Osteoarthritis Research Society International Grading Research Articles

Glaucocalyxin A delays the progression of OA by inhibiting NF-κB and MAPK signaling pathways

BackgroundOsteoarthritis (OA) is a common degenerative joint condition marked by inflammation and cartilage breakdown. Currently, there is a dearth of treatment medications that can clearly slow the course of OA. Glaucocalyxin A (GLA) is a diterpene chemical identified and extracted from Rabdosia japonica with antithrombotic, anticoagulant, anti-tumor, anti-inflammatory, anti-oxidant, and other pharmacological properties. Previous research has linked inflammation to abnormalities in the homeostasis of the extracellular matrix (ECM). Although GLA has been shown to have anti-inflammatory qualities, its effects on the progression of OA are unknown. As a result, the goal of this study was to see if GLA could slow the course of OA.MethodsATDC5 cells were stimulated by IL-1β to create an inflammatory chondrocyte damage model. Quantitative polymerase chain reaction, Western Blot, high-density culture, and immunofluorescence were used to detect the expression levels of associated gene phenotypes. We also created a mouse model of OA induced by destabilization of the medial meniscus (DMM) instability, and GLA was administered intraperitoneally once every two days for eight weeks. Mice knee specimens were stained with hematoxylin–eosin, Safranin O/fast green, and immunohistochemical, and the Osteoarthritis Research Society International grade system and Mankin’s score were used to assess the protective effect of GLA on cartilage.ResultsIn vitro and in vivo, we explored the effects and molecular processes of GLA as a therapy for OA. The findings demonstrated that GLA might reduce the expression of associated inflammatory mediators and protect the ECM by inhibiting the NF-κB and MAPK signaling pathways. Animal research revealed that GLA could protect against the DMM-induced OA model mice by stabilizing ECM.ConclusionTaken together, our findings show that GLA has a protective impact on cartilage throughout OA progression, implying that GLA could be employed as a possible therapeutic agent for OA, thus giving a new therapeutic method for the treatment of OA.

Asymmetric Post-Traumatic Knee Arthritis Is Closely Correlated With Both Severity and Time for Lower Limb Coronal Plane Malalignment.

Mechanical alignment of the lower limbs has been suggested to cause abnormal uneven loading across the compartments at the knee, but its contribution to the initiation and progression of arthritis remains controversial. This study aimed to establish whether malalignment of the lower limb after trauma is associated with worsened arthritis scores in the theoretically overloaded compartment, and if arthritis scores continuously correlate with the degree of malalignment and time with deformity. After screening 1160 X-rays, 60 patients were identified with long-leg radiographs > 2 years after fracture. Measurement of mechanical axis deviation (MAD) divided into groups of varus malalignment (n = 16, >16 mm), valgus (n = 25, <0 mm), and normal alignment (n = 19). Alignment and bilateral knee compartmental arthritis scores were recorded by three clinicians, compared via analysis of variance and assessed with linear regression against time since injury using MAD as a covariate. In varus and valgus malalignment, there was a greater mean arthritis score in the "overloaded" compartment compared to the contralateral side, with varus medial Osteoarthritis Research Society International (OARSI) scores 5.17 ± 2.91 vs 3.50 ± 2.72 (P = 0.006) and Kellegren-Lawrence scores 2.65 ± 1.19 vs 1.79 ± 1.24 (P ≤ 0.001). In a linear regression model, OARSI arthritis score was significantly associated with absolute MAD (0.6/10 mm MAD, P < 0.001) and time (0.7/decade, P ≤ 0.001). Malalignment consistently results in more advanced arthritis scores in the overloaded compartment, most likely related to abnormal loading across the knee. Severity of arthritis using OARSI grading continuously correlates with degree of malalignment and time with deformity after post-traumatic malunion.

Medial Meniscus Posterior Root Repair Reduces but Does Not Avoid Histologic Progression of Osteoarthritis: Randomized In Vivo Experimental Study in a Rabbit Model

Background: The optimal treatment option for meniscus root tears is still challenging, and whether the meniscus root repair ultimately can arrest or delay osteoarthritic changes is still a concern. Purpose/Hypothesis: The purpose of this study was 2-fold: (1) to describe and compare histopathologic findings of 3 different therapeutic options for medial meniscus posterior root tear: nonoperative management, partial meniscectomy, and meniscus root repair; and (2) to test the hypothesis that meniscus root tears treated nonoperatively predispose to a lower risk of osteoarthritic progression compared with partial meniscectomy. Study Design: Controlled laboratory study. Methods: Posteromedial meniscus root tears were carried out in 39 New Zealand White rabbits. Animals were randomly assigned into 3 experimental groups: partial meniscectomy after root tear (PM; n = 13), root tears treated conservatively (CT; n = 13), and transtibial root repair (RR; n = 13). Contralateral limbs were used as healthy controls. The animals were euthanized at 16 weeks postoperatively; tissue samples of femoral and tibial articular cartilage were collected and processed for macro- and microscopic assessment to detect signs of early osteoarthritis (OA). Each sample was histopathologically assessed using the Osteoarthritis Research Society International grading and staging system. Results: Osteoarthritic changes were the hallmark in all 3 experimental groups. The RR group had the lowest scores for cartilage damage (mean, 2.5; range, 2-3), and the PM group exhibited higher and more severe signs of OA (mean, 16; range, 9-16) compared with the CT group (mean, 5; range, 4-6). The between-group comparison revealed significant differences, as the PM group showed a significantly higher rate of macro- and microscopic osteoarthritic changes compared with the RR (P < .001) and CT (P < .001) groups. The weightbearing area of the medial femoral condyle was the most severely affected, and tidemark disruption was evident in all tissue samples. Conclusion: Meniscus root repair cannot completely arrest the histopathologic progression of knee OA but leads to significantly less severe degenerative changes than partial meniscectomy and nonoperative treatment. Partial meniscectomy leads to the most severe osteoarthritic progression, while stable radial tears left in situ have lower progression compared with partial meniscectomy. Clinical Relevance: Histologic assessment is an essential tool and metric for guiding and understanding osteoarthritic features, providing insight into the disease development and progression. This study provides histopathologic evidence on osteoarthritic progression after medial meniscus posterior root repair. This knowledge can help to set more realistic expectations and can lead to the future development of augmented techniques.

Activated intestinal microbiome-associated tryptophan metabolism upregulates aryl hydrocarbon receptor to promote osteoarthritis in a rat model

To evaluate the role of aryl hydrocarbon receptor in the pathogenesis of osteoarthritis (OA) and its association with intestinal microbiome-related tryptophan metabolism. Cartilage was isolated from OA patients undergoing total knee arthroplasty and analyzed for expression of aryl hydrocarbon receptor (AhR) and cytochrome P450 of family 1, subfamily A, and polypeptide 1 (CyP1A1). To gain mechanistic insights, OA model was induced in Sprague Dawley rats after antibiotic pretreatment combined with a tryptophan-rich diet (or not). The severity of OA was assessed eight weeks after surgery according to the Osteoarthritis Research Society International grading system. Expression of AhR, CyP1A1 as well as markers of bone and cartilage metabolism, inflammation, and intestinal microbiome-related tryptophan metabolism was assessed. Severity of OA in cartilage from patients positively correlated with expression of AhR and CyP1A1 in chondrocytes. In the rat model of OA, antibiotic pretreatment led to lower expression of AhR and CyP1A1 and lower serum levels of lipopolysaccharide (LPS). Conversely, antibiotics upregulated Col2A1 and SOX9 in cartilage, which mitigated the cartilage damage and synovitis, reduced the relative abundance of Lactobacillus. Additional tryptophan supplementation activated intestinal microbiome-related tryptophan metabolism, antagonizing the effects of antibiotics, exacerbating OA synovitis. Our study established an underlying intestinal microbiome associated tryptophan metabolism-OA connection which sets a new target for exploring OA pathogenesis. The alteration of tryptophan metabolism might prompt the activation and synthesis of AhR, accelerating the development of OA.

What is the Effect of Bevacizumab on Cartilage and Synovium in a Rabbit Model of Hemophilic Arthropathy?

Hemophilic arthropathy can cause recurrent hemarthroses and severe damage to the synovium and articular cartilage. Previous studies have shown that vascular endothelial growth factor (VEGF) plays an essential role in neoangiogenesis. Bevacizumab, a monoclonal VEGF inhibitor, is used clinically to prevent angiogenesis. However, its effects on hemophilic arthropathy are unknown. Using a hemophilic arthropathy rabbit model, we asked: Does an intra-articular injection of bevacizumab (1) inhibit VEGF, (2) decrease signal intensity in dynamic contrast-enhanced MRI (DCE-MRI) as an assessment of capillary permeability and neoangiogenesis, (3) reduce cartilage damage, (4) reduce synovial changes, and (5) affect macroscopic changes during the development of hemophilic arthropathy? Twenty-five male New Zealand rabbits were divided into four groups. Eight knees from four rabbits were used as the control group. We used an established animal model for hemophilic arthropathy in the remaining 21 rabbits. Animals were assigned randomly to three groups with seven rabbits in each group. One group was used to establish mild arthropathy, and the other two were used to establish severe arthropathy. Autologous blood from the rabbits' ears was injected into the right and left knees twice per week for 8 weeks to represent mild arthropathy and for 16 weeks to represent severe arthropathy. In the mild arthropathy group, bevacizumab was injected into the right knee once every 2 weeks. Bevacizumab was injected into the right knee of rabbits in one of the severe arthropathy groups once every 2 weeks for 16 weeks, and intra-articular bevacizumab injections were administered to the right knees of rabbits in the other severe arthropathy group once every 2 weeks after the eighth week. An equal volume of 0.9% saline was injected into the left knee of rabbits in all arthropathy groups. To explore the efficacy of bevacizumab, joint diameters were quantitatively measured, and cartilage and synovial changes were examined. Degeneration of articular cartilage was evaluated with the semiquantitative Osteoarthritis Research Society International grading system. Synovial damage was analyzed with a semiquantitative microscopic scoring system. In addition, we evaluated perfusion and angiogenesis using DCE-MRI (quantitative signal intensity changes). Immunohistochemical testing was used to measure VEGF levels (analyzed by Western blotting). Intra-articular bevacizumab treatment inhibited VEGF in our rabbit model of hemophilic arthropathy. VEGF protein expression levels were lower in the mild arthropathy group that received intra-articular bevacizumab (0.89 ± 0.45) than the mild arthropathy control group (1.41 ± 0.61) (mean difference -0.52 [95% CI -0.898 to -0.143]; p = 0.02). VEGF levels were lower in the severe arthropathy group that received treatment for 16 weeks (0.94 ± 0.27) than in the control knees (1.49 ± 0.36) (mean difference -0.55 [95% CI -0.935 to -0.161]; p = 0.01). In the severe arthropathy group, the Osteoarthritis Research Society International score indicating cartilage damage was lower in the group that received intra-articular bevacizumab treatment from the beginning than in the control group (median 17 [range 13 to 18] versus 18 [range 17 to 20]; difference of medians 1; p = 0.02). Additionally, the scores indicated synovial damage was lower in the group that received intra-articular bevacizumab treatment from the beginning than the control group (median 5 [range 4 to 9] versus 9 [range 8 to 12]; difference of medians 4; p = 0.02). The mean of mean values for signal intensity changes was higher in the nontreated severe groups than in the group of healthy knees. The signal intensity changes were higher in the severe arthropathy control groups (Groups BC and CC) (median 311.6 [range 301.4 to 361.2] and 315.1 [range 269.7 to 460.4]) than in the mild arthropathy control group (Group AC) (median 234.1 [range 212.5 to 304.2]; difference of medians 77.5 and 81, respectively; p = 0.02 and p = 0.04, respectively). In the severe arthropathy group, discoloration caused by hemosiderin deposition in the cartilage and synovium was more pronounced than in the mild arthropathy group. In the severe arthropathy group treated with intra-articular bevacizumab, joint diameters were smaller than in the control group (Group BT median 12.7 mm [range 12.3 to 14.0] versus Group BC median 14.0 mm [range 13.1 to 14.5]; difference of medians 1.3 mm; p = 0.02). Hemarthrosis damages the synovial tissues and cartilage in the knees of rabbits, regardless of whether they are treated with intra-articular bevacizumab. However, intra-articular injection of bevacizumab may reduce cartilage and synovial damage in rabbits when treatment is initiated early during the development of hemophilic arthropathy. If the findings in this study are replicated in larger-animal models that consider the limitations of our work, then a trial in humans might be appropriate to ascertain whether intra-articular injection of bevacizumab could reduce cartilage damage and synovial changes in patients with hemophilia whose hemarthroses cannot otherwise be controlled.

Lateral meniscal body extrusion is associated with MRI-defined knee structural damage progression over 4 years: Data from the osteoarthritis initiative

PurposeTo investigate the association of lateral meniscal body extrusion (LMBE) with OA-related knee structural damage progression over 4 years and to obtain thresholds of LMBE in predicting knee structural damage progression. MethodWe studied 196 subjects (67 male) with a mean age of 59.5 ± 7.9 (SD) years (range45-78 years) that were randomly selected from the Osteoarthritis Initiative. Radiological assessment was performed using the Osteoarthritis Research Society International grading system. Baseline LMBE was quantified on coronal sections of intermediate-weighted MRI sequences obtained at 3.0 T scanner. Knee structural damages were measured using the whole-organ MRI score. Linear regression analysis and binary logistic regression analysis was used to assess the correlation between LMBE and knee structural damage. ROC analysis and Youden index were used for calculating thresholds. ResultsCross-sectionally, increased LMBE was significantly associated with more severe lateral meniscal damage, patellofemoral and lateral compartment cartilage damage, and posterior cruciate ligament damage. Longitudinally, LMBE was statistically associated with progression of lateral meniscal damage, lateral compartment cartilage damage and bone marrow edema patterns, posterior cruciate ligament lesions and popliteal cysts. The thresholds of LMBE in suggesting progression of lateral meniscal lesions and lateral compartment cartilage lesions were 1.4 mm and 1.3 mm, respectively. ConclusionBaseline LMBE was associated with structural damage progression over 4 years in knees with or at risks for OA. Thresholds of 1.4 mm and 1.3 mm could be used in predicting progression over 4 years of lateral meniscal damage and lateral compartment cartilage damage, respectively.

The role of cam morphology in the progression of radiographic hip osteoarthritis.

To the editor As faithful readers, there is no doubt that we have learned a lot after reading the paper.1 By using the methods mentioned in the article, we can infer that cam morphology was linked with age, higher weight, male gender, and early signs of radiographic damage. These findings are likely to suggest that cam morphology plays a significant role in early osteoarthritis (OA) and may be a precursor or contribute to hip OA in later life. As the author mentions in the article, there were tons of data proving the association between cam morphology and osteoarthritis.1-4 In fact, the results prove that your inference is correct, and we have two points in mind hoping they would be beneficial to your paper. The first point we would like to focus on is the assessment of OA. According to the paper, the assessment of hip OA was used by Prof. Graeme Jones and Dr. Helen Cooley.1 They followed the Osteoarthritis Research Society International grading system and assessed the radiographs. Radiographs were graded on a 4-point scale (range 0 to 3, where 0 represents no disease and 3 represents severe disease). We thought that the judgment on a 4-point scale of OA was vague. The evaluation of a 4-point scale can only be defined by the doctor as artificial. To be argued, the result of the 4-point scale may not be the same due to different patient OA diagnoses. Therefore, we thought that you could try another method that is more automatic and objective in diagnosing patients with OA, such as the Kellgren and Lawrence scale (K-L scale), erythrocyte sedimentation rate, and C-reactive protein.5 These assessments are more objective and are used in many countries. Compared to the 4-point scale in the paper, K-L scale is more specific than the 4-point scale. Therefore, it could be a better choice for you to assess the participants. The second point that we would like to focus on is the method to measure and evaluate participants' hip pain feeling. In the article, the author uses the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index pain score as the measurement of hip pain.1 To a great degree, the feeling of pain is subjective, which largely depends on the participants themselves. For different participants, the same pain level may cause different pain feelings. Therefore, it is tough and complicated to evaluate participants' pain feelings accurately and rigorously.6 Under this premise, we have learned a lot and consider that the pain evaluating method is great and relatively accurate, compared to many other methods. After all, WOMAC is specific to OA. Data from the participants at 3 and 5 years from baseline is also a great decision. During this period, participants' pain feelings are more obvious. If choosing 0–3 years, that pain feeling and impact may not be obvious enough to evaluate. Meanwhile, if choosing more than 5 years, participants may get used to the painful feelings, which could affect the final evaluation of participants' hip pain feelings, and this is probably because the pain evaluation method is self-reported. However, after reading and searching through lots of information, we have an interesting thought about pain feeling evaluation. WOMAC is good and suitable for OA, without a doubt. But why not try using other pain evaluation systems? If using other pain scales, the result might be different. There are various pain evaluation systems, such as the Brief Pain Inventory (BPI), McGill Pain Questionnaire (MPQ), Visual Analog Scale (VAS), Face, Legs, Activity, Cry, and Consolability (FLACC) scale, etc.7, 8 Every system uses different degrees of grading, marks, choosing forms, and so on. In a different system, even the same sign could have a different meaning. As stated above, all of these could give rise to different results when participants do pain feeling evaluation self-reportedly in the different evaluation systems. All authors (KSSM, PEK, SBY, and KHC) provided their ideas and critical contribution. KSSM, PEK, SBY, and KHC contributed to the editing of the manuscript. KSSM and PEK contributed equally as first authors. KSSM, PEK, SBY, and KHC contributed equally as corresponding authors. None declared. The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for profit sectors. The authors declare no conflict of interest. Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research. Not required. Not commissioned; internally peer reviewed.

T2 mapping of cartilage in the equine distal interphalangeal joint with corresponding histology using 0.27 T and 3.0 T magnetic resonance imaging.

Low-field magnetic resonance imaging (MRI) is widely available to equine veterinarians yet is insensitive at detecting cartilage damage in the distal interphalangeal joint (DIPJ). T2 mapping is a quantitative imaging technique that can detect cartilage damage before morphological change is apparent. Validation of a T2 mapping sequence on a low-field MR system. Correlation of the mean T2 relaxation time in sections of cartilage with varying levels of pathology using low- and high-field MRI. Cross-sectional study. Eight phantoms with known (nominal) T2 values underwent low-field (0.27 T) MRI and 38 ex vivo DIPJs were imaged. A further 9 ex vivo DIPJs were imaged on both the low- and high-field MR systems. Immediately after imaging, the DIPJs were disarticulated and samples collected for histology. Histological sections were graded using the Osteoarthritis Research Society International (OARSI) scoring system. Fiji ImageJ software with the MRIAnalysisPak plugin was used to calculate T2 maps and draw the regions of interest (ROIs). There was close agreement between the nominal and the measured T2 values in the phantom study. Spearman's rank correlation demonstrated significant positive correlation between low- and high-field T2 measurements, rho 0.644 (p < 0.001). The intrarater agreement for T2 measurements was excellent, intraclass correlation coefficient (ICC)=0.99 (95% confidence interval [CI]=0.99-1.00), the inter-rater agreement was excellent, ICC=0.88 (95% CI=0.82-0.92) and there was good intrarater agreement for OARSI scores (к=0.76). Only a small number of histological samples were analysed. Both articular cartilage surfaces were measured within the ROI. There were no OARSI grade 0 control samples. A T2 mapping sequence on a low-field 0.27 T MR system was validated. There was a positive correlation between low- and high-field T2 measurements. The findings suggest a higher mean T2 relaxation time in pathological cartilage tissue examined in this study compared to normal equine cartilage tissue.

Articular fragment restoration is critical to mitigate post-traumatic osteoarthritis in a porcine pilon fracture model

ObjectiveDuring articular fracture reconstruction, orthopedic surgeons are frequently faced with the dilemma of retaining small articular fragments versus discarding these fragments. The purpose of this study was to compare post-traumatic osteoarthritis (PTOA) development between tibial plafond fractures and plafond fractures with a missing articular fragment (MF) in a porcine model. DesignHigh-energy tibial plafond fractures in skeletally mature Yucatan mini pigs (n ​= ​12) were created. During surgery, a 3 ​× ​3 mm section of the articular surface was removed in six animals (MF group). Ankle synovial fluid was analyzed for IL-1β, IL-1Ra, IL-6, IL-8, and IL-10 concentrations obtained at initial surgery and 12 weeks post-surgery. Plafond and talus sections were evaluated for subchondral bone porosity and stained with Sanderson's Rapid Bone Stain and blindly evaluated to determine the Osteoarthritis Research Society International (OARSI) grade and vascular invasion. ResultsFractured ankles had greater concentrations of IL-1β, IL-1Ra, IL-6, IL-8, and IL-10 compared to control ankles. There was no difference in cytokine concentrations between fractured and fractured ​+ ​MF ankles. Fractured ankles had significantly greater bone porosity, vascular invasion, and OARSI grade as compared to the control group. In comparing tibial plafonds, the MF group had significantly more bone porosity, more vascular invasion, and a higher average OARSI grade than the anatomically reconstructed group. In comparing the talus, the MF group had higher average OARSI grade and similar bone porosity. ConclusionsArticular fractures with a MF had worse PTOA development as measured by bone porosity, vascular invasion, and OARSI grade than the anatomically reconstructed fractures.

Complement C3-α and C3-β Levels in Synovial Fluid But Not in Blood Correlate With the Severity of Osteoarthritis Research Society International Histopathological Grades in Primary Knee Osteoarthritis

BackgroundPrimary osteoarthritis (OA) is the most common cause of knee arthritis worldwide. The knee synovial fluid complement C3-β chain levels have been shown to correlate with clinical symptoms of knee OA. It is not known whether the complement C3 in the synovial fluid is derived from the circulation or is produced locally in the knee. MethodsFifty primary OA patients undergoing a total knee arthroplasty procedure were evaluated for biochemical analyses of C3-α and C3-β chains in the synovial fluid and blood plasma. These levels were corelated with the severity of corresponding knee OA based on the Osteoarthritis Research Society International (OARSI) grade. ResultsBoth synovial C3-α and C3-β levels correlated significantly with the severity of OA. Neither plasma C3-α levels nor C3-β levels significantly correlated with OARSI grading. Neither synovial C3-α levels nor C3-β correlated significantly with plasma C3-α or C3-β levels, respectively. Synovial C3-α chain and C3-β chain levels were significantly higher in the grade >6 group. In plasma, neither C3-α chain levels nor C3-β chain levels were significantly different between the groups. Neither synovial C3-α nor C3-β levels significantly correlated with plasma erythrocyte sedimentation rate or C-reactive protein levels. ConclusionIn knee primary OA, C3 seems to be produced and released locally into the synovial fluid instead of being derived from blood in the circulation. Synovial C3 levels, but not blood plasma C3, correlate with the histopathological severity of primary OA in the knee. Synovial C3 may be an important factor in the pathogenesis of primary OA clinical symptoms and a potential target for therapeutic intervention.

Evaluation of cartilage degeneration using multiparametric quantitative ultrashort echo time-based MRI: an ex vivo study.

The quantitative MR techniques developed rapidly, vary MR-biomarkers have shown the ability to assess the quality of articular cartilage. This study aimed to investigate the diagnostic efficacy of multi-parametric quantitative ultrashort echo time (UTE)-based MRI for evaluating human cartilage degeneration. Twenty fresh anterolateral femoral condyle samples were obtained from 20 patients (age, 58.8±6.6 years; 6 females) who underwent total knee arthroplasty due to primary osteoarthritis (OA). The samples were imaged using UTE-based magnetization transfer (UTE-MT), UTE-based adiabatic T1ρ (UTE-AdiabT1ρ), UTE-based T2* (UTE-T2*), and CubeQuant-T2 sequences. Cartilage degeneration was classified based on the OA Research Society International grade and polarized light microscopy (PLM) collagen organization score. Spearman's correlation analysis was used to determine the relationships between quantitative MRI biomarkers [UTE-MT ratio (UTE-MTR), UTE-AdiabT1ρ, UTE-T2*, and CubeQuant-T2], OA Research Society International grade, and PLM collagen organization score. The diagnostic efficacy of each MRI biomarker for the detection of mild cartilage degeneration was assessed using the area under the receiver operating characteristic (ROC) curve (AUC). Of the quantitative MRI biomarkers, UTE-MTR had the strongest correlation with both OA Research Society International grade (r=-0.709, P<0.001) and PLM collagen organization score (r=0.579, P<0.001). The UTE-MTR and UTE-AdiabT1ρ values showed significant differences between the normal group and the mild degeneration group (P=0.047 and 0.015, respectively), while UTE-T2* and CubeQuant-T2 did not. The UTE-MTR values were 15.90%±1.06% and 14.59%±1.35% for normal and mildly degenerated cartilage, respectively. The UTE-AdiabT1ρ values were 40.19±2.87 and 42.6±2.26 ms for normal and mildly degenerated cartilage, respectively. ROC analysis showed that UTE-MTR (AUC =0.805, P=0.001, sensitivity =73.7%, specificity =89.5%) had the highest diagnostic efficacy for mild cartilage degeneration, while UTE-AdiabT1ρ (AUC =0.727, P=0.017) and CubeQuant-T2 (AUC =0.712, P=0.026) showed lower diagnostic efficacy. Quantitative UTE-MT and UTE-AdiabT1ρ biomarkers may potentially be used in the evaluation of early cartilage degeneration.

Histological and Inflammatory Cytokine Analysis of Osteochondral Lesions of the Talus After Failed Microfracture: Comparison With Fresh Allograft Controls.

Background:The most common first-line treatment of osteochondral lesions of the talus (OLTs) is microfracture. Although many patients do well with this procedure, a number fail and require reoperation. The mechanism of failure of microfracture is unknown, and to our knowledge there has been no research characterizing failed microfracture regarding histological and inflammatory makeup of these lesions that may contribute to failure.Purpose:To characterize the structural and biochemical makeup of failed microfracture lesions.Study Design:Case series; Level of evidence, 4.Methods:Specimens from 8 consecutive patients with symptomatic OLTs after microfracture who later underwent fresh osteochondral allograft transplantation were analyzed. For each patient, the failed microfracture specimen and a portion of the fresh allograft replacement tissue were collected. The allograft served as a control. Histology of the failed microfracture and the allograft replacement was scored using the Osteoarthritis Research Society International (OARSI) system. Surface roughness was also compared. In addition, tissue culture supernatants were analyzed for 16 secreted cytokines and matrix metalloproteinases (MMPs) responsible for inflammation, pain, cartilage damage, and chondrocyte death.Results:The OARSI grade, stage, and total score as well as surface smoothness were significantly worse in the failed microfracture sample, indicating better cartilage and bone morphology for the allografts compared with the failed microfracture lesions. Analyzed cytokines and MMPs were significantly elevated in the microfracture tissue culture supernatants when compared with fresh osteochondral tissue supernatants.Conclusion:These data demonstrate a significantly rougher cartilage surface, cartilage and subchondral bone histology that more closely resembles osteoarthritis, and elevated inflammatory cytokines and MMPs responsible for pain, inflammation, cartilage damage, and chondrocyte death when compared with fresh osteochondral allografts used as controls.

Relationship Between Inflammation Parameters Which Are Obtained From Blood Count And Knee Osteophytes

Objective:Osteoarthritis is no longer considered a degenerative disease. The presence of underlying low-grade inflammation has been well demonstrated. Although osteophytes are used to determining the radiological stage, the development mechanism is not fully understood. The aim of this study is to separately evaluate the relationship between various inflammation parameters associated with complete blood count with osteophytes and radiological stage. Methods:Patients who met the American College of Rheumatology clinical knee osteoarthritis criteria, retrospectively selected. Kellgren-Lawrence grading scale was used for disease severity and Osteoarthritis research society international grading was used for osteophyte size evolution. Red blood cell distribution width, platelet to lymphocyte ratio, neutrophil to lymphocyte ratio, neutrophil to monocyte ratio, lymphocyte to monocyte ratio, and mean platelet volume obtained from complete blood count, and C-reactive protein levels were recorded. The relationship between inflammation markers and osteophytes and disease stage was evaluated by logistic regression analysis. Results:A significant correlation was shown between CRP and PLR in the early stage of the disease. No correlation was found in the advanced stage. No correlation was found between osteophyte progression and inflammatory markers in the analysis based on osteophyte size Conclusion:In this study, we have shown that there is a relationship between systemic low-grade markers of inflammation and early stages of knee osteoarthritis, but this relationship was not detected in advanced stages. There was not a relation between osteophyte progression and these markers. Even though it seems to be running together, we can assume that the progression of the disease and osteophyte formation have different mechanisms.

Optimization of histologic grading schemes in spontaneous and surgically-induced murine models of osteoarthritis

To compare the Osteoarthritis Research Society International (OARSI) and Articular Cartilage Structure (ACS) grading schemes applied to multiple and single sections, along with additional histologic measures, in two mouse models of Osteoarthritis (OA). Six coronal histologic stifle joint sections were collected from 40 C57BL/6J mice, including aged mice with spontaneous OA (approximately 18 months of age; n=15) and young (12-week-old) mice that either underwent destabilization of the medial meniscus (DMM) surgery (n=15) or sham surgery (n=10). Sections were evaluated with the standard OARSI (0-6) scheme, a modified OARSI scheme, the ACS (0-12) scheme, histomorphometry of cartilage and bone, and scoring of osteophytes (0-3) and synovial hyperplasia (0-3). Principal components analysis (PCA) was used to determine the features explaining the greatest variability among the sections. The grading schemes performed similarly when applied to a single mid-coronal section or six total coronal sections per joint. OARSI grading produced similar results when applied to hematoxylin and eosin or toluidine blue-stained sections. Aged mice had higher severity scores in the LTP than DMM mice (mid-coronal OARSI grade aged=2.3 and DMM=1.1, p=0.0006; ACS grade aged=4.1 and DMM=1.6, p=0.0024). PCA resulted in retention of four factors that accounted for 78.4% of the total variance. Factor 1 (36.4%) included the OARSI grade, ACS grade, Toluidine blue grade, articular cartilage area and thickness and the osteophyte grade. Grading of a single mid-coronal section using either the OARSI or ACS schemes combined with osteophyte and histomorphometric measures can consistently define OA severity in mice.

Predicting outcomes in patients undergoing intra-articular corticosteroid hip injections.

To investigate the associations between clinical, procedural, and radiographic factors and outcomes of steroid hip injections, including long-term and immediate pain reduction, time to arthroplasty, time to reinjection, and the total number of injections. All intra-articular anesthetic and steroid injections of the hip under fluoroscopic guidance between January 2014 and March 2016 were retrospectively reviewed. Hip radiographs were scored using the Kellgren-Lawrence (KL) and Osteoarthritis Research Society International (OARSI) scores. Immediate pain relief and response were evaluated using a change in visual analog scale and OMERACT-OARSI criteria respectively. Long-term pain relief was evaluated at 2‑7months after injection by reviewing the medical records. Correlation between patient characteristics, procedural variations, and radiographic factors with injection outcomes was analyzed by using linear and logistic regression models. Of 361 injections, 79.8% showed an immediate pain response and 32.7% had subjective long-term pain relief (> 2months). There was no significant correlation between immediate pain relief and response with long-term pain relief and other outcomes. Older age and higher KL score, OARSI-central joint space narrowing (JSN), and inferior acetabular osteophyte were correlated with long-term pain relief (p = 0.01‑0.03). Higher KL and OARSI grades, particularly JSN, were significantly correlated with increased immediate pain relief and total number of injections but decreased time to arthroplasty. Baseline pain positively correlated with immediate pain response (p < 0.001). Older patients with higher grades of radiographic OA and high baseline pain were good candidates for steroid injections, particularly for those patients awaiting hip arthroplasty.

Automatic Grading of Individual Knee Osteoarthritis Features in Plain Radiographs Using Deep Convolutional Neural Networks.

Knee osteoarthritis (OA) is the most common musculoskeletal disease in the world. In primary healthcare, knee OA is diagnosed using clinical examination and radiographic assessment. Osteoarthritis Research Society International (OARSI) atlas of OA radiographic features allows performing independent assessment of knee osteophytes, joint space narrowing and other knee features. This provides a fine-grained OA severity assessment of the knee, compared to the gold standard and most commonly used Kellgren–Lawrence (KL) composite score. In this study, we developed an automatic method to predict KL and OARSI grades from knee radiographs. Our method is based on Deep Learning and leverages an ensemble of residual networks with 50 layers. We used transfer learning from ImageNet with a fine-tuning on the Osteoarthritis Initiative (OAI) dataset. An independent testing of our model was performed on the Multicenter Osteoarthritis Study (MOST) dataset. Our method yielded Cohen’s kappa coefficients of 0.82 for KL-grade and 0.79, 0.84, 0.94, 0.83, 0.84 and 0.90 for femoral osteophytes, tibial osteophytes and joint space narrowing for lateral and medial compartments, respectively. Furthermore, our method yielded area under the ROC curve of 0.98 and average precision of 0.98 for detecting the presence of radiographic OA, which is better than the current state-of-the-art.

Orientation anisotropy of quantitative MRI parameters in degenerated human articular cartilage.

Quantitative magnetic resonance (MR) relaxation parameters demonstrate varying sensitivity to the orientation of the ordered tissues in the magnetic field. In this study, the orientation dependence of multiple relaxation parameters was assessed in cadaveric human cartilage with varying degree of natural degeneration, and compared with biomechanical testing, histological scoring, and quantitative histology. Twelve patellar cartilage samples were imaged at 9.4 T MRI with multiple relaxation parameters, including T1 , T2 , CW - T1ρ , and adiabatic T1ρ , at three different orientations with respect to the main magnetic field. Anisotropy of the relaxation parameters was quantified, and the results were compared with the reference measurements and between samples of different histological Osteoarthritis Research Society International (OARSI) grades. T2 and CW - T1ρ at 400 Hz spin-lock demonstrated the clearest anisotropy patterns. Radial zone anisotropy for T2 was significantly higher for samples with OARSI grade 2 than for grade 4. The proteoglycan content (measured as optical density) correlated with the radial zone MRI orientation anisotropy for T2 (r = 0.818) and CW - T1ρ with 400 Hz spin-lock (r = 0.650). Orientation anisotropy of MRI parameters altered with progressing cartilage degeneration. This is associated with differences in the integrity of the collagen fiber network, but it also seems to be related to the proteoglycan content of the cartilage. Samples with advanced OA had great variation in all biomechanical and histological properties and exhibited more variation in MRI orientation anisotropy than the less degenerated samples. Understanding the background of relaxation anisotropy on a molecular level would help to develop new MRI contrasts and improve the application of previously established quantitative relaxation contrasts.

Are There Harmful Effects of Preoperative Mild Lateral or Patellofemoral Degeneration on the Outcomes of Open Wedge High Tibial Osteotomy for Medial Compartmental Osteoarthritis?

Background:Early osteoarthritis of the knee joint mostly affects the medial compartment, making osteotomy a rational approach to slow the progression of the disease. However, some patients show asymptomatic mild degeneration in the lateral or patellofemoral compartment.Purpose:To evaluate the effect of asymptomatic mild lateral or patellofemoral degeneration on the outcomes of medial open wedge high tibial osteotomy (OWHTO) by assessing the outcomes according to the preoperative status of the lateral or patellofemoral degenerative changes.Study Design:Cohort study; Level of evidence, 3.Methods:A total of 114 patients (121 knees) who underwent biplanar OWHTO with second-look arthroscopic surgery and postoperative magnetic resonance imaging (MRI) were retrospectively enrolled. Patients were categorized into 4 groups according to the Osteoarthritis Research Society International (OARSI) and MRI Osteoarthritis Knee Score (MOAKS) classification systems. The International Cartilage Repair Society (ICRS) grade was used to evaluate the preoperative and postoperative cartilage status. Clinical outcomes were assessed by the American Knee Society (AKS) score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and 36-item Short Form Health Survey (SF-36).Results:No degenerative changes in the lateral and patellofemoral compartments of knees (group I) were identified in 51.2% of cases (62 knees). Asymptomatic degenerative changes only in the lateral compartment (group II: OARSI grades 1-3 and MOAKS grades 1-3) were identified in 15.7% of cases (19 knees), changes only in the patellofemoral compartment (group III: OARSI grades 1-3 and MOAKS grades 1-3) were identified in 10.7% of cases (13 knees), and changes in both the lateral and the patellofemoral compartments (group IV) were identified in 22.3% of cases (27 knees). In the medial compartment, there was no significant difference in the improvement of MOAKS and ICRS grades among all groups (P = .813 and .985, respectively). In the lateral and patellofemoral compartments, there was no significant difference in the decline of MOAKS (P = .649 and .421, respectively) and ICRS grades (P = .927 and .676, respectively) among all groups.Conclusion:The presence of mild lateral or patellofemoral degenerative changes did not affect the MRI, arthroscopic, and clinical outcomes of OWHTO. However, long-term observations are necessary to draw definitive conclusions as to whether OWHTO can be indicated in such patients without harmful effects.

Automatic grading of individual knee osteoarthritis features in plain radiographs using deep convolutional neural networks

Knee osteoarthritis (OA) is the most common musculoskeletal disease in the world. In primary healthcare, knee OA is diagnosed using clinical examination and radiographic assessment. Osteoarthritis Research Society International (OARSI) atlas of OA radiographic features allows to perform independent assessment of knee osteophytes, joint space narrowing and other knee features. This provides a fine-grained OA severity assessment of the knee, compared to the gold standard and most commonly used Kellgren-Lawrence (KL) composite score. However, both OARSI and KL grading systems suffer from moderate inter-rater agreement, and therefore, the use of computer-aided methods could help to improve the reliability of the process. In this study, we developed a robust, automatic method to simultaneously predict KL and OARSI grades in knee radiographs. Our method is based on Deep Learning and leverages an ensemble of deep residual networks with 50 layers, squeeze-excitation and ResNeXt blocks. Here, we used transfer learning from ImageNet with a fine-tuning on the whole Osteoarthritis Initiative (OAI) dataset. An independent testing of our model was performed on the whole Multicenter Osteoarthritis Study (MOST) dataset. Our multi-task method yielded Cohen's kappa coefficients of 0.82 for KL-grade and 0.79, 0.84, 0.94, 0.83, 0.84, 0.90 for femoral osteophytes, tibial osteophytes and joint space narrowing for lateral and medial compartments respectively. Furthermore, our method yielded area under the ROC curve of 0.98 and average precision of 0.98 for detecting the presence of radiographic OA (KL $\geq 2$), which is better than the current state-of-the-art.

Automated Knee Osteoarthritis Assessment Increases Physicians' Agreement Rate and Accuracy: Data from the Osteoarthritis Initiative.

Objective. To assess the impact of a computerized system on physicians' accuracy and agreement rate, as compared with unaided diagnosis. Methods. A set of 124 unilateral knee radiographs from the Osteoarthritis Initiative (OAI) study were analyzed by a computerized method with regard to Kellgren-Lawrence (KL) grade, as well as joint space narrowing, osteophytes, and sclerosis Osteoarthritis Research Society International (OARSI) grades. Physicians scored all images, with regard to osteophytes, sclerosis, joint space narrowing OARSI grades and KL grade, in 2 modalities: through a plain radiograph (unaided) and a radiograph presented together with the report from the computer assisted detection system (aided). Intraclass correlation between the physicians was calculated for both modalities. Furthermore, physicians' performance was compared with the grading of the OAI study, and accuracy, sensitivity, and specificity were calculated in both modalities for each of the scored features. Results. Agreement rates for KL grade, sclerosis, and osteophyte OARSI grades, were statistically increased in the aided versus the unaided modality. Readings for joint space narrowing OARSI grade did not show a statistically difference between the 2 modalities. Readers' accuracy and specificity for KL grade >0, KL >1, sclerosis OARSI grade >0, and osteophyte OARSI grade >0 was significantly increased in the aided modality. Reader sensitivity was high in both modalities. Conclusions. These results show that the use of an automated knee OA software increases consistency between physicians when grading radiographic features of OA. The use of the software also increased accuracy measures as compared with the OAI study, mostly through increases in specificity.