Early OA Research Articles

Evaluation of an automated laminar cartilage T2 relaxation time analysis method in an early osteoarthritis model.

A fully automated laminar cartilage composition (MRI-based T2) analysis method was technically and clinically validated by comparing radiographically normal knees with (CL-JSN) and without contra-lateral joint space narrowing or other signs of radiographic osteoarthritis (OA, CL-noROA). 2D U-Nets were trained from manually segmented femorotibial cartilages (n = 72) from all 7 echoes (AllE), or from the 1st echo only (1stE) of multi-echo-spin-echo (MESE) MRIs acquired by the Osteoarthritis Initiative (OAI). Because of its greater accuracy, only the AllE U-Net was then applied to knees from the OAI healthy reference cohort (n = 10), CL-JSN (n = 39), and (1:1) matched CL-noROA knees (n = 39) that all had manual expert segmentation, and to 982 non-matched CL-noROA knees without expert segmentation. The agreement (Dice similarity coefficient) between automated vs. manual expert cartilage segmentation was between 0.82 ± 0.05/0.79 ± 0.06 (AllE/1stE) and 0.88 ± 0.03/0.88 ± 0.03 (AllE/1stE) across femorotibial cartilage plates. The deviation between automated vs. manually derived laminar T2 reached up to - 2.2 ± 2.6ms/ + 4.1 ± 10.2ms (AllE/1stE). The AllE U-Net showed a similar sensitivity to cross-sectional laminar T2 differences between CL-JSN and CL-noROA knees in the matched (Cohen's D ≤ 0.54) and the non-matched (D ≤ 0.54) comparison as the matched manual analyses (D ≤ 0.48). Longitudinally, the AllE U-Net also showed a similar sensitivity to CL-JSN vs. CS-noROA differences in the matched (D ≤ 0.51) and the non-matched (D ≤ 0.43) comparison as matched manual analyses (D ≤ 0.41). The fully automated T2 analysis showed a high agreement, acceptable accuracy, and similar sensitivity to cross-sectional and longitudinal laminar T2 differences in an early OA model, compared with manual expert analysis. Clinicaltrials.gov identification: NCT00080171.

Identification and experimental validation of key genes in osteoarthritis based on machine learning algorithms and single-cell sequencing analysis

PurposeOsteoarthritis (OA) is a prevalent cause of disability in older adults. Identifying diagnostic markers for OA is essential for elucidating its mechanisms and facilitating early diagnosis. MethodsWe analyzed 53 synovial tissue samples (n = 30 for OA, n = 23 for the control group) from two datasets in the Gene Express Omnibus (GEO) database. We identified differentially expressed genes (DEGs) between the groups and applied dimensionality reduction using six machine learning algorithms to pinpoint characteristic genes (key genes). We classified the OA samples into subtypes based on these key genes and explored the differences in biological functions and immune characteristics among subtypes, as well as the roles of the key genes. Additionally, we constructed a protein-protein interaction network to predict small molecules that target these genes. Further, we accessed synovial tissue sample data from the single-cell RNA dataset GSE152805, categorized the cells into various types, and examined variations in gene expression and their correlation with OA progression. Validation of key gene expression was conducted in cellular experiments using the qPCR method. ResultsFour genes AGMAT, MAP3K8, PER1, and XIST, were identified as characteristic genes of OA. All can independently predict the occurrence of OA. With these genes, the OA samples can be clustered into two subtypes, which showed significant differences in functional pathways and immune infiltration. Eight cell types were obtained by analyzing the single-cell RNA data, with synovial intimal fibroblasts (SIF) accounting for the highest proportion in each sample. The key genes were found over-expressed in SIF and significantly correlated with OA progression and the content of immune cells (ICs). We validated the relative levels of key genes in OA and normal cartilage tissue cells, which showed an expression trend consistency with the bioinformatics result except for XIST. ConclusionFour genes, AGMAT, MAP3K8, PER1, and XIST are closely related to the progression of OA, and play as diagnostic and predictive markers in early OA.

Investigating the relationship between radiographic joint space width loss and deep learning-derived magnetic resonance imaging-based cartilage thickness loss in the medial weight-bearing region of the tibiofemoral joint

ObjectiveTo investigate the relationship between measures of radiographic joint space width (JSW) loss and magnetic resonance imaging (MRI)-based cartilage thickness loss in the medial weight-bearing region of the tibiofemoral joint over 12–24 months. To stratify this relationship by clinically meaningful subgroups (sex and pain status). DesignWe analyzed a subset of knees (n ​= ​256) from the Osteoarthritis Initiative (OAI) likely in early stage OA based on joint space narrowing (JSN) measurements. Natural logarithm transformation was used to approximate near normal distributions for JSW loss. Pearson Correlation coefficients described the relationship between ln-transformed JSW loss and several versions of deep learning-derived MRI-based cartilage thickness loss parameters (minimum, maximum, and mean) in subregions of the femoral condyle, tibial plateau, and combined femoral and tibial regions. Linear mixed-effects models evaluated the associations between the ln-transformed radiographic and MRI-derived measures including potential confounders. ResultsWe found weak correlations between ln-transformed JSW loss and MRI-based cartilage thickness ranging from R ​= ​−0.13 (p ​= ​0.20) to R ​= ​0.26 (p ​< ​0.01). Correlations were higher (still poor) among females compared to males and painful compared to non-painful knees. Model results showed weak associations for nearly all MRI-based measures, ranging from no association to β (95% CI) ​= ​0.25 (0.11, 0.39). Associations were higher among females compared to males and minimal differences between painful and non-painful knees. ConclusionsDespite its recommended use in disease-modifying OA drug clinical trials, results suggest that JSW loss is an ineffective proxy measure of cartilage thickness loss over 12–24 months and within a localized region of the tibiofemoral joint.

Osteoarthritis patients exhibit an autonomic dysfunction with indirect sympathetic dominance

BackgroundOsteoarthritis (OA) is a chronic degenerative joint disease causing limited mobility and pain, with no curative treatment available. Recent in vivo studies suggested autonomic alterations during OA progression in patients, yet clinical evidence is scarce. Therefore, autonomic tone was analyzed in OA patients via heart rate variability (HRV) measurements.MethodsTime-domain (SDRR, RMSSD, pRR50) and frequency-domain (LF, HF, LF/HF) HRV indices were determined to quantify sympathetic and parasympathetic activities. In addition, perceived stress, WOMAC pain as well as serum catecholamines, cortisol and dehydroepiandrosterone-sulphate (DHEA-S) were analyzed. The impact of the grade of disease (GoD) was evaluated by linear regression analysis and correlations with clinical data were performed.ResultsGoD significantly impacted the autonomic tone in OA patients. All time-domain parameters reflected slightly decreased HRV in early OA patients and significantly reduced HRV in late OA patients. Moreover, frequency-domain analysis revealed decreased HF and LF power in all OA patients, reflecting diminished parasympathetic and sympathetic activities. However, LF/HF ratio was significantly higher in early OA patients compared to late OA patients and implied a clear sympathetic dominance. Furthermore, OA patients perceived significantly higher chronic stress and WOMAC pain levels compared to healthy controls. Serum cortisol and cortisol/DHEA-S ratio significantly increased with GoD and positively correlated with WOMAC pain. In contrast, serum catecholamines only trended to increase with GoD and pain level.ConclusionsThis prospective study provides compelling evidence of an autonomic dysfunction with indirect sympathetic dominance in early and late knee OA patients for the first time based on HRV analyses and further confirmed by serum stress hormone measurements. Increased sympathetic activity and chronic low-grade inflammation in OA as well as in its major comorbidities reinforce each other and might therefore create a vicious cycle. The observed autonomic alterations coupled with increased stress and pain levels highlight the potential of HRV as a prognostic marker. In addition, modulation of autonomic activity represents an attractive future therapeutic option.Graphical abstract

Adiposity and cartilage lesions following ACL reconstruction

ObjectiveTo determine if global, central, or peripheral adiposity is associated with prevalent and worsening cartilage lesions following anterior cruciate ligament reconstruction (ACLR). MethodsIn 107 individuals one-year post-ACLR, adiposity was assessed globally (body mass index, BMI), centrally (waist circumference), and peripherally (knee subcutaneous adipose tissue thickness) from magnetic resonance imaging (MRI). Tibiofemoral and patellofemoral cartilage lesions were assessed from knee MRIs at 1- and 5-years post-ACLR. Poisson regression evaluated the relation of adiposity with prevalent and worsening tibiofemoral and patellofemoral cartilage lesions adjusting for age, sex, and activity level. ResultsThe prevalence ratios of adiposity with tibiofemoral (presence in 49%) and patellofemoral (44%) cartilage lesions ranged from 0.99 to 1.03. Adiposity was more strongly associated with longitudinal changes in tibiofemoral (worsening in 21%) and patellofemoral (44%) cartilage lesions. One-unit increase in global (kg/m2), central (cm), and peripheral (mm) adiposity was associated with a higher risk of worsening tibiofemoral cartilage lesions by 17% (risk ratios [95% CI]: 1.17 [1.09 to 1.23]), 5% (1.05 [1.02 to 1.08]), and 9% (1.09 [1.03 to 1.16]), and patellofemoral cartilage lesions by 5% (1.05 [1.00 to 1.12]) 2% (1.02 [1.00 to 1.04]) and 2% (1.02 [1.00 to 1.04]), respectively. ConclusionGreater adiposity was a risk factor for worsening cartilage lesions up to 5 years post-ACLR. Clinical interventions aimed at mitigating excess adiposity may be beneficial in preventive approaches for early post-traumatic OA.

Disease severity versus pain severity: Range of motion differences during single- and multiplanar tasks in women with carpometacarpal osteoarthritis.

In carpometacarpal osteoarthritis (CMC OA) of the thumb, to what extent treatments should be directed by radiographic disease severity versus pain-based indicators remains an open question. To address this gap, this study investigated the relative impact of disease severity and pain severity on the range of motion in participants with CMC OA. We hypothesized larger differences would exist between extremes in the pain severity cohort than the disease severity cohort, suggesting pain modulates movement to a greater extent than joint degradation. Thirty-one female participants (64.6 ± 10.9 years) were grouped as symptomatic or asymptomatic (pain severity cohort) and early stage OA or end-stage OA (disease severity cohort) using radiographs and questionnaires. Kinematics were measured during single-planar and multiplanar range of motion tasks. Joint angle differences between groups were statistically compared. Differences in self-reported pain, function, and disability were evident in both participant cohorts. Notably, substantial distinctions emerged exclusively during multiplanar tasks, with a greater prevalence in the disease severity cohort compared to the pain severity cohort. Participants with end-stage OA also exhibited similar overall area covered during circumduction in comparison to those with early-stage OA, despite having a decreased range of motion at the CMC joint. The study underscores the importance of assessing multiplanar tasks, potentially leading to earlier identification of CMC OA. While movement compensations such as employing the distal thumb joints over the CMC joint were observed, delving deeper into the interplay between pain and movement could yield greater insight into the underlying factors steering these compensatory mechanisms.

The relationship between periarticular muscle properties and knee pain in non-overweight postmenopausal females

ObjectiveTo determine how properties of periarticular muscle relate to knee OA outcomes, specifically how inter- and intramuscular fat (IMF) content (percentage, volume) and muscle volume relate to knee pain and function among non-overweight postmenopausal females (non-OW PMF). MethodsIn this cross-sectional study, 51 non-OW PMF (BMI<25 kg/m2, 50–85 years) with evidence of early knee OA underwent 3T knee magnetic resonance (MR) imaging (T1-weighted, 2-point Dixon, in-phase images, voxel size: 0.7 × 0.7 × 2.0 mm). Muscle features from MR images of the knee were segmented to compute muscle properties (percentage and volume of IMF, muscle volume). Multivariable linear regression determined the relationships between these muscle properties (slice-wise and volume-wise) and of knee pain (Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire, Intermittent and Constant Osteoarthritis Pain) and function (40 m walk, 30 s chair stand, 9-step stair climb). ResultsDue to missing parameters, only 42 participants were included in the final analysis (mean age = 62±9 years, BMI = 22.7 ± 3.2 kg/m2, KL score ≥ 2: 14(34.2 %)). A 10 % higher IMF percentage across the full volume of calf slices, but not thigh, was associated with pain scores reflecting greater KOOS knee pain (b = -25.27(-38.44, -12.10)), intermittent pain (b = 36.81(19.25, -54.38)), and constant pain (b = 21.32(2.00, 40.64), as well as longer 40 m walk times (b = 8.43(0.64, 16.21)). b refers to the unstandardized beta coefficient. ConclusionGreater IMF in the periarticular calf is associated with greater knee pain and worse functional status among non-OW PMW with varying degrees of knee pain. Our finding highlights the need to closely study the role of the periarticular calf in knee OA by extending knee MRI scans to encompass a larger field of view to capture more muscle both proximal and distal from the joint line.

ABNORMAL CHONDROCYTE MORPHOLOGY, CLUSTERING, AND CELL SWELLING IN A SCRAPED HUMAN CARTILAGE MODEL OF OSTEOARTHRITIS

AbstractObjectivesOsteoarthritis (OA) is a complex joint disorder characterised by the loss of extracellular matrix (ECM) leading to cartilage degeneration. Changes to cartilage cell (chondrocyte) behaviour occur including cell swelling, the development of fine cytoplasmic processes and cell clustering leading to changes in cell phenotype and development of focal areas of mechanically-weak fibrocartilaginous matrix[1]. To study the sequence of events in more detail, we have investigated the changes to in situ chondrocytes within human cartilage which has been lightly scraped and then cultured with serum.MethodsHuman femoral heads were obtained with Ethical permission and consent from four female patients (mean age 74 yrs) undergoing hip arthroplasty following femoral neck fracture. Osteochondral explants of macroscopically-normal cartilage were cultured as a non-scraped control, or scraped gently six times with a scalpel blade and both maintained in culture for up to 2wks in Dulbecco's Modified Eagle's Medium (DMEM) with 25% human serum (HS). Explants were then labelled with CMFDA (5-chloromethylfluorescein-diacetate) and PI (propidium iodide) (10μM each) to identify the morphology of living or dead chondrocytes respectively. Explants were imaged using confocal microscopy and in situ chondrocyte morphology, volume and clustering assessed quantitatively within standardised regions of interest (ROI) using Imaris® imaging software.ResultsWithin 2wks of culture with HS, chondrocyte volume increased significantly from 412±9.3µm3 (unscraped) at day 0 to 724±16.6 µm3 (scraped) [N(n) = 4(380)] (P=0.0002). Chondrocyte clustering was a prominent feature of HS culture as the percentage of clusters in the cell population increased with scraping from 4.8±1.4% to 14.9±3.9% [N(n) = 4(999)] at week 2 (P=0.0116). In addition, the % of the chondrocyte population within clusters increased from approximately 38% to 60%, and the number of cells per cluster increased significantly from 3.2±0.08 to 4±0.22 (P=0.031). The development of abnormal ‘fibroblastic-like’ chondrocyte morphology demonstrating long (&gt;5µm) cytoplasmic processes also occurred, however the time course of this was more variable. For some samples, clustering occurred before abnormal morphology, but for others the opposite occurred. Typically, by the second week, 17±2.64% of the cell population had processes and this increased to 22±4.02% [N(n) = 4(759)] with scraping.ConclusionsScraping the cartilage will remove surface constituents including lubricants (e.g. lubricin, hyaluronic acid, phospholipids), extracellular matrix constituents (collagen, proteoglycans – potentially the ‘lamina splendens’) and cells (chondrocytes and mesenchymal stromal cells (MSCs)). Although we do not know which of these component(s) is important, the effect is to dramatically increase the permeation of serum factors into the cartilage matrix and signal the development of cytoplasmic processes, cell clustering and swelling. It is notable that these cellular changes are similar to those occurring in early OA[1]. This raises the interesting possibility that scraped cartilage cultured with human serum recapitulates some of the changes to in situ chondrocytes during early stages of cartilage degeneration and as such, could be a useful model for following the deleterious changes to matrix metabolism.Declaration of Interest(b) declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported:I declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

F-ACTIN DISTRIBUTION OF THE CHONDROCYTE CYTOSKELETON AND ITS ASSOCIATION WITH EARLY OSTEOARTHRITIC CHONDROCYTE PROPERTIES

AbstractObjectivesOsteoarthritis (OA) is a painful and debilitating disorder of diarthroidal joints. Progressive degeneration of the cartilage extracellular matrix (ECM) together with abnormal chondrocyte characteristics occur leading to a switch to a fibroblast-like phenotype and production of mechanically-weak cartilage. Early changes to chondrocytes within human cartilage have been observed including chondrocyte swelling[1] together with the development of thin cytoplasmic processes which increase in number and length with degeneration[2]. Changes to chondrocyte phenotype in degenerate cartilage are associated with F-actin redistribution and stress fibres (SF) formation, leading to morphologically-dedifferentiated (fibroblast-like) chondrocytes[3,4]. It is unclear if these processes are a consequence of ‘passive’ cell swelling into a defective ECM or an ‘active’ event driven by changes in cell metabolism resulting in alterations to cell shape. To address this, we have quantified and compared the distribution and levels of F-actin, a key cytoskeletal protein involved in the formation of cytoplasmic processes, within in situ chondrocytes in non-degenerate and mildly degenerate human cartilage.MethodsHuman femoral head cartilage was obtained from 21 patients [15 females, 6 males, average age 69.6yrs, (range 47–90yrs)] following femoral neck fracture, with Ethical Approval and patient's permission. Cartilage explants were removed from areas graded non-degenerate grade 0 (G0) or mildly degenerate grade 1 (G1) and cultured for up to 3wks in Dulbecco's Modified Eagle's Medium (DMEM) +/− 25% human serum (HS). In situ chondrocytes were stained with CMFDA (5-chloromethylfluoresceindiacetate, Cell-Tracker Green®) and phalloidin (F-actin labelling) and imaged by confocal microscopy and analysed quantitatively using ImageJ and Imaris® software.ResultsThere were significant increases in the total amount (TA) of F-actin and its distribution [intense punctuate (IP) and intense areas (IA)] between the whole chondrocyte populations of G0 and G1 cartilage (P=0.0356; 0.0112; 0.016, respectively). Where the volume of chondrocytes was divided into normal (&lt;1000 µm³) and swollen (≥1000 µm³) cells, F-actin TA increased in swollen cells (P=0.036 within G0 and G1, and P=0.0009 between grades) compared to chondrocytes of normal volume in each grade. Moreover, IP and IA within and between G0 and G1 were higher compared to normal chondrocytes (with P&lt;0.0001 for IP and P&lt;0.001 for IA). In addition, tissue culture experiments demonstrated that 90% of chondrocytes with cytoplasmic processes had strong F-actin intensity (either IP or IA with P&lt;0.0001). Furthermore, 83% of this F-actin was associated with cytoplasmic processes, with &gt;65% situated at the base of the process (P&lt;0.0001).ConclusionsThe increases in chondrocyte F-actin levels (TA) and its localisation (IP, IA) appear to be associated with cell swelling and development of cytoplasmic processes, which are both characteristics of early OA cartilage[1]. This suggests the formation of chondrocyte cytoplasmic processes is an ‘active’ event potentially involving changes to matrix metabolism rather than a ‘passive’ cell swelling into a defective extracellular matrix.Declaration of Interest(b) declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported:I declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

High tibial osteotomy as a treatment protocol for osteoarthritis of a knee- time for a change?

Osteoarthritis is a common degenerative condition of the joints, consisting of retrogressive sequence of cell and matrix changes that result in loss of articular cartilage structure and function. It affects all ethnic groups in all geographic locations. There are several treatment options available for early OA knee including non pharmacological, pharmacological treatment and various surgical treatment. An arthroplasty is a good option for low demand and older patients there remains a significant concern regarding the longevity of implant, particularly in younger patients whereas high tibial osteotomy is joint preserving surgery . The normal anatomical tibial bone shape is maintained after the HTO, which allows for conversion to knee replacement if required in future . Early ambulation and weight bearing on operated limb is possible with use of orthofix .Orthofix does not require additional surgery for implant removal and bone graft is also not needed.

Poster 112: Epigenetic Dysregulation during the OA Progression in Hip FAI

Objectives: Femoroacetabular impingement (FAI) is considered a leading cause of early hip OA, but initial molecular mechanisms that lead FAI patients to OA progression remains to be elucidated. Recent articles revealed that epigenetic changes are associated with OA progression, specifically, DNA methyltransferase 3B (DNMT3B) plays a critical role on cartilage homeostasis by attenuating catabolic gene expression. This study aimed to examine the catabolic state of articular chondrocyte (ACs) during OA progression in hip FAI disease, particularly the expressions of DNMT3B and 4-aminobutyrate aminotransferase (ABAT, downstream of DNMT3B), to assess how epigenetic dysregulation contributes to OA progression. Methods: Full-thickness cartilage samples were collected from the impingement zone. In total, twelve patients underwent hip preservation surgery for cam FAI (early-FAI) and twelve patients underwent total hip replacement for advanced OA secondary to cam FAI (late FAI-OA) were included in this study. As a non-disease (ND) group, five healthy samples were procured from hip joint cadavers. The explants were cultured in unstimulated conditions or catabolic stimulus (IL1β). Histological analyses was performed with safranin-O/fast-green. Gene expression was analyzed via qPCR for GAPDH, DNMT3B, ABAT, MMP-13, and COL10A1. Protein expression was analyzed by western blotting analysis for DNMT3B and ABAT. Methylation specific PCR was performed to assess the methylation status at ABAT promoter (epigenetic change). Results: The early FAI group included younger subjects with lower Tönnis grade than the late FAI OA group; however, there were no significant differences in gender, BMI, and α-angle between groups. Cartilage samples in early-FAI and late FAI-OA showed a histological OA phenotype (Figure 1A). RT-PCR confirmed increased expression of MMP-13 and COL10A1 in early and late FAI-OA (Figure 1B), confirming cartilage degeneration, catabolism, and chondrocyte hypertrophy when compared to ND group. Interestingly, RT-PCR revealed that expression of DNMT3B gradually declined as the disease progressed (ND vs early p&lt;0.001, early vs late p=0.016), while ABAT increased as the disease progressed (ND vs early p&lt;0.001, early vs late p=0.035, Figure 1B). IF staining confirmed that DNMT3B was abundantly expressed in chondrocytes of normal cartilage but the expression gradually decreased with disease progression, contrary ABAT expression gradually increased as the disease progressed (Figure 1C). These results were supported by protein expression in western blotting analysis (Figure 1D). In MSP analysis, the human ABAT promoter is characterized by a typical CpG island (Figure 2A, blue area). Additionally, there was hypomethylation at the ABAT promoter during end stage of disease (ND vs early p=0.022, early vs late p=0.042) (Figure 2B). Catabolic stimulus with IL1β for early FAI and late FAI-OA, accentuated the ABAT promoter hypomethylation (early FAI: nontreatment vs IL1β p=0.056, late FAI-OA: nontreatment vs IL1β p=0.015, Figure 2C) and resulted in further overexpression of ABAT and catabolic markers and decreased expression of DNMT3B (Figure 3A-C). These findings are supported by protein expression in western-blotting analysis (Figure 3D). Conclusions: In the present study, histological findings were similar in early and late FAI, but DNMT3B expression levels gradually decreased with OA progression, while ABAT and catabolic marker expression levels increased, suggesting a less catabolic phenotype in the early stage of disease. MSP analysis confirmed ABAT promoter hypo-methylation (epigenetically dysregulation) as hip OA progresses. Notably, in the current study, the inflammatory stimulus with IL1β further reduced DNA methylation at the ABAT promoter and resulted in a concomitant excessive increase of ABAT and catabolic markers in human hip OA ACs. This study suggests, for the first time, that cartilage degeneration in the impingement zone in hip FAI is progressive at the molecular level and may be controlled in part by an epigenetic dysregulation. Understanding the mechanism of OA disease in hip FAI will potentially provide concomitant interventional treatment to hip pre-OA disease.

Targeting Adenosine Signalling in Knee Chondropathy: The Combined Action of Polydeoxyribonucleotide and Pulsed Electromagnetic Fields: A Current Concept Review.

Chondropathy of the knee is one of the most frequent degenerative cartilage pathologies with advancing age. Scientific research has, in recent years, advanced new therapies that target adenosine A2 receptors, which play a significant role in human health against many disease states by activating different protective effects against cell sufferance and damage. Among these, it has been observed that intra-articular injections of polydeoxyribonucleotides (PDRN) and Pulsed Electromagnetic Fields (PEMF) can stimulate the adenosine signal, with significant regenerative and healing effects. This review aims to depict the role and therapeutic modulation of A2A receptors in knee chondropathy. Sixty articles aimed at providing data for our study were included in this review. The present paper highlights how intra-articular injections of PDRN create beneficial effects by reducing pain and improving functional clinical scores, thanks to their anti-inflammatory action and the important healing and regenerating power of the stimulation of cell growth, production of collagen, and the extracellular matrix. PEMF therapy is a valid option in the conservative treatment of different articular pathologies, including early OA, patellofemoral pain syndrome, spontaneous osteonecrosis of the knee (SONK), and in athletes. PEMF could also be used as a supporting therapy after an arthroscopic knee procedure total knee arthroplasty to reduce the post-operative inflammatory state. The proposal of new therapeutic approaches capable of targeting the adenosine signal, such as the intra-articular injection of PDRN and the use of PEMF, has shown excellent beneficial results compared to conventional treatments. These are presented as an extra weapon in the fight against knee chondropathy.

Enabling early detection of knee osteoarthritis using diffusion–relaxation correlation spectrum imaging

To present a technique that enables detection of early stage OA of the knee using diffusion-relaxation correlation spectrum imaging (DR-CSI).Fifty-five early osteoarthritis patients (OA, Kellgren-Lawrence [KL] score 1 to 2; mean age, 56.4 years) and 49 healthy volunteers (mean age, 56.7 years) were underwent magnetic resonance imaging (MRI) with T2-mapping and DR-CSI techniques. Maps of mean apparent diffusion coefficient (ADC), T2 relaxation time and volume fraction Vi for DR-CSI compartment i (A, B, C, D) sensitivity, specificity, and positive and negative likelihood ratio (PLR, NLR) were assessed to determine the diagnostic accuracy for detection of early-stage degeneration of knee articular cartilage. The structural abnormalities of articular cartilage were evaluated using modified Whole-Organ MR Imaging Scores (WORMS).All intra- and interobserver agreements for DR-CSI compartment volume fractions and modified WORMS of cartilage were excellent. Early OA versus the controls had higher VC, lower VA and VB (p<0.001), but comparable VD (p>0.05). VA, VB and VC had a moderate association with WORMS. No significant correlation was identified between VD and WORMS. VC had better ability than VA,VB, VD, T2 and ADC to discriminate early OA patients from healthy controls (area under the curve, 0.898). Sensitivity, specificity, PLR, and NLR of VC with a cut-off value of 29.9% were 81.8% (95% confidence interval [CI], 69.1-90.9%), 95.9% (86-99.5%), 20.05% (5.13-78.34%), and 0.19% (0.11-0.33%).DR-CSI compartment volume fractions may be sensitive indicators for detecting early-stage degeneration in knee articular cartilage.

E059 A retrospective analysis of the effectiveness &amp; safety of platelet rich plasma injections in primary osteoarthritis in knee joint, in patients attending a tertiary care hospital, Sri Lanka; a cohort study

Abstract Background/Aims Osteoarthritis (OA) is a common, challenging condition and is a leading cause of disability and impaired quality of life in Sri Lanka due to its ageing population and obesity pandemic. Conventional therapies for OA such as non-pharmacological measures, analgesics and surgical interventions have their own limitations. Platelet rich plasma (PRP) has been suggested as a second-line treatment by European Alliance of Associations for Rheumatology (EULAR) for early and moderate OA, which needs further evaluation to prove its efficacy and safety. This is a retrospective analysis of the effectiveness and safety of PRP injections, in a cohort of patients, attending the National Hospital of Sri Lanka for primary knee OA. Methods A total of 33 patients who had been treated with PRP injections were examined immediately prior to injection as well as 3 weeks, 3 months and 6 months later. Details of clinical variables, demographic data, and assessment of efficacy and safety were gathered by the pre-treatment form filled at the routine clinics. Pre-treatment form is comprised of inclusion and exclusion criteria, gender, biochemical investigations, radiological evidences in the knee joint, usage of previous pharmacological and non-pharmacological treatment received by the patient, weight, height and body mass index (BMI). Pain at the site of infection, stiffness, bleeding and local infection were examined as measures of safety. Pain score according to visual analogue scale and Western Ontario and McMaster Universities Osteoarthritis index (WOMAC) score were used as measures of effectiveness. Descriptive statistics was used to present demographic and clinical variables. Friedman test with Wilcoxon signed rank test for pairwise comparisons were used in the analysis of related samples of pain scores and WOMAC scores pre and post PRP therapy in order to assess effectiveness. Results Stiffness following PRP injection was experienced by 8 (24.2%) participants but none of the patients developed pain and bleeding. Median of pain score before PRP injection was 7.00 and it was reduced to 3.00 after 6 months of therapy. Median of WOMAC score before PRP injection was 54.00 and it was reduced to 30.00 after 6 months of therapy. Significant reduction of pain score (p = 0.000) as well as WOMAC score (p = 0.000) was observed. A significant gradual reduction of both pain score and WOMAC score was observed at 3 weeks, 3 months and 6 months post PRP injection (p = 0.000). Conclusion PRP injections had a good safety profile in our study. A similar trend of improvement of knee OA was observed in terms of both pain score and WOMAC score which ensures its effectiveness. However, with a guidance of these data in Sri Lankan patients, a randomized double blinded clinical trial is recommended. Disclosure R.M. Wickramarachchi: None. S. Janagan: None. W. Udeshika: None. G. Chandana: None. Y. Udara: None. S. Fernando: None.

Trimalleolar Fractures Treated by Open Reduction Internal Fixation Compared With Arthroscopically Assisted Reduction and Minimally Invasive Surgery

Currently, the standard of treatment for trimalleolar (TM) fracture is osteosynthesis through open reduction and internal fixation (ORIF). This study assessed whether arthroscopically assisted reduction and minimally invasive surgery (AARMIS) can be an alternative surgical method for TM fractures. This retrospective cohort study included 49 patients with TM that were surgically treated. 27 patients received ORIF and 22 patients underwent AARMIS . At baseline, we recorded the patient's demographic features, fracture pattern (AO-OTA and Haraguchi classification), and surgical method. For postoperative results, we examined the patient's radiographic outcome, including time to union, quality of fracture reduction, as well as functional outcomes (American Orthopaedic Foot & Ankle Society ankle hindfoot score, ankle range of motion, and visual analog scale of pain) and perioperative complications. At mean follow-up of 46.6 (ORIF) and 36.4 months (AARMIS), both groups had comparable radiographic outcomes. No significant difference in rates of early ankle OA were detected. In terms of functional outcome, VAS pain and AOFAS score at postoperative day 3, postoperative month 3, and at final follow-up were not different. In terms of range of motion, we did not find a significant difference in mean range of motion. Patients with TM fractures treated with AARMIS achieved satisfactory results and was not significantly different in radiographic and functional performance compared with ORIF. Level III, retrospective cohort study.

Low-intensity pulsed ultrasound irradiation attenuates collagen degradation of articular cartilage in early osteoarthritis-like model mice

PurposeOsteoarthritis (OA) is a combination of degeneration and destruction of articular cartilage due to mechanical stress, secondary synovitis, and bone remodelling. In recent years, early knee OA, a preliminary stage of structural failure in OA, has attracted attention as a potential target for therapy to prevent the onset of OA. Intra-articular administration of monoiodoacetic acid (MIA) induces OA-like symptoms, and low doses of MIA induce early OA like symptoms. In this experiment, a low-dose of MIA was induced to early OA model mice, which were then irradiated with low-intensity pulsed ultrasound (LIPUS) to examine whether LIPUS improves symptoms of early OA.MethodsAfter 4 weeks of LIPUS irradiation, articular cartilage was observed at 1 and 4 weeks. The Osteoarthritis Research Society International (OARSI) scores were calculated using Safranin-O staining results. Cartilage degeneration was detected using Denatured Collagen Detection Reagent (DCDR).ResultsWe observed a significant decrease in OARSI scores in the LIPUS irradiated group at week 4. The non-LIPUS group showed widespread areas of double positivity for Type II collagen and DCDR, whereas the LIPUS group showed only a small number of DCDR-positive areas. In addition, macrophage numbers counted in the articular capsule at week 1 showed a significant decrease in the LIPUS irradiated group. Lubricin detection showed that lubricin positive cell number was significantly increased by LIPUS irradiation at week 4.ConclusionsThese results suggest that LIPUS attenuates cartilage degeneration in early OA by relieving inflammation and enhancing the inhibitory effect of lubricin on cartilage degeneration.

Is There a Role for Ordering a DEXA (Dual Energy X-Ray Absorptiometry) Scan for Patients with Symptomatic Advanced Knee Osteoarthritis?

Osteoarthritis of the knee (OA) and osteoporosis are two conditions that have a significant impact on society, have a great impact on quality of life, and can lead to functional impairment. However, the relationship between knee OA and osteoporosis is unclear. The aim of this study was to examine if there is a link between symptomatic advanced knee osteoarthritis and low bone mineral density. A total of 430 patients with symptomatic and advanced radiographic knee OA served as participants in this study. Plain radiographs were used to screen participants for osteoarthritis, and a Dual Energy X-ray Absorptiometry (DEXA) scan was used to determine each participant's bone mineral density (BMD). The lumbar spine, whole femur, and femoral neck BMD levels were statistically higher in the early OA (Kelldren-Lawrence (KL) I and II) group compared with the advanced (III and IV) OA group. Higher BMD at the whole femur and femoral neck but not at the lumbar spine was observed when comparing patients with grades I, II, and III with patients with grade IV after adjustment for body mass index. The findings of this study indicate that the degree of knee OA is correlated with a decline in BMD. These findings lend credence to the theory that the two conditions may be linked to one another. Our study concluded that patients with advanced knee osteoarthritis are at risk of developing osteoporosis. As a result, orthopedic doctors are required to screen for osteoporosis in patients with advanced knee osteoarthritis to both prevent and treat osteoporosis at an earlier stage.

AGREEMENT OF AUTOMATED LAMINAR FEMOROTIBIAL CARTILAGE TRANSVERSE RELAXATION TIME (T2) ANALYSIS WITH MANUAL EXPERT SEGMENTATION

Articular cartilage transverse relaxation time (T2) on MRI has been observed to reflect collagen integrity, orientation, and hydration, and to be associated with cartilage histological grading, mechanical properties, and early knee OA status. Previously, we reported high agreement of cartilage segmentations obtained from multi echo spin echo (MESE) MRI, using fully automated deep learning methods, in comparison with manual ones. As these results were based on 3T MRI (of the OAI), we here explored the agreement between fully automated segmentation of MESE cartilage at 1.5T. To analyze the agreement between automated, U-Net-based segmentation of femorotibial cartilage from MESE by convolutional neural networks vs. manual expert segmentation with quality control of the same images, and to compare laminar femorotibial cartilage T2 between both approaches. We studied 20 ACL-deficient patients with persistent dynamic knee instability (non-copers), 22 without instability (copers), 13 with surgical ACL reconstruction, and 16 healthy controls. Further patient characterizations are described in a parallel abstract at this conference. Sagittal MESE MRIs were acquired at 1.5T (Siemens Avanto; slice thickness/spacing 3/3.5mm, in-plane resolution 0.31mm, TR 1500ms, TE 9.7/19.4/29.1/38.8/48.5/58.2/67.9ms), at baseline (n=71) and 1 year later (n=55). Manual cartilage segmentation was done by experienced readers, with quality control by an expert (Fig. 1). The U-Net was trained using medial and lateral MRIs from the same scanner (training/ validation set n=50/9) obtained in volleyball athletes of different age groups, and in patients with posterior cruciate ligament (PCL) surgery, segmented by the above readers. Training of the U-net was performed for both all 7 echos and only the 1st echo. Automated U-Net segmentation was then applied to the current study MRIs, without manual intervention or correction. Yet, automated post-processing was employed to correct obvious segmentation errors. The agreement between manual and automated U-Net-based segmentations was evaluated using the Dice Similarly Coefficient (DSC), and by evaluating systematic differences and correlations in cartilage T2 of the 50% superficial and 50% deep layer. When all echoes were used for training, the overall DSC was 0.89 for MT/LT, and 0.83 for cMF/cLF. When only the 1st echo was used,DSCs were 0.87/0.88 and 0.81/0.79. Automated analysis overestimated the segmented tissue volume significantly in most regions, with correlations ranging from 0.93-0.96 for all echoes, and from 0.87-0.94 for the 1st echo. Deep layer T2 across the joint was 45.7ms for manual analysis, 45.7ms with all echoes, and 46.1ms with the 1st echo model; superficial layer T2 was 52.1, 53.2 and 54.4ms. There were statistically significant (albeit small) differences of automated vs. manual analysis across most regions for the superficial layer, and for LT and cLF in the deep layer. The correlation of deep layer T2 across the plates ranged from 0.91-0.99 for all echoes model, and from 0.85-0.98 for the 1st echo model, and that of the superficial T2 from 0.86-0.97, and from 0.73-0.81. Fully automated (U-Net-based) laminar analysis of femorotibial cartilage T2 appears feasible at 1.5T, albeit the agreement for T2 at 3T, and that for cartilage thickness was previously reported to be higher. The agreement with manual analysis was greater when training a model with 7 echoes than with the 1st echo only, and it was greater for the deep than for the superficial layer. No significant change in T2 was observed over 1 year; thus, longer intervals may be required for longitudinal validation.

Development of Intraoperative Robotic System “RMA-OCDS” Diagnosing Early OA based on Doppler OCT

Development of Intraoperative Robotic System “RMA-OCDS” Diagnosing Early OA based on Doppler OCT

Increased Synovial CD14 mRNA Expression and Proportion of CD14high Subsets in Early-Stage Hip Osteoarthritis: Propensity Matched Score Analysis.

The pathophysiology of early-stage hip osteoarthritis (EOA) is not fully understood. Although a previous study in an age-unmatched cohort reported that the number of macrophages was increased in knee EOA compared to late OA (LOA), it remained unclear whether increased macrophages in EOA accurately reflect EOA pathology. We investigated the differences in CD14 expression levels between EOA and LOA using age-unmatched and -matched cohorts. Synovial tissues were obtained from 34 EOA (Tönnis grades 0 and 1) and 80 LOA (Tönnis grades 2 and 3) patients. To correct for differences in demographics between patients with LOA and EOA, we also created propensity score-matched cohorts (16 EOA and 16 LOA). CD14 expression and its association with pain was estimated in LOA and EOA before and after propensity matching. We performed flow cytometry on tissues from the 16 patients, with 8 from each group, to assess for CD14+ subsets in the cells. The CD14 expression in EOA was higher than that in LOA both before and after propensity matching. The proportion of CD14high subsets in EOA was higher than that in LOA. The CD14 expression was associated with pain in EOA before matching. However, no difference was observed between the pain and CD14 expression after matching in EOA. The increased CD14 expression and the proportion of CD14high subsets may be important features associated with hip EOA pathology. To accurately compare early and late OA, the analysis of a propensity score-matched cohort is necessary.