKA SEBT results show significant improvement, with a large effect size. There were large-to-medium correlations between SEBT and PBOMs before and after TKA, while OKS correlated only before surgery. The magnitude of change in SEBT, PBOMs and OKS did not correlate. Conclusions: SEBT is an extremely reliable tool for assessing dynamic balance in all three directions of severe KOA patients. It is sensitive enough to detect balance changes at 6 and 12 months post TKA. SEBT cannot be used to reflect the change in functional outcome improvement after TKA.

The effectiveness of vitamin D supplementation in patients with end-stage knee osteoarthritis: Study protocol for a double-blinded, randomized controlled trial.

Osteoarthritis (OA) knee is one of the most common chronic degenerative conditions that imposes clinical and economic burdens on individuals and societies worldwide. Previous studies showed vitamin D levels correlated positively with lean muscle mass and grip strength, implying that vitamin D supplementation may improve muscle health in knee OA subjects. This randomized controlled trial (RCT) aims to compare the effects of vitamin D supplementation on knee muscle strength, physical function, pain, and sarcopenia status in patients with end-stage knee OA. Patients and outcome assessors will be blinded to group allocation. Fifty-six end-stage knee OA patients with vitamin D insufficiency fulfilling our inclusion criteria will be invited to participate in this study. Patients will be randomly assigned to take vitamin D supplementation (4,000 IU capsule daily) or placebo for six months. Measurements will be taken at baseline, three and six-month after the commencement of the vitamin D supplement, and 6-month after the interventional period. The primary outcome includes the isometric quadriceps and hamstring muscle strength measured by a hand-held dynamometer. Secondary outcomes include pain, performance-based and self-reported physical function and sarcopenia status. The success of this study will provide scientific evidence of whether the relatively cheap and well-tolerated vitamin D supplement can improve quadriceps muscle strength, physical function, pain symptoms, and sarcopenia status of this increasingly large population for end-stage knee OA patients. The study has great clinical significance given Hong Kong's lengthy and growing waiting list for complete knee replacement procedures. Trial registration: The trial was registered on clinicaltrials.gov (NCT05981534) on 31st July 2023.

Hemisphere lateralization of graph theoretical network in end-stage knee osteoarthritis patients

Hemisphere functional lateralization is a prominent feature of the human brain. However, it is not known whether hemispheric lateralization features are altered in end-stage knee osteoarthritis (esKOA). In this study, we performed resting-state functional magnetic imaging on 46 esKOA patients and 31 healthy controls (HCs) and compared with the global and inter-hemisphere network to clarify the hemispheric functional network lateralization characteristics of patients. A correlation analysis was performed to explore the relationship between the inter-hemispheric network parameters and clinical features of patients. The node attributes were analyzed to explore the factors changing in the hemisphere network function lateralization in patients. We found that patients and HCs exhibited “small-world” brain network topology. Clustering coefficient increased in patients compared with that in HCs. The hemisphere difference in inter-hemispheric parameters including assortativity, global efficiency, local efficiency, clustering coefficients, small-worldness, and shortest path length. The pain course and intensity of esKOA were positively correlated with the right hemispheric lateralization in local efficiency, clustering coefficients, and the small-worldness, respectively. The significant alterations of several nodal properties were demonstrated within group in pain-cognition, pain-emotion, and pain regulation circuits. The abnormal lateralization inter-hemisphere network may be caused by the destruction of regional network properties.

Tetraspanin profiles of serum extracellular vesicles reflect functional limitations and pain perception in knee osteoarthritis.

Emerging evidence suggests that extracellular vesicles (EVs) can play roles in inflammatory processes and joint degradation in primary osteoarthritis (OA), a common age-associated joint disease. EV subpopulations express tetraspanins and platelet markers that may reflect OA pathogenesis. The present study investigated the associations between these EV surface markers and articular cartilage degradation, subjectively and objectively assessed pain, and functional limitations in primary knee OA (KOA). Serum EVs were determined by high-sensitivity flow cytometry (large CD61+ EVs) and single particle interferometric reflectance imaging sensor (small CD41+, CD63+, CD81+, and CD9+ EVs) from end-stage KOA patients and controls (n = 8 per group). Knee pain and physical functions were assessed with several health- and pain-related questionnaires, established measurements of physical medicine, and neuromuscular examination. The obtained data were analyzed using supervised and unsupervised univariate and multivariate models. With the combined dataset of cartilage thickness, knee function, pain, sensation, and EV molecular signatures, we identified highly correlated groups of variables and found several EV markers that were statistically significant predictors of pain, physical limitations, and other aspects of well-being for KOA patients, for instance CD41+/CD63+/CD9+ small EVs associated with the range of motion of the knee, physical performance, and pain sensitivity. Particular serum EV subpopulations showed clear associations with KOA pain and functional limitations, suggesting that their implications in OA pathophysiology warrant further study.

Prevalence and associations of sarcopenia, obesity and sarcopenic obesity in end-stage knee osteoarthritis patients

ObjectiveTo identify the prevalence of obesity, sarcopenia, sarcopenic obesity in end-stage knee osteoarthritis (KOA) patients and analyze influences of obesity and sarcopenia in the progression of KOA.MethodsA cross-sectional study was carried out among end-stage KOA patients who consecutively admitted to Orthopedic Department for TKA. We suppose that the level of decreased physical activities would be influenced by unilateral or bilateral KOA. Patient information, albumin, hemoglobin, pace, step frequency, number of comorbid conditions were collected. Bioelectrical impedance analyzer was used to analyze body composition. Obesity, sarcopenia, sarcopenic obesity rate were analyzed with accepted diagnosis criteria. Correlations between body mass index (BMI) or age and fat mass (FM), appendicular skeletal muscle mass (ASM) were analyzed.Results138 patients (male 30, female 108) in southwest of China including 67 patients with unilateral KOA and 71 patients with bilateral KOA were analyzed. No statistic difference was found in mean albumin, prealbumin and hematocrystallin, body composition values and number of comorbid conditions. We found that BMI was positively correlated with FM (Male: R2 = 0.7177, p < 0.0001, Female: R2 = 0.8898, p < 0.0001), ASM (Male: R2 = 0.2640, p = 0.0037, Female: R2 = 0.2102, p < 0.0001), FM index (FMI) (Male: R2 = 0.6778, p < 0.0001, Female: R2 = 0.8801, p < 0.0001), and ASM index (ASMI) (Male: R2 = 0.3600, p = 0.0005, Female: R2 = 0.4208, p < 0.0001) in end-stage KOA patients. However, age was not obviously correlated with FM or FMI (Male: FM, R2 = 0.006911, p = 0.3924; FMI, R2 = 0.7554, p = 0.0009196; Female: FM, R2 = 0.001548, p = 0.8412; FMI, R2 = 0.002776, p = 0.7822). And slightly negatively correlated with ASM (Male: R2 = 0.05613, p = 0.0136, Female: R2 = 0.01327, p = 0.5433) and ASMI (Male: R2 = 0.02982, p = 0.3615; Female: R2 = 0.03696, p = 0.0462). The prevalence of obesity, sarcopenia and obesity sarcopenia differs according to different diagnosis criteria. No difference in the occurrence rate of obesity was found between bilateral KOA and unilateral KOA patients, and occurrence rates of sarcopenia and sarcopenic obesity were statistically higher in bilateral KOA than that in unilateral KOA patients.ConclusionsObesity, sarcopenia and sarcopenic obesity are highly prevalent in end-stage KOA patients, sarcopenic obesity are more prevalent in bilateral KOA patients than that in unilateral KOA patients.

Identification and quantification of degradome components in human synovial fluid reveals an increased proteolytic activity in knee osteoarthritis patients vs controls.

Synovial fluid (SF) may contain cleavage products of proteolytic activities. Our aim was to characterize the degradome through analysis of proteolytic activity and differential abundance of these components in a peptidomic analysis of SF in knee osteoarthritis (OA) patients versus controls (n=23). SF samples from end-stage knee osteoarthritis patients undergoing total knee replacement surgery and controls, that is, deceased donors without known knee disease were previously run using liquid chromatography mass spectrometry (LC-MS). This data was used to perform new database searches generating results for non-tryptic and semi-tryptic peptides for studies of degradomics in OA. We used linear mixed models to estimate differences in peptide-level expression between the two groups. Known proteolytic events (from the MEROPS peptidase database) were mapped to the dataset, allowing the identification of potential proteases and which substrates they cleave. We also developed a peptide-centric R tool, proteasy, which facilitates analyses that involve retrieval and mapping of proteolytic events. We identified 429 differentially abundant peptides. We found that the increased abundance of cleaved APOA1 peptides is likely a consequence of enzymatic degradation by metalloproteinases and chymase. We identified metalloproteinase, chymase, and cathepsins as the main proteolytic actors. The analysis indicated increased activity of these proteases irrespective of their abundance.

Cost-Effectiveness of Robot-Assisted Total Knee Arthroplasty: A Markov Decision Analysis

BackgroundRobot-assisted total knee arthroplasty (rTKA) may improve clinical outcomes for patients who have end-stage osteoarthritis of the knee. However, the costs of rTKA are high, and there is a paucity of data evaluating the cost-effectiveness of rTKA. We aimed to analyze the cost per quality-adjusted life-year (QALY) of rTKA relative to manual TKA. MethodsA Markov decision analysis was performed using known parameters for costs, outcomes, implant survivorships, and mortalities. The cost-effectiveness of rTKA relative to manual TKA was assessed for end-stage knee osteoarthritis patients who had a mean age of 65 years (range, 27 to 94 years). The rTKA costs were calculated for a pay-per-use contract robot. ResultsUsing the Markov Model with an annual case volume of 500 patients and a mean age of 65 years, the overall health gain per patient was 13.34 QALYs after rTKA and 13.31 QALYs after manual TKA. This resulted in an overall gain in QALYs of 0.03 for each patient undergoing an rTKA compared with manual TKA and an incremental cost of $128,526 Singapore Dollars per QALY. ConclusionRobotic TKA is not a cost-effective alternative to conventional TKA using a pay-per-use contract robot.

Surgery avoidance rates among total knee replacement candidates following a non-invasive biomechanical intervention: A retrospective cohort study

Background Nearly twenty million people are affected by osteoarthritis (OA) across the UK. For end-stage knee OA, total knee replacement (TKR) is considered as the standard of care, but this major surgery carries high costs, long waiting lists, and risk for further revision surgeries. Health systems are therefore looking for effective alternatives to treat these cohorts, significantly delaying, and potentially avoiding joint replacement surgery altogether. The purpose of this study was to examine the 2-year surgery avoidance rate amongst TKR candidates that received a non-invasive biomechanical intervention. Methods A retrospective clinical audit was conducted on 365 NHS patients with end-stage knee OA patients eligible for TKR. Each patient was individually fitted with a non-invasive, shoe-like, biomechanical device, that alters the foot center of pressure, minimizes reported symptoms, and promotes neuromuscular control training using convex pods under the sole. Patients used the device for short periods during activities of daily living and were followed for two years. The primary outcome was surgery status after 2 years. Secondary outcomes were evaluated using the generalized linear mixed-models procedure and included changes in pain, function (WOMAC and Oxford Knee Score (OKS), and spatiotemporal gait measured at 3, 6, 12, and 24 months from baseline. Results Of the 365 candidates for TKR, 305 (84%) avoided surgery at 2 years. Patients displayed significant clinical improvements over time. Six months after starting treatment, average pain decreased by 42%, average function improved by 39%, and average OKS increased by 7.6 points. These continued to improve over the 2 years. All spatial-temporal gait measures improved over time (p&lt;0.001). Conclusions The current results suggest that a non-invasive biomechanical treatment may help end-stage knee OA patients delay knee replacement surgery for at least 2 years or avoid it altogether. This treatment may provide an effective non-surgical alternative for managing these patients in the community, alleviating pain, and improving gait and function.

Mass spectrometry imaging spatially identifies complex-type N-glycans as putative cartilage degradation markers in human knee osteoarthritis tissue

N-Glycan alterations contribute to the pathophysiology and progression of various diseases. However, the involvement of N-glycans in knee osteoarthritis (KOA) progression at the tissue level, especially within articular cartilage, is still poorly understood. Thus, the aim of this study was to spatially map and identify KOA-specific N-glycans from formalin-fixed paraffin-embedded (FFPE) osteochondral tissue of the tibial plateau relative to cadaveric control (CTL) tissues. Human FFPE osteochondral tissues from end-stage KOA patients (n=3) and CTL individuals (n=3), aged >55 years old, were analyzed by matrix‐assisted laser desorption/ionization mass spectrometry imaging (MALDI‐MSI) and liquid chromatography–tandem mass spectrometry (LC-MS/MS). Overall, it was revealed that 22 N-glycans were found in the cartilage region of KOA and CTL tissue. Of those, 15 N-glycans were more prominent in KOA cartilage than CTL cartilage. We then compared sub-regions of KOA and CTL tissues based on the Osteoarthritis Research Society International (OARSI) histopathological grade (1 to 6), where 1 is an intact cartilage surface and 6 is cartilage surface deformation. Interestingly, three specific complex-type N-glycans, (Hex)4(HexNAc)3, (Hex)4(HexNAc)4, and (Hex)5(HexNAc)4, were found to be localized to the superficial fibrillated zone of degraded cartilage (KOA OARSI 2.5-4), compared to adjacent cartilage with less degradation (KOA OARSI 1-2) or relatively healthy cartilage (CTL OARSI 1-2). Our results demonstrate that N-glycans specific to degraded cartilage in KOA patients have been identified at the tissue level for the first time. The presence of these N-glycans could further be evaluated as potential diagnostic and prognostic biomarkers.

The application of Caprini Risk Assessment Model in evaluation of deep vein thrombosis for patients with end-stage osteoarthritis before arthroplasty

BackgroundDeep vein thrombosis (DVT) was a fatal complication of knee arthroplasty. We had neglected the risk factors of preoperative DVT although patients undergoing knee arthroplasty were at high risk for VTE. This study was to determine the risk factors for preoperative DVT and application of Caprini Risk Assessment Model (RAM) in patients with end-stage knee osteoarthritis (OA).MethodsWe retrospectively analyzed 1808 cases with end-stage knee OA undergoing primary knee arthroplasty from May 2015 to December 2020. Based on the results of ultrasonography in lower extremities, all patients were divided into non-DVT group and DVT group. Distribution of risk factors and risk levels were compared using χ2 test between two groups. Binary logistic regression analysis was used to determine the risk factors and relationship of risk levels and preoperative DVT.ResultsThe incidence of preoperative DVT was 5.53% (n = 100). Distribution of the study population by risk level was low, 4.09%; moderate, 23.95%; high, 66.98%; and highest 4.98%. Female (P = 0.002), age (P = 0.012), swollen legs (P = 0.035) and history of blood clots (P < 0.001) was correlated with preoperative DVT. Difference among four risk levels was significant (P = 0.007). Patients with highest risk level had statistically significant association with preoperative DVT (P = 0.005, OR = 2.93, 95%CI [1.375–6.246]).ConclusionThe incidence of preoperative DVT was 5.53% in end-stage knee OA patients. The gender (female) and age were independent risk factors for preoperative DVT. The risk group classification by Caprini RAM was significantly associated with preoperative DVT. The usage of Caprini RAM before knee arthroplasty may be beneficial for prophylaxis of DVT.

Duloxetine in OsteoArthritis (DOA) study: effects of duloxetine on pain and function in end-stage hip and knee OA \u2013 a pragmatic enriched randomized controlled trial

BackgroundSome osteoarthritis (OA) patients experience inadequate pain relief from analgesics like acetaminophen and nonsteroidal anti-inflammatory drugs. This could be the result of experienced non-nociceptive centralized pain. Placebo-controlled randomized trials (RCT) have proven the effectiveness of duloxetine for OA and several chronic pain conditions where central sensitization (CS) is one of the key underlying pain mechanisms.ObjectivesAssess the efficacy of an 8-week duloxetine treatment compared to usual care in end-stage knee and hip OA patients with a level of centralized pain.DesignPragmatic, enriched, open-label RCT.MethodsPatients were randomized to duloxetine or to care-as-usual. Primary outcome was pain in the index joint, measured with the pain domain of the Knee injury and Osteoarthritis Outcome Score (KOOS) or the Hip disability and Osteoarthritis Outcome Score (HOOS). The intention-to-treat principle was used, with mixed-model repeated measures to analyze the effect.ResultsOne hundred eleven patients were randomized. Nearly 44% felt much to very much better after duloxetine usage compared to 0% in the care-as-usual group (p < 0.001). The duloxetine group scored 11.3 points (95%CI: 5.8, 16.8) better on the pain domain of the KOOS/HOOS (p < 0.001). Knee patients improved significantly more than hip patients (18.7 [95%CI: 11.3, 26.1] versus 6.0 [95%CI: − 2.6, 14.5] points better).ConclusionsAdding duloxetine treatment seems to be beneficial for end-stage knee OA patients with neuropathic-like symptoms (at risk of CS). End stage Hip OA patients seem to be nonresponsive to duloxetine.Trial registrationDutch Trial Registry with number NTR 4744 (15/08/2014) and in the EudraCT database with number 2013–004313-41.

Toward Preventing Arthritis: A Comparison of Synovial RNA in Osteoarthritic Ankles and Knees

Category:Ankle; Ankle Arthritis; Basic Sciences/Biologics; TraumaIntroduction/Purpose:Osteoarthritis (OA) of the lower limb is a debilitating, incurable, expensive and prevalent condition in people over 45. Although ankle posttraumatic OA (PTOA) has the highest incidence, primary OA is increasingly recognized. The difference in OA incidence between lower limb joints is partly driven by differences in cartilage architecture and chondrocyte function at each site, with ankle chondrocytes showing reduced responsiveness to inflammatory mediators and more metabolic activity than those in the knee. Synovium also contributes to the pathogenesis of OA, however its potentially differential role in knee versus ankle OA remains an unanswered question. We aim to understand the molecular contribution of synovial dysregulation in the progression of ankle and knee OA to uncover candidate pathways for the development of targeted therapeutic paradigms.Methods:After obtaining informed consent from patients undergoing total knee or ankle replacement, basic surgical, past medical history, and imaging data was collected. Synovium samples were harvested during surgery and processed for RNA. Bulk 150 bp, paired-end RNA seq was conducted using standard protocols using the Illumina NovaSeq6000 platform. After quality control trimming, reads were aligned to human reference genome (GRCh38) using STAR (v 2.5) using the Maximum Mappable Prefix method and HTSeq (V0.6.1) was used to index mappable reads per gene. Counts were corrected for gene length using the FPKM method. Differential expression was determined using the edgeR (v 3.16.5) package for R, after adjustment using a scaling normalization factor and P-values were corrected using the Benjamini and Hochberg method. Similarities between samples were determined using Spearman Correlation and degree of similarity was visualized considering the first three Principal Components (PC).Results:RNA was obtained from 6 end-stage ankle OA, 1 end-stage knee OA patients. Of the ankle samples, two were PTOA and the remaining four were primary OA. The PTOA and the primary OA samples showed high sample correlation regardless of class (correlation coefficients ranged from 0.844 to 0.941). In contrast, the total knee sample was less correlated with the ankle samples (correlation coefficients ranged from 0.719 to 0.878). By using the first three PC, we observed that there was no obvious differentiation among the ankle OA samples, but there was clear separation between ankle and total knee samples. We observed an enrichment of genes annotated to the Gene Ontology clusters 'Extracellular Structure Organization' and 'Inflammatory Response' when comparing the two types of OA.Conclusion:These initial pilot results of an ongoing study support our hypothesis that synovial transcriptome differs between the knee and ankle in end-stage osteoarthritis and that anatomic site is a larger driver of synovial expression differences than OA type. This is supported by previous differences reported between ankle and knee chondrocytes in end-stage OA. These findings emphasize the importance of investigating synovial tissue to better understand the microenvironment of the ankle joint and pathogenesis of all etiologies of OA. The ultimate goal is the development of clinical tests and therapeutics aimed at slowing or discontinuing the degenerative process in ankle arthritis.

The Association of Blood Biomarkers and Body Mass Index in Knee Osteoarthritis: A Cross-Sectional Study.

ObjectiveDespite massive efforts, there are no diagnostic blood biomarkers for knee osteoarthritis (KOA). This study investigated several candidate diagnostic biomarkers and the metabolic phenotype in end-stage KOA in the context of obesity.DesignIn this cross-sectional study, adult patients undergoing knee arthroplasty were enrolled and KOA severity was assessed using the Lequesne index. Blood biomarkers with an important role in obesity, the metabolic syndrome, or KOA (oxidized form of low-density lipoprotein [oxLDL], advanced glycation end product [AGE], soluble AGE receptor [sRAGE], fatty acid binding protein 4 [FABP4], phospholipase A2 group IIA [PLA2G2A], fibroblast growth factor 23 [FGF-23], ghrelin, leptin, and resistin) were measured using enzyme-linked immunosorbent assay (ELISA; n = 70) or Luminex technique (subgroup of n = 35). H1-NMR spectroscopy was used for the quantification of metabolite levels (subgroup of n = 31). The hip-knee-ankle angle was assessed. Multivariable and multivariate regression analysis was used to examine the relationship of biomarkers with body mass index (BMI) and KOA severity in complete case and multiple imputation analysis.ResultsWhile most of the investigated biomarkers were not associated with KOA severity, FABP4 and leptin were found to correlate with BMI and gender. Resistin was associated with Lequesne index in complete case analysis. Using a targeted metabolomics approach, BMI-dependent changes in the metabolome were hardly visible.ConclusionsOur findings confirm studies on FABP4, leptin, and resistin with regard to obesity and the metabolic syndrome. There was no association of the investigated biomarkers with KOA severity, most likely due to the patient selection (end-stage KOA patients). Based on this absence of BMI-dependent changes in the metabolome, we might assume that BMI is not correlated with KOA severity in this specific patient group.

Fatty Acid-Binding Protein 4 (FABP4) Is Associated with Cartilage Thickness in End-Stage Knee Osteoarthritis.

There is no single blood biomarker for the staging of knee osteoarthritis (KOA). The purpose of this study was to assess the relationship of obesity, serum biomarkers, the hip-knee-ankle angle (HKAA) with sonographic cartilage thickness. We conducted a cross-sectional study of n = 33 patients undergoing knee arthroplasty. Body mass index (BMI) was recorded, and patients were grouped based on BMI. Serum blood samples were collected, and the following biomarkers were measured using the ELISA technique (subgroup of n = 23): oxidized low-density lipoprotein (oxLDL), soluble receptor for advanced glycation end-products (sRAGE), fatty acid-binding protein 4 (FABP4), membrane-bound phospholipase A2 (PLA2G2A). The HKAA was analyzed on full-length limb standing x-ray images. Cartilage thickness was assessed on ultrasound images. Multivariable regression analysis was performed to account for confounding. After adjusting for age, gender, and HKAA, obese patients had thicker medial femoral cartilage (β = 0.165, P = 0.041). Furthermore, lateral cartilage thickness was negatively correlated with FABP4 level after adjusting for of age, gender, BMI, and HKAA (β = -0.006, P = 0.001). Confirming previous studies, after adjustment, FABP4 level was associated with a higher BMI group (β = 42.99, P < 0.001). None of the other markers (oxLDL, PLA2G2A, and sRAGE) was associated with BMI or cartilage thickness. Our results indicate that BMI has a weak, positive association with cartilage thickness in end-stage KOA patients. FABP4 levels were negatively associated with cartilage thickness. While our study is limited by a small sample size, these results further highlight the role of FABP4 as promising biomarkers of burden of disease in KOA.

Effects of tourniquet use on clinical outcomes and cement penetration in TKA when tranexamic acid administrated: a randomized controlled trial

BackgroundThe role of a tourniquet is still controversial for patients undergoing total knee arthroplasty (TKA). Our current study was performed to determine whether the nonuse of the tourniquet combine with tranexamic acid (TXA) application in TKA patients with end-stage osteoarthritis would accelerate the perioperative recovery rate and provide enough cement mantle thickness for implant fixation.MethodsIn this prospective, randomized controlled trial, 150 end-stage knee osteoarthritis patients receiving TKA were divided into three groups: group A (tourniquet group), group B (non-tourniquet group), and group C (tourniquet in cementation group). All enrolled patients received 3 g of intravenous TXA and 1 g topical TXA. The primary outcomes included blood loss variables and transfusion values. The secondary outcomes included VAS pain score, inflammatory factors level, range of motion, HSS score, postoperative hospital stay, and complication. Furthermore, by using a digital linear tomosynthesis technique, tibial baseplate bone cement mantle thickness was measured in four zones based on the knee society scoring system.ResultsNo significant difference was found among the three groups with regards to total blood loss, transfusion, and complication. However, patients in group B showed lower inflammatory factors levels, shorter length of hospital stay, better range of motion, and lower postoperative pain. No significant difference was found among the three groups in four zones in terms of bone cement mantle thickness.ConclusionsFor end-stage knee osteoarthritis patients, the absence of tourniquet did not appear to affect blood loss and cement penetration in TKA patients. Furthermore, less inflammation reaction and better knee function can be achieved without a tourniquet. We recommend no longer use a tourniquet in primary TKA for patients with end-stage osteoarthritis when TXA is administrated.Trial registrationChiCTR-INR-16009026.Level of evidenceTherapeutic Level I.

Association between knee alignment, osteoarthritis disease severity, and subchondral trabecular bone microarchitecture in patients with knee osteoarthritis: a cross-sectional study

BackgroundKnee osteoarthritis (OA) is a common disabling disease involving the entire joint tissue, and its onset and progression are affected by many factors. However, the current number of studies investigating the relationship between subchondral trabecular bone (STB), knee alignment, and OA severity is limited. We aimed to investigate the variation in tibial plateau STB microarchitecture in end-stage knee OA patients and their association with knee alignment (hip-knee-ankle, HKA, angle) and OA severity.MethodsSeventy-one knee OA patients scheduled for total knee arthroplasty (TKA) underwent preoperative radiography to measure the HKA angle and Kellgren-Lawrence grade. Tibial plateaus collected from TKA were scanned using micro-computed tomography to analyze the STB microarchitecture. Histological sections were used to assess cartilage degeneration (OARSI score). Correlations between the HKA angle, OA severity (OARSI score, Kellgren-Lawrence grade), and STB microarchitecture were evaluated. Differences in STB microstructural parameters between varus and valgus alignment groups based on the HKA angle were examined.ResultsThe HKA angle was significantly correlated with all STB microarchitecture parameters (p < 0.01). The HKA angle was more correlated with the medial-to-lateral ratios of the microarchitecture parameters than with the medial or lateral tibia plateaus. The HKA angle and all STB microarchitecture parameters are significantly correlated with both the OARSI score and Kellgren-Lawrence grade (p < 0.01).ConclusionsThe STB microarchitecture is associated with the HKA angle and OA severity. With the increase of the knee alignment deviation and OA severity, the STB of the affected side tibial plateau increased in bone volume, trabecular number, and trabecular thickness and decreased in trabecular separation.

OA synovial fluid induces proliferation and dedifferentiation of non-OA human articular chondrocytes

Purpose: A major hallmark of osteoarthritis (OA) is cartilage degeneration. Synovial fluid is in direct contact with the articular cartilage and other joint tissues, functioning as a source of nutrients and morphogens. Synovial fluid plays a crucial role in regulating cartilage homeostasis and repair, and alterations in the composition of synovial fluid have been associated with adverse effects on cartilage integrity and function. Chondrocytes residing in cartilage from OA patients are described to adopt hypertrophic and fibrochondrocytic phenotypes. Whether OA synovial fluid has a role in directing chondrocytes into such phenotypic changes has been poorly studied. Therefore, we aimed to investigate the response of non-OA chondrocytes when cultured in vitro for an extended period of time with synovial fluid derived from end-stage OA patients. Methods: A pool of Human knee Articular Chondrocytes (HACs) from four non-OA donors was cultured in 10% (v/v) FCS, 10% (v/v) knee OA synovial fluid (OA-SF) (pool of 24 donors, mean age = 60 ±13 years old) or 10% (v/v) synovial fluid (pool of 8 donors, mean age = 57±10 years old) derived postmortem from macroscopically unaffected knees (non-OA). Cells were formalin-fixated and fluorescently stained with DAPI/Hoechst33342 for DNA quantification. In parallel, cells were harvested for RNA isolation. Expression of chondrocyte marker genes was determined by RT-qPCR and normalized to PPIA. Full ethics for use of HACs and SF are in place. Results: Cell proliferation was significantly increased by OA-SF compared to non-OA synovial fluid after two days stimulation (Figure 1A). In addition, chondrocyte proliferation was monitored for thirteen days and was strongly induced by OA-SF when compared to FCS (Figure 1B). In the first days both FCS and OA-SF induced proliferation, followed by a proliferation halt in the presence of FCS, while OA-SF supported a continued induction of chondrocyte proliferation up until day 13. Expression of genes associated with cartilage extracellular matrix, like COL2A1 (Figure 1C) and COMP, were specifically downregulated by OA-SF in a time-dependent manner. PRG4 expression was gradually decreased for both OA-SF as well as FCS. ACAN expression was maintained in both conditions. Similar to COL2A1 and COMP expression dynamics, SOX9 was strongly downregulated by OA-SF. Expression of dedifferentiation-associated genes COL1A1 (Figure 1D) and COL3A1 remained stable over time. Moreover, SERPINF1, a gene associated with chondrocyte proliferation and a fibrochondrocytic phenotype was steadily upregulated over time. Expression of genes related to chondrocyte hypertrophy and inflammation demonstrated variable responses over time after OA-SF exposure. Conclusions: Our data demonstrate that synovial fluid from end-stage knee OA patients induces a profound change in chondrocyte proliferation and their phenotype that resembles dedifferentiation. This was supported by decreased expression of cartilage-specific ECM genes, maintenance of dedifferentiation markers COL1A1 and COL3A1, induced expression of fibrochondrocyte marker SERPINF1, and sustained proliferative capacity. Notably, the effect of OA-SF on proliferation was greater than non-OA synovial fluid. Interestingly, ACAN expression was not affected by OA-SF treatment. This suggests that the expression of this particular gene is differently regulated compared to other major cartilage ECM-encoding genes. Further research should be undertaken to explore what OA-SF-induced signaling pathways are responsible for the phenotypic shift towards dedifferentiation.

Association between cytokines and exosomes in synovial fluid of individuals with knee osteoarthritis

Background: Cytokines in synovial fluid (SF) play a crucial role in knee osteoarthritis (KOA). Exosomes are nanovesicles that are abundant in SF and carry a large quantity of signaling molecules. The purpose of this study was to evaluate the cytokine profiles of SF-derived exosomes and try to explore its biological function.Methods: Twenty-four KOA patients who were scheduled for their first intra-articular injection or knee replacement surgery were enrolled and divided into the KL1–2 group and the KL3–4 group according to the Kellgren and Lawrence (KL) classification. SF was collected from the patient’s knee for the isolation of exosomes. A multiplex cytokine assay was performed to detect the 21 cytokines in the exosomes. The SF derived-exosomes were exposed to PBMCs and chondrocytes to assess their immunomodulatory potential.Results: Exosomes were successfully extracted from the SF, with an average diameter of 92 nm. Most cytokines were detectable in the SF-derived exosomes. Twelve inflammatory cytokines and eight chemokines were elevated in the exosomes of the KL3–4 group compared to that of the KL1–2 group (p < .05). A higher number of PBMCs were chemo attracted and the proliferation of chondrocytes was restrained by the SF-derived exosomes from the KL3–4 group in comparison with the KL1–2 group (p < .05).Conclusion: Our data indicated that most cytokines in SF are not only in a free form but also associated with and enriched in exosomes. Exosomes from end-stage KOA patients have a higher level of cytokines, especially chemokines, in comparison with the cytokine profiles of the soluble SF. SF-derived exosomes recruit inflammatory cells and inhibit cartilage proliferation, thus promoting joint degeneration. These data provide a new perspective for understanding the changes in the inner environment of KOA.

Interleukin-17 is a potential contributor to the inflammatory environment in the OA joint

Purpose: Osteoarthritis (OA) has been historically viewed as a degenerative disease caused by ‘wear and tear’, with the loss of articular cartilage as the most important clinical feature. Modern imaging techniques have shown us over the last decade that OA is a multifactorial disorder that affects multiple tissues in the joint, including the subchondral bone and synovium. Synovitis is now increasingly recognised to be involved in OA pathogenesis, with in vitro studies showing production and release of pro-inflammatory cytokines (such as interleukin (IL)-6, IL-8, and IL-17, infiltration of mononuclear cells, and increased angiogenesis. This study aimed to establish whether the pro-inflammatory cytokine IL-17 contributes to the inflammatory environment within the OA joint. We hypothesized that IL-17 can contribute to inflammatory cell recruitment to the OA synovium and that IL-17 responsive stromal cell populations within the OA joint can further drive inflammation. Methods: Formalin-fixed paraffin-embedded synovial tissue from injured and early-stage knee OA patients was stained for IL-17 receptor A (IL-17RA) and IL-17 receptor C (IL-17RC) as well as for the macrophage markers CD68 and CD206. Freshly isolated synovium from end-stage knee OA patients was digested for FACS analysis using a macrophage panel. Stromal cells from synovium (synovial fibroblasts) and cartilage (chondrocytes) from end-stage knee OA patients were cultured to passage 3 and assessed for IL-17R mRNA expression by RT-qPCR. In addition, these stromal cells were treated for 24h with 10 ng/ml rh IL-17 and RNA was harvested for RNA-Seq analysis. Results: We detected IL17RA and IL17RC mRNA in cultured chondrocytes and synovial fibroblasts from end-stage OA patients and showed that IL-17 receptors IL-17RA and IL-17RC are expressed in synovial tissue sections derived from injured and early-stage OA patients. While protein expression of IL-17RA was significantly higher in patients with a high synovitis score compared to a low synovitis score (p=0.012), IL-17RC did not show this difference (p=0.98). IL-17RA staining showed a trend toward correlation with CD68 (p=0.07) and correlated significantly with CD206 staining (p=0.004). IL-17RC did not correlated with CD206 (p=0.88), but showed a trend towards significance with CD206 (p=0.53). FACS data confirmed the presence of CD206+ macrophages in end-stage OA synovium. In cultured synovial fibroblasts and chondrocytes from end-stage OA patients, IL-17 treatment significantly upregulated the mRNA expression of several granulocyte-attracting and -regulating factors such as CCL2, CXCL3, CXCL6, and CXCL8. Conclusions: This study shows that IL-17 may contribute to the inflammatory environment in the joint by acting on synovial fibroblasts and chondrocytes to driving mononuclear cell influx. As IL-17 responsive cells are correlated with macrophage populations, IL-17 may be able to further drive inflammation by acting on these inflammatory cells as well as on synovial fibroblasts and chondrocytes.

Adipokines production in metabolic-associated osteoarthritis of the knee joint

Purpose: Obesity is a known risk factor for knee osteoarthritis (OA). It is speculated that adipokines produced by excess adipose tissue can trigger a low grade inflammatory state that may contribute to joint damage. The presence of health comorbidities is also presumed to exacerbate the condition further. The aims are 1: To determine the plasma concentrations of leptin, apelin and progranulin in end stage knee OA patients with differing gender, BMI, cardiovascular and metabolic conditions status. 2: To relate these factors with evaluation of clinical function, radiological status and circulating inflammatory markers of the patients. Methods: A total of 114 gender-matched participants were recruited into three equal groups (n = 38): non-obese (Md age = 74.00 ± 36.00 years), obese (Md age = 62.00 ± 46.00 years), and metabolic syndrome (MetS) (Md age = 71.50 ± 38.00 years). Clinical parameters included patient reported outcome measures (WOMAC and SF-12); OA grading was assessed using the Kellgren-Lawrence (KL) criteria; and blood plasma leptin, apelin, progranulin and S100A8/A9 were analysed via enzyme-linked immunosorbent assay technique. Results: Plasma leptin level was lowest in nonobese patients compared to both other groups (Md = 6.59 ng/ml, P < 0.01). The concentration of leptin was significantly higher in females than in males (Md = 39.07 vs Md = 16.25, P < 0.001). Plasma levels for apelin and progranulin did not show any statistical difference across either patient groups or gender. Plasma leptin showed significant positive correlation with BMI (rs = 0.681, P < 0.001) and S100A8/A9 (rs = 0.289, P < 0.01) with inverse relationship with SF-12 (rs = −0.350, P < 0.001). On further analysis, plasma apelin levels were positively correlated with physical component scores of SF-12 (rs = 0.311, P = 0.001) whilst plasma progranulin concentration showed negative correlation with S100A8/A9 (rs = −0.222, P < 0.05). No statistically significant relationship was seen between the investigated adipokines. Clinically, higher proportion of female individuals had upper limb OA than males (42.11% vs 14.04%, P = 0.001). Conclusions: Plasma leptin, was strongly correlated with BMI levels unlike plasma apelin and progranulin. The findings indicated that raised leptin concentrations was associated with reduced general health whilst the opposite was seen for plasma apelin. An increased systemic progranulin was associated with reduced inflammation, perhaps demonstrating a protective role in osteoarthritis. Further studies are warranted to gain insight into the roles of these adipokines in disease progression and prognosis especially in obesity.