Search

Objective: To explore and to compare the magnitude and spatial pattern of in vivo femorotibial cartilage deformation in healthy and in osteoarthritic (OA) knees.Methods: One knee each in 30 women (age: 55 ± 6 years; BMI: 28 ± 2.4 kg/m(2); 11 healthy and 19 with radiographic femorotibial OA) was examined at 3Tesla using a coronal fat-suppressed gradient echo SPGR sequence. Regional and subregional femorotibial cartilage thickness was determined under unloaded and loaded conditions, with 50% body weight being applied to the knee in 20° knee flexion during imaging.Results: Cartilage became significantly (p < 0.05) thinner during loading in the medial tibia (-2.7%), the weight-bearing medial femur (-4.1%) and in the lateral tibia (-1.8%), but not in the lateral femur (+0.1%). The magnitude of deformation in the medial tibia and femur tended to be greater in osteoarthritic knees than in healthy knees. The subregional pattern of cartilage deformation was similar for the different stages of radiographic OA.Conclusion: Osteoarthritic cartilage tended to display greater deformation upon loading than healthy cartilage, suggesting that knee OA affects the mechanical properties of cartilage. The pattern of in vivo deformation indicated that cartilage loss in OA progression is mechanically driven. [ABSTRACT FROM AUTHOR]

Objective: The Osteoarthritis Initiative (OAI) is targeted at identifying sensitive biomarkers and risk factors of symptomatic knee osteoarthritis (OA) onset and progression. Quantitative cartilage imaging in the OAI relies on validated fast low angle shot (FLASH) sequences that suffer from relatively long acquisition times, and on a near-isotropic double echo steady-state (DESS) sequence. We therefore directly compared the sensitivity to cartilage thickness changes and the correlation of these protocols longitudinally.Methods: Baseline (BL) and 12 month follow-up data of 80 knees were acquired using 1.5 mm coronal FLASH and 0.7 mm sagittal DESS (sagDESS) sequences. In these and in 1.5 mm coronal multi-planar reconstructions (MPR) of the DESS the medial femorotibial cartilage was segmented with blinding to acquisition order. In the weight-bearing femoral condyle, a 60% (distance between the trochlear notch and the posterior femur) and a 75% region of interest (ROI) were studied.Results: The standardized response mean (SRM = mean change/standard deviation of change) in central medial femorotibial (cMFTC) cartilage thickness was -0.34 for coronal FLASH, -0.37 for coronal MPR DESS, -0.36 for sagDESS with the 60% ROI, and -0.38 for the 75% ROI. Using every second 0.7 mm sagittal slice (DESS) yielded similar SRMs in cMFTC for the 60% and 75% ROI from odd (-0.35/-0.36) and even slice numbers (-0.36/-0.39), respectively. BL cartilage thickness displayed high correlations (r > or = 0.94) between the three protocols; the correlations of longitudinal changes were > or = 0.79 (Pearson) and > or = 0.45 (Spearman).Conclusions: Cartilage morphometry with FLASH and DESS displays similar longitudinal sensitivity to change. Analysis of every second slice of the 0.7 mm DESS provides adequate sensitivity to change. [ABSTRACT FROM AUTHOR]

Objective: To identify subregional differences in femorotibial cartilage morphology between healthy controls and women with different grades of radiographic knee osteoarthritis (OA).Design: 158 women aged > or =40 years were studied. Weight-bearing extended anterior-posterior (AP) and Lyon schuss radiographs were obtained and the Kellgren Lawrence grade (KLG) determined. 97 women had a body mass index (BMI)< or =28, no symptoms, and were AP KLG0. 61 women had a BMI> or =30, symptoms in the target knee, and mild (KLG2=31) to moderate (KLG3=30) medial femorotibial radiographic OA in the AP views. Coronal spoiled gradient echo water excitation sequences were acquired at 3.0 Tesla. Total plate and regional measures of cartilage morphology of the weight-bearing femorotibial joint were quantified.Results: KLG2 participants displayed, on average, thicker cartilage than healthy controls in the medial femorotibial compartment (particularly anterior subregion of the medial tibia (MT) and peripheral [external, internal] subregions of the medial femur), and in the lateral femur. KLG3 participants displayed significantly thinner cartilage than KLG0 participants in the medial weight-bearing femur (central subregion), in the external subregion of the MT, and in the internal subregion of the lateral tibia. These differences were generally unaffected when possible effects of demographic covariates were considered.Conclusions: The results indicate that in femorotibial OA regional cartilage thickening and thinning may occur, dependent on the (radiographic) disease status of the joint. These changes appear to display a heterogeneous spatial pattern, where certain subregions are more strongly affected than others. [ABSTRACT FROM AUTHOR]

Background: Joint space width (JSW) evaluated in millimeters on plain X-rays is the currently optimal recognized technique to evaluate osteoarthritis (OA) structural progression. Data obtained can be presented at the group level (e.g., mean+/-standard deviation of the changes). Such presentation makes difficult the interpretation of the clinical relevance of the reported results. Therefore, a presentation at the individual level (e.g., % progressors) seems more attractive but requires to determining a cut-off. Several methodologies have been proposed to define cut-offs in JSW: arbitrary chosen cut-off, cut-off based on the validity to predict a relevant end-point such as the requirement of total articular replacement or cut-off based on the measurement error such as smallest detectable difference (SDD).Objectives: The objective of this OARSI-OMERACT initiative was to define a cut-off evaluated in millimeters on plain X-rays above which a change in JSW could be considered as relevant in patients with hip and knee OA.Methods: The first step consisted in a systematic literature research performed using Medline database up to July 2007 to obtain all manuscripts published between 1990 and 2007 reporting a cut-off value in JSW evaluated in millimeters at either the knee or hip level. The second step consisted in a consensus based on the best knowledge of the 11 experts with the support of the available evidence.Results: Among the 506 articles selected by the search, 47 articles reported cut-off of JSW in millimeters. There was a broad heterogeneity in cut-off values, whatever the methodologies or the OA localization considered (e.g., from 0.12 to 0.84 mm and from 0.22 to 0.78 mm for Knee (seven studies) and hip (seven studies), respectively when considering the data obtained based on the reliability). Based on the data extracted in the literature, the expert committee proposed a definition of relevant change in JSW based on plain X-rays, on an absolute change of JSW in millimeters and on the measurement error e.g., calculation of the SDD using the Bland and Altman technique. The results of the analysis of JSW should be expressed in terms of a dichotomous variable (e.g., progressors yes/no): a patient with a change in JSW during the study over such SDD will fulfill the definition of "progressor". Moreover, the pilot study aimed at evaluating the measurement error should be designed to reflect the different characteristics of the primary study in which the analysis of the radiological findings will be based on (patient's characteristics, centers characteristics, readers).Conclusion: This initiative based on both an Evidence Based Medicine (Systematic Literature Research) and Expert Opinion approach resulted in a proposal of definition of relevant radiological progression in OA to be used as end-point in clinical trials and also recommendations on the conduct of the reliability study allowing such definition. [ABSTRACT FROM AUTHOR]

Objective: To determine the association between changes in the delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) index over 2 years as a measure of cartilage proteoglycan concentration, with changes in cartilage thickness in the medial tibiofemoral compartment of knees in middle-aged women., Methods: One hundred and forty-eight women (one knee for each subject) aged ≥40 years were included. 3.0 T MR images of the knee were acquired at baseline, 1 year and 2 years. Three-dimensional (3D) spoiled gradient recalled echo (SPGR) sequences (for cartilage thickness) and 3D inversion recovery-prepared SPGR sequences after dGEMRIC were acquired. Segmentation was performed in the medial central (weight-bearing) femur and tibia to determine cartilage proteoglycan concentration and thickness. The association of change in the dGEMRIC indices between baseline and 1-year follow-up with (a) concomitant changes in cartilage thickness and (b) change in cartilage thickness between 1 and 2 years was assessed using linear regression., Results: In the whole-sample model, a decrease in dGEMRIC indices over time at the central medial femur significantly predicted an increase in cartilage thickness at both the central medial femur (p=0.008) and the medial tibia (p=0.04)., Conclusions: A decrease in dGEMRIC indices was associated with an increase in cartilage thickness in the medial compartment. Our results suggest that an increase in cartilage thickness may also be related to a decrease in proteoglycan concentration, which may represent swelling of cartilage in early stages of degeneration., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Imaging in clinical trials is used to evaluate subject eligibility, and/or efficacy of intervention, supporting decision making in drug development by ascertaining treatment effects on joint structure. This review focusses on imaging of bone and cartilage in clinical trials of (knee) osteoarthritis. We narratively review the full-text literature on imaging of bone and cartilage, adding primary experience in the implementation of imaging methods in clinical trials. Aims and constraints of applying imaging in clinical trials are outlined. The specific uses of semi-quantitative and quantitative imaging biomarkers of bone and cartilage in osteoarthritis trials are summarized, focusing on radiography and magnetic resonance imaging (MRI). Studies having compared both imaging methodologies directly and those having established a relationship between imaging biomarkers and clinical outcomes are highlighted. To make this review of practical use, recommendations are provided as to which imaging protocols are ideal for capturing specific aspects of bone and cartilage tissue, and pitfalls in their usage are highlighted. Further, the longitudinal sensitivity to change, of different imaging methods is reported for various patient strata. From these power calculations can be accomplished, provided the strength of the treatment effect is known. In conclusion, current imaging methodologies provide powerful tools for scoring and measuring morphological and compositional aspects of most articular tissues, capturing longitudinal change with reasonable to excellent sensitivity. When employed properly, imaging has tremendous potential for ascertaining treatment effects on various joint structures, potentially over shorter time scales than required for demonstrating effects on clinical outcomes., (Copyright © 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: To compare the rate and sensitivity to change of quantitative cartilage thickness change with magnetic resonance imaging (MRI) across specific radiographic strata of knee osteoarthritis (KOA) from central expert readings of the Osteoarthritis Initiative (OAI). Specifically, we explored whether Kellgren Lawrence grade (KLG) 2 knees with radiographic joint space narrowing (JSN) displayed greater cartilage loss than those without JSN, and whether knees with medial JSN grade2 had greater loss than those with grade1., Methods: One-year femorotibial cartilage thickness change was obtained for 836 knees, 112 without, and 724 with definite radiographic KOA based on baseline site readings. The maximum subregional cartilage loss, and cartilage thickness change in the total femorotibial joint (FTJ) and medial femorotibial compartment (MFTC) were analyzed across different radiographic strata (central vs site readings)., Results: The maximum subregional rate of change was significantly greater in central&#95;KLG2 knees with than in those without JSN (172 ± 152 vs 134 ± 100 μm; P = 0.03). In contrast, the rate did not differ significantly between central&#95;KLG1 knees with and without JSN. MFTC cartilage loss in central&#95;medial&#95;grade2 JSN knees was substantially and significantly greater than in grade1 knees (-70 ± 159 vs -31 ± 126 μm; P = 0.02). For comparison, the loss in grade3 knees was -72 ± 122 μm., Conclusions: In KLG2 knees, presence of radiographic JSN was associated with significantly and substantially greater rates of subregional cartilage loss. Differentiating knees with mild vs moderate medial JSN, and definite radiographic OA knees with vs without JSN is important in predicting structural progression of KOA, and for planning clinical trials testing the efficacy of disease modifying drugs (DMOADs)., (Copyright © 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: To evaluate the relationship between medial meniscal pathology and cartilage matrix status using delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) in medial tibiofemoral cartilage in a sample of middle-aged women., Methods: A total of 148 women ages ≥40 years were included, and 3.0T MRI of the knee was performed at baseline and at 1 year. T2-weighted, fat-suppressed and 3-dimensional inversion recovery-prepared spoiled gradient-recalled echo sequences were acquired 90 minutes after gadolinium injection. Baseline medial meniscal pathology was scored on a scale of 0-3, where 0 = normal, 1 = intrasubstance meniscal signal change, 2 = single tears, and 3 = complex tears/maceration. The central medial femur, the medial tibial plateau, and the posterior medial femur were subjected to dGEMRIC at baseline and at 1 year. Analysis of covariance was used to examine whether baseline and 1-year dGEMRIC indices in the same regions were related to the severity of meniscal damage at baseline, using normal medial menisci (grade 0) as the reference., Results: Medial compartments with grade 3 lesions showed significantly lower dGEMRIC indices (less proteoglycan content) at the central medial femur region compared with compartments with normal menisci. Mean ± SEM differences in dGEMRIC indices between grade 3 and grade 0 menisci at the central medial femur were -119.1 ± 34.2 msec at baseline (P = 0.03) and -120.3 ± 35.2 msec at followup (P = 0.04)., Conclusion: High-grade damage of the medial meniscus showed significant associations with lower dGEMRIC indices. The dGEMRIC technique may be a useful tool in detecting early degenerative changes of cartilage when meniscal function is lost., (Copyright © 2014 by the American College of Rheumatology.)

Objective: To determine the predictive value of unicompartimental joint space narrowing (JSN) for MRI-based cartilage thickness loss in the narrowed and the non-narrowed femorotibial compartment., Methods: 922 knees from 922 Osteoarthritis Initiative (OAI) participants (62.2 ± 9.0 years, 61% females) with radiographic OA (158 without JSN [noJSN], 175 with lateral JSN [latJSN], 589 with medial JSN [medJSN]) were analyzed using 3 T MRI. One-year cartilage thickness change was determined in the lateral (LFTC) and medial femorotibial compartment (MFTC), and in femorotibial subregions. The probability of subsequent cartilage loss was calculated using predefined thresholds. The predictive value of JSN for the probability and magnitude of cartilage loss was compared between latJSN, medJSN and noJSN knees using Fisher's exact and Mann-Whitney-U tests., Results: The probability of cartilage loss was greater in the narrowed compartment of latJSN/medJSN knees (34.9%/32.4%) than in noJSN knees (13.3%/12.7%, P ≤ 6.4 × 10(-6)) and so was the magnitude of cartilage thickness change (P ≤ 8.2 × 10(-6)). No significant differences were observed between the narrowed compartments of latJSN vs. medJSN knees (probability: P = 0.58, magnitude: P = 0.19) or between the non-narrowed compartment of latJSN/medJSN vs. noJSN knees (probability: P ≥ 0.35, magnitude: P = ≥0.23). These results were confirmed by the location-independent ordered value (OV) analyses of femorotibial subregions., Conclusion: The predictive value of latJSN for lateral compartment cartilage loss was comparable to that of medJSN for medial compartment cartilage loss, whereas cartilage loss in the non-narrowed compartment was similar to that in noJSN knees. These findings provide important clues to predicting progression of knee OA, and in tailoring inclusion criteria for clinical trials., (Copyright © 2013 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: Determine the effect of loading upon MRI-based mean medial femorotibial cartilage thickness (mMFT&#95;th) and radiograph-based minimum joint space width (mJSW), and determine loading's effect on the relationship between these measures., Methods: MRI and radiographs were analyzed of 25 knees in weight-bearing and non-weight-bearing conditions. Eight subjects had a Kellgren-Lawrence (KL) grade of 0, indicating no evidence of radiographic OA. The rest were KL = 2 or KL = 3, indicating mild to moderate OA. The change from unloaded to loaded conditions was calculated., Results: Joint space measures decreased from unloaded to loaded conditions for both radiographs (mJSW = 3.29 mm unloaded to 3.16 mm loaded, P < 0.05) and MRI (mMFT&#95;th = 2.70 mm unloaded to 2.55 mm loaded P < 0.001). The mean absolute difference measured from radiographs was larger for the OA group than the control group, at -0.20 mm for OA vs +0.01 mm for control. Loaded X-ray and loaded MRI joint space values from our study were no better correlated to one another than loaded X-ray and unloaded MRI., Conclusion: Knee loading does not add a very significant value to the study of joint space on healthy knees, but loading may play a role in the study of OA knees. Unloaded MRI assessments of cartilage thickness are as correlated to loaded JSW as to loaded MRI measurements. More study is necessary to determine whether loaded MRI adds significant value to the study of OA progression., (Published by Elsevier Ltd.)

Objective: Using placebo data from a recently completed disease-modifying osteoarthritis (OA) drug trial, we seek to inform study design of future radiographic studies., Methods: Eligible patients aged ≥40 years, with body mass index (BMI) 25-40kg/m(2) and symptomatic knee OA diagnosed by modified Kellgren and Lawrence grade (KLG) 2 or 3 and pain/stiffness and/or use of medication for knee pain in the past year, were assessed by radiography using a modified Lyon-schuss (mL/S) protocol for joint space narrowing (JSN) (primary outcome variable) at baseline and weeks 48 and 96. Multifaceted quality control was conducted throughout. Repeat images were requested when the medial tibial plateau (MTP) was not aligned (inter-margin distance [IMD] >1.5mm) or for other quality issues. Data are given mean ± standard deviation., Results: Patients (74.9% female; 61.3 ± 9.1 years) had BMI 31.6 ± 4.1kg/m(2) at baseline; 222 (173 females) had KLG2, 264 (191 female) KLG3. A significant loss in joint space width (JSW) from baseline to week 48 (-0.13 ± 0.36mm) and to week 96 (-0.22 ± 0.45mm) was observed for all randomised placebo patients (p < 0.001 for both), and at both time points when stratified by KLG2 or KLG3. Standard deviations were small relative to mean changes, providing standardised response means for all placebo patients of 0.35 (week 48) and 0.48 (week 96)., Conclusions: Using a tightly controlled radiographic technique, JSN is a viable outcome variable for determining disease progression in mild-to-moderate knee OA. The mL/S protocol is a sensitive and feasible method for OA studies aiming to assess rate of JSN in the knee., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: To ascertain the importance of alignment of the medial tibial plateau (MTP), as determined by the distance between the anterior and posterior margins of the plateau (intermargin distance [IMD]), for measurements of joint space width (JSW) in radiographs of normal knees., Methods: JSW and IMD were measured in paired baseline and 12-month knee films of 122 subjects from the osteoarthritis initiative (OAI). Relationships between JSW and IMD, and between the variation in JSW and variation in IMD, were evaluated., Results: In cross-sectional analysis, a non-linear relationship existed between JSW and the concurrent IMD. With poor MTP alignment (IMD>1.7 mm), a 1.0-mm increase in IMD resulted in a 0.16-mm (95%CI: 0.11-0.21) increase in JSW (P<0.0001). In a longitudinal analysis, the effect of IMD variation on variation in JSW was also highly significant (P<0.0001). A variation of 1 mm between IMD(Baseline) and IMD(12month) was associated with a 0.10-mm (95% CI: 0.06-0.13) variation in JSW, with variations in JSW and IMD occurring in the same direction. An IMD variation less than or equal to 1.0mm was determined to be acceptable for accurate evaluation of JSW in serial radiographs., Conclusion: The error in measurement of JSW caused by variation in IMD in serial radiographs of normal knees can be as large, or larger, than the mean rate of 12-month joint space narrowing (JSN) in OA knees. MTP alignment and replication of alignment in serial knee films are required for accurate determination of JSN in OA knee., (Copyright © 2012. Published by Elsevier SAS.)

Objective: To determine if inhibition of inducible nitric oxide synthase (iNOS) with cindunistat hydrochloride maleate slows progression of osteoarthritis (OA) METHODS: This 2-year, multinational, double-blind, placebo-controlled trial enrolled patients with symptomatic knee OA (Kellgren and Lawrence Grade (KLG) 2 or 3). Standard OA therapies were permitted throughout. Patients were randomly assigned to cindunistat (50 or 200 mg/day) or placebo. Randomisation was stratified by KLG. Radiographs to assess joint space narrowing (JSN) were acquired using the modified Lyon-schuss protocol at baseline, week 48 and 96., Results: Of 1457 patients (50 mg/day, n=485; 200 mg/day, n=486; placebo, n=486), 1048 (71.9%) completed the study. Patients were predominantly women; 56% had KLG3. The primary analysis did not demonstrate superiority of cindunistat versus placebo for rate of change in JSN. In KLG2 patients, JSN after 48 weeks was lower with cindunistat 50 mg/day versus placebo (p=0.032). Least-squares mean±SE JSN with cindunistat 50 mg/day ( -0.048±0.028 mm) and 200 mg/day (-0.062±0.028 mm) were 59.9% (95% CI 6.8% to 106.9%) and 48.7% (95% CI -8.4% to 93.9%) of placebo, improvement was not maintained at 96 weeks. No improvement was observed for KLG3 patients at either time-point. Cindunistat did not improve joint pain or function, but was generally well tolerated., Conclusions: Cindunistat (50 or 200 mg/day) did not slow the rate of JSN versus placebo. After 48-weeks, KLG2 patients showed less JSN; however, the improvement was not sustained at 96-weeks. iNOS inhibition did not slow OA progression in KLG3 patients. CLINICAL TRIAL LISTING: NCT00565812.

Objective: Minimum radiographic joint space width (mJSW) represents the Food and Drug Administration (FDA) standard for demonstrating structural therapeutic benefits for knee osteoarthritis (KOA), but only shows moderate responsiveness (sensitivity to change). We directly compare the responsiveness of magnetic resonance imaging (MRI)-based cartilage thickness and JSW measures from fixed-flexion radiography (FFR) and explore the correlation of region-matched changes between both methods., Methods: Nine hundred and sixty-seven knees of Osteoarthritis Initiative participants with radiographic KOA were studied: 445 over 1 year with coronal FLASH MRI and FFR, and 375/522 over 1/2 years with sagittal DESS MRI and FFR. Standardized response means (SRM) of cartilage thickness and mJSW were compared using the sign-test., Results: With FLASH MRI, SRM was -0.28 for medial femorotibial compartment (MFTC) cartilage loss vs -0.15 for mJSW, and -0.32 vs -0.22 for the most sensitive MRI subregion (central MFTC) vs the most sensitive fixed-location JSW(x = 0.25). With DESS MRI, 1-year SRM was -0.34 for MFTC vs -0.22 for mJSW and -0.44 vs -0.28 for central MFTC vs JSW(x = 0.225). Over 2 years, the SRM was significantly greater for MFTC than for mJSW (-0.43 vs -0.31, P = 0.017) and for central MFTC than for JSW(x = 0.225) (-0.51 vs -0.44, P < 0.001). Correlations between changes in spatially matched MRI subregions and fixed-location JSW were not consistently higher (r = 0.10-0.51) than those between non-matched locations (r = 0.15-0.50)., Conclusions: MRI displays greater responsiveness in KOA than JSW FFR-based JSW, with the greatest SRM observed in the central medial femorotibial compartment. Fixed-location radiographic measures appear not capable of determining the spatial distribution of femorotibial cartilage loss., (Copyright © 2012 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objectives: To characterize the utility of nitrotyrosine (NT) as a biomarker for arthritis and joint injury., Design: Synovial fluid, plasma, and urine from patients diagnosed with osteoarthritis (OA), rheumatoid arthritis (RA), anterior cruciate ligament (ACL) injury, meniscus injury and pseudogout, and knee-healthy volunteers were analyzed for concentrations of NT, nitrate and nitrite (NO(x)), matrix metalloproteinase (MMP)-3, MMP-1, MMP-9, more than 40 chemokines and cytokines., Results: In OA, plasma and synovial fluid NT were increased versus healthy volunteers. Synovial fluid to plasma NT ratios were elevated in OA patients. Synovial fluid from patients with ACL and meniscus injury and pseudogout had increased levels of NT (P < 0.001). In these samples, NT levels significantly correlated with ARGS-aggrecan neoepitope generated by aggrecanase cleavage of aggrecan (P ≤ 0.001), cross-linked C-telopeptides of type II collagen (P < 0.001), MMP-1 (P = 0.008), and MMP-3 (P ≤ 0.001). In RA, plasma NT decreased following 6 months of anti-tumor necrosis factor (TNF) treatment. For every 1.1% change in log(10) NT, there was a 1.0% change in the log(10) disease activity scores (DAS28-3 CRP). Both predicted and observed DAS28-3 CRP showed a robust linear relationship with NT. RA plasma NT positively correlated with CRP, MMP-3 and interferon γ-induced protein 10., Conclusions: NT may serve as a useful biomarker for arthritis and joint injury. In RA, NT is highly correlated with several biomarkers and clinical correlates of disease activity and responds to anti-TNF therapy., (Copyright © 2012 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Purpose: Standard knee MRI is performed under unloading (ULC) conditions and not much is known about changes of the meniscus, ligaments or cartilage under loading conditions (LC). The aim is to study the influence of loading of different knee structures at 3Tesla (T) in subjects with osteoarthritis (OA) and normal controls., Materials and Methods: 30 subjects, 10 healthy and 20 with radiographic evidence of OA (10 mild and 10 moderate) underwent 3T MRI under ULC and LC at 50% body weight. All images were analyzed by two musculoskeletal radiologists identifying and grading cartilage, meniscal, ligamentous abnormalities. The changes between ULC and LC were assessed. For meniscus, cartilage and ligaments the changes of lesions, signal and shape were evaluated. In addition, for the meniscus changes in extrusion were examined. A multivariate regression model was used for correlations to correct the data for the impact of age, gender, BMI. A paired T-Test was performed to calculate the differences in meniscus extrusion., Results: Subjects with degenerative knee abnormalities demonstrated significantly increased meniscus extrusion under LC when compared to normal subjects (p=0.0008-0.0027). Subjects with knee abnormalities and higher KL scores showed significantly more changes in lesion, signal and shape of the meniscus (80% (16/20) vs. 20% (2/10); p=0.0025), ligaments and cartilage during LC., Conclusion: The study demonstrates that axial loading has an effect on articular cartilage, ligament, and meniscus morphology, which is more significant in subjects with degenerative disease and may serve as an additional diagnostic tool for disease diagnosis and assessing progression in subjects with knee OA., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Objective: Despite a growing body of Magnetic Resonance Imaging (MRI) literature in osteoarthritis (OA), there is little uniformity in its diagnostic application. We envisage in the first instance the definition requiring further validation and testing in the research setting before considering implementation/feasibility testing in the clinical setting. The objective of our research was to develop an MRI definition of structural OA., Methods: We undertook a multistage process consisting of a number of different steps. The intent was to develop testable definitions of OA (knee, hip and/or hand) on MRI. This was an evidence driven approach with results of a systematic review provided to the group prior to a Delphi exercise. Each participant of the steering group was allowed to submit independently up to five propositions related to key aspects in MRI diagnosis of knee OA. The steering group then participated in a Delphi exercise to reach consensus on which propositions we would recommend for a definition of structural OA on MRI. For each round of voting, ≥60% votes led to include and ≤20% votes led to exclude a proposition. After developing the proposition one of the definitions developed was tested for its validity against radiographic OA in an extant database., Results: For the systematic review we identified 25 studies which met all of our inclusion criteria and contained relevant diagnostic measure and performance data. At the completion of the Delphi voting exercise 11 propositions were accepted for definition of structural OA on MRI. We assessed the diagnostic performance of the tibiofemoral MRI definition against a radiographic reference standard. The diagnostic performance for individual features was: osteophyte C statistic=0.61, for cartilage loss C statistic=0.73, for bone marrow lesions C statistic=0.72 and for meniscus tear in any region C statistic=0.78. The overall composite model for these four features was a C statistic=0.59. We detected good specificity (1) but less optimal sensitivity (0.46) likely due to detection of disease earlier on MRI., Conclusion: We have developed MRI definition of knee OA that requires further formal testing with regards their diagnostic performance (especially in datasets of persons with early disease), before they are more widely used. Our current analysis suggests that further testing should focus on comparisons other than the radiograph, that may capture later stage disease and thus nullify the potential for detecting early disease that MRI may afford. The propositions are not to detract from, nor to discourage the use of traditional means of diagnosing OA., (Copyright © 2011 Osteoarthritis Research Society International. All rights reserved.)

Objective: To examine whether ordered values of (sub)regional femorotibial cartilage thickness change are superior to region-based approaches in detecting risk factors for cartilage loss in osteoarthritis (OA)., Methods: 58 women with knee OA had 3 Tesla MR images acquired at baseline and 24 months. Changes in cartilage thickness (∆ThCtAB) were determined in eight medial femorotibial subregions. An ascending sort of individual ∆ThCtAB measurements was done to create "ordered values". Risk factors for cartilage loss considered were: age, BMI, anatomical knee axis (AAA), minimal (medial) joint space width (mJSW), and percent of medial tibial plateau covered by the meniscus (percent cover). All change metrics were tested for association with the risk factors using Kendall's τ and relative sensitivity of multiple tests of subregions and ordered values were compared with single metrics of change from plate and compartment summaries and the first ordered value., Results: The associations between subregion ∆ThCtAB and AAA (P=0.0002), mJSW (P=0.016), and age (P=0.011) were significant, but only AAA (at α=0.05) and age (at α=0.1) remained significant after adjusting for multiple subregions. In contrast, cMFTC had P-values<0.05 for AAA (P=0.0001), mJSW (P=0.016), and meniscus subluxation (0.04). The first ordered value had significant associations with AAA (P=0.0004), mJSW (P=0.003), meniscus subluxation (P=0.02) and percent cover (P=0.031) all of which were significant at α=0.05 after adjusting for tests on multiple risk factors., Conclusion: Ordered values of ∆ThCtAB were more sensitive in detecting risk factors of cartilage loss than subregional ∆ThCtAB. Sensitivity was further enhanced by considering the minimum ordered value as a single test, thus not requiring adjustment for multiple tests. Using ordered values there was a significant association between ∆ThCtAB and baseline AAA, mJSW, meniscus subluxation and meniscus percent cover. This study provides an important step in validating ordered values of cartilage change., (Copyright © 2010 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: To evaluate the effect of acute loading on healthy and osteoarthritic knee cartilage T(1ρ) and T(2) relaxation times., Design: Twenty subjects with radiographic evidence of osteoarthritis (OA) and 10 age-matched controls were enrolled. Magnetic resonance imaging (MRI) acquisition, including T(1ρ) and T(2) map sequences were performed unloaded and loaded at 50% body mass. Cartilage masks were segmented semi-automatically on registered high-resolution spoiled gradient-echo (SPGR) images for each compartment (medial and lateral). Cartilage lesions were identified using a modified Whole Organ Magnetic Resonance Imaging Score (WORMS) score. Statistical differences were explored using separate two-way (group×loading condition) Analysis of Variance (ANOVA) using age as a covariate to evaluate the effects of loading on T(1ρ) and T(2) relaxation times., Results: A significant decrease in T(1ρ) (44.5±3.8 vs 40.2±4.8ms for unloaded and loaded, respectively; P<0.001) and T(2) (31.8±3.8 vs 30.5±4.8ms for unloaded and loaded, respectively; P<0.001) relaxation times was observed in the medial compartment with loading while no differences were observed in the lateral compartment. This behavior occurred independent of WORMS score. Cartilage compartments with small focal lesions experienced greater T(1ρ) change scores with loading when compared to cartilage without lesions or cartilage with larger defects (P=0.05)., Conclusions: Acute loading resulted in a significant decrease in T(1ρ) and T(2) relaxation times of the medial compartment, with greater change scores observed in cartilage regions with small focal lesions. These data suggest that changes of T(1ρ) values with loading may be related to cartilage biomechanical properties (i.e., tissue elasticity) and may be a valuable tool for the scientist and clinician at identifying early cartilage disease., (Copyright © 2010 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

This study was designed to characterize the reproducibility and sensitivity to change of magnetic resonance imaging-based cartilage morphology metrics and femoral regions of interest (ROIs), in order to provide preferable outcome measures in longitudinal studies of cartilage morphology. Test-retest acquisitions were obtained at 3 tesla (T) in 33 subjects with and without radiographic signs of osteoarthritis (OA) (reproducibility study) as well as baseline and 2-year follow-up acquisitions in 28 subjects with radiographic signs of advanced OA (sensitivity study). Cartilage was segmented in the tibia and two distinct anatomical femoral ROIs, a 'long' ROI extending 60% from the trochlear notch to the posterior end of the condyles, and a 'short' ROI extending to the intercondylar bone bridge. Coefficients of variation (reproducibility study) and standardized response means (SRMs, sensitivity study) were obtained for different morphology metrics and anatomical regions. The subchondral bone area of the long ROI was 20% greater and less variable than that of the short ROI; cartilage morphology metrics were generally more reproducible in the long ROI. Normalized cartilage volume (VCtAB) and mean cartilage thickness (over the entire subchondral bone area; ThCtAB.Me) tended to be more reproducible and more sensitive to change (SRM up to -0.62) than cartilage volume (SRM up to -0.44), cartilage thickness over the cartilaginous area (ThCcAB; SRM up to -0.48) or maximum cartilage thickness (ThCtAB; SRM up to -0.35). The long femoral cartilage ROI provided more reproducible measurements than the short one. VCtAB and ThCtAB.Me may be preferable metrics in longitudinal studies of articular cartilage adaptation or OA., (Copyright © 2010 S. Karger AG, Basel.)

Purpose: The purpose of the study was to determine if a positive association exists between arterial vessel wall thickness and generalized osteoarthritis (OA). Our hypothesis is that generalized OA is another facet of the metabolic syndrome., Materials and Methods: The medical ethical review board of our institution approved the study. Written informed consent was obtained from each patient prior to the study. Magnetic resonance (MR) images of the knee were obtained in 42 patients who had been diagnosed with generalized OA at multiple joint sites. Another 27 MR images of the knee were obtained from a matched normal (non-OA) reference population. Vessel wall thickness of the popliteal artery was quantitatively measured by dedicated software. Linear regression models were used to investigate the association between vessel wall thickness and generalized OA. Adjustments were made for age, sex, and body mass index (BMI). Confidence intervals (CI) were computed at the 95% level and a significance level of alpha = 0.05 was used., Results: Patients in the generalized OA population had a significant higher average vessel wall thickness than persons from the normal reference population (p < or = alpha), even when correction was made for sex, age, and BMI. The average vessel wall thickness of the popliteal artery was 1.09 mm in patients with generalized OA, and 0.96 mm in the matched normal reference population., Conclusion: The association found between increased popliteal artery vessel wall thickness and generalized osteoarthritis suggests that generalized OA might be another facet of the metabolic syndrome.

Objective: To ascertain the contribution of articular cartilage morphometry and meniscal position on MRI to joint space width (JSW) measured in the Lyon schuss radiograph of the knee., Design: 62 obese women with knee OA and 99 non-obese female controls (mean age 56.6 years) were imaged using 3T MRI and coronal water excitation spoiled gradient echo sequences. Segmentation of femorotibial cartilage morphology and regional morphometric analysis was performed using custom software. Meniscal position was measured quantitatively in sagittal and coronal planes. Minimum space width (mJSW) was measured in the Lyon Schuss knee radiograph; Kellgren and Lawrence grades (KLG) were assigned on standing anteroposterior knee films. The relative contribution of regional cartilage thickness and meniscal position to mJSW was assessed initially in univariate models and subsequently with multivariable modelling., Results: 65% of the variation in mJSW was explained by regional cartilage thickness measures, different KLG and meniscal coverage. Of these measures the medial tibia cartilage thickness measures and central region of the central medial femur (ccMF) play a consistent role in variations in mJSW observed across all KLG. Further ccMF and the addition of percent meniscal coverage to this model explains the remaining differences in mean mJSW found between those subjects with definite joint space narrowing (KLG3) and those without OA., Conclusion: The variation in radiographic mJSW is best described by five regional cartilage thickness measures and percent meniscal coverage. The magnitude of each measures contribution differs according to radiographic severity with more variability explained by cartilage thickness of ccMF cartilage thickness and percent meniscal coverage with more severe disease.

The progression of osteoarthritis is traditionally measured using radiographic joint space width (JSW). Numerous knee radiograph protocols have been developed with various levels of complexity and performance as it relates to detecting JSW loss (ie, joint space narrowing). Sensitivity to joint space narrowing is improved when radioanatomic alignment of the medial tibial plateau is achieved. Semiautomated software has been developed to improve the accuracy of JSW measurement over manual methods. JSW measurements include minimum JSW, mean JSW or joint space area, and JSW at fixed locations.

Accurate and highly reproducible measurements of the rate of progression of osteoarthritis is crucial to assessing structural change, and requires adherence to exacting standards of positioning, which include specifications for flexion and rotation of the joint, and angulation of the x-ray beam. The progression of osteoarthritis traditionally has been measured using radiographic joint space width (JSW). Over the past two decades, numerous knee radiographic protocols have been developed with various levels of complexity and performance as they relate to detecting JSW loss (ie, joint space narrowing). Semiautomated software has been developed to improve the accuracy of JSW measurement over manual methods. JSW measurements include minimum JSW, mean JSW or joint space area and JSW at fixed locations.

Objective: The Osteoarthritis Initiative (OAI) is aimed at validating (imaging) biomarkers for monitoring progression of knee OA. Here we analyze regional femorotibial (FT) cartilage thickness changes over 1 year using 3 Tesla MRI. Specifically, we tested whether changes in central subregions exceed those in the total cartilage plates., Methods: The right knees of a subsample of the OAI progression subcohort (n=156, age 60.9+/-9.9 years) were studied. Fifty-four participants had definite radiographic osteoarthritis (OA) (KLG 2 or 3) and a BMI>30. Mean and minimal cartilage thickness were determined in subregions of the medial/lateral tibia (MT/LT), and of the medial/lateral weight-bearing femoral condyle (cMF/cLF), after paired (baseline, follow up) segmentation of coronal FLASHwe images with blinding to the order of acquisition., Results: The central aspect of cMF displayed a 5.8%/2.8% change in mean thickness in the group of 54/156 participants, respectively, with a standardized response mean (SRM) of -0.47/-0.31, whereas cartilage loss in the total cMF was 4.1%/1.9% (SRM -0.49/-0.30). In the central MT, the rate of change was -1.6%/-0.9% and the SRM -0.29/-0.20, whereas for the entire MT the rate was -1.0%/-0.5% and the SRM -0.21/-0.12. Minimal thickness displayed greater rates of change, but lower SRMs than mean thickness., Conclusions: This study shows that the rate of cartilage loss is greater in central subregions than in entire FT cartilage plates. The sensitivity to change in central subregions was higher than for the total cartilage plate in the MT and was similar to the total plate in the medial weight-bearing femur.

Introduction: The aim was to investigate the relationship of cartilage loss (change in medial femorotibial cartilage thickness measured with magnetic resonance imaging (MRI)) with compartment-specific baseline radiographic findings and MRI cartilage morphometry features, and to identify which baseline features can be used for stratification of fast progressors., Methods: An age and gender stratified subsample of the osteoarthritis (OA) initiative progression subcohort (79 women; 77 men; age 60.9 +/- 9.9 years; body mass index (BMI) 30.3 +/- 4.7) with symptomatic, radiographic OA in at least one knee was studied. Baseline fixed flexion radiographs were read centrally and adjudicated, and cartilage morphometry was performed at baseline and at one year follow-up from coronal FLASH 3 Tesla MR images of the right knee., Results: Osteophyte status at baseline was not associated with medial cartilage loss. Knees with medial joint space narrowing tended to show higher rates of change than those without, but the relationship was not statistically significant. Knees with medial femoral subchondral bone sclerosis (radiography), medial denuded subchondral bone areas (MRI), and low cartilage thickness (MRI) at baseline displayed significantly higher cartilage loss than those without, both with and without adjusting for age, sex, and BMI. Participants with denuded subchondral bone showed a standardized response mean of up to -0.64 versus -0.33 for the entire subcohort., Conclusions: The results indicate that radiographic and MRI cartilage morphometry features suggestive of advanced disease appear to be associated with greater cartilage loss. These features may be suited for selecting patients with a higher likelihood of fast progression in studies that attempt to demonstrate the cartilage-preserving effect of disease-modifying osteoarthritis drugs.

Objective: This study evaluated the longitudinal performance of a modified Lyon schuss (LS) knee examination in the detection of radiographic joint space narrowing (JSN) in knees with osteoarthritis (OA). The modified LS exam entails two to four iterative acquisitions with empirically adjusted angulation of the X-ray beam to achieve superimposition of the anterior and posterior margins of the medial tibial plateau (MTP), a marker of parallel radioanatomic alignment that the original LS exam achieves with fluoroscopically guided beam angulation., Methods: Seventy-four obese women with symptomatic knee OA underwent LS and fixed-flexion (FF, caudal 10 degrees beam angulation) X-ray exams at baseline and 1 year later. For 47 subjects, beam angulation for both LS exams was guided by fluoroscopy. For 27 subjects, the modified LS exam was performed at one or both times. Modified and original LS procedures were evaluated relative to concurrent FF radiographs with respect to the inter-margin distance (IMD) at the MTP midpoint (quality and reproducibility of alignment) and sensitivity to JSN., Results: Compared to FF radiographs, modified LS radiographs afforded a smaller mean IMD at baseline (0.89 vs 2.06 mm, P=0.002), more reproducible IMD (mean change=0.49 vs 0.91 mm, P=0.007) and more rapid JSN (mean=0.25 vs 0.02 mm/yr, P=0.005). These differences paralleled those observed between original LS and FF procedures with respect to baseline alignment (0.96 vs 1.94 mm, P<0.001), reproducibility of alignment (0.49 vs 1.00 mm, P<0.001) and sensitivity to JSN (0.16 vs -0.01 mm/yr, P=0.007)., Conclusion: In clinical centers where the absence of fluoroscopy equipment precludes use of the original LS protocol, a modified procedure employing iterative, empirical adjustment of the beam angle to achieve parallel radioanatomic alignment with the MTP affords a degree of superiority over the FF protocol with respect to quality and reproducibility of positioning and sensitivity to JSN in OA knees similar to that of the original.

Objective: Progression of joint damage in osteoarthritis (OA) is likely to result from an imbalance between cartilage degradation and synthesis processes. Markers reflecting these two components appear to be promising in predicting the rate of OA progression. Both N- and C-terminal propeptides of type II collagen reflect the rates of collagen type II synthesis. The ability to quantify the procollagen peptides in biological fluids would enable a better understanding of OA disease pathology and provide means for assessing the proof of mechanism of anabolic disease modifying OA drugs (DMOADs)., Methods: A polyclonal antibody that recognizes the sequence GPKGQKGEPGDIKDI in the propeptide region of rat, dog, and human type II collagen was raised in chicken and peptide-affinity purified. The immunoaffinity liquid chromatography mass spectrometry (LC-MS/MS) was used to extensively characterize N-terminal procollagen type II (NPII) peptides found in biological fluids. The novel competition enzyme-linked immunosorbent assay (ELISA) assay was developed to quantitatively measure the NPII peptides., Results: Several peptides ranging from 17 to 41 amino acids with various modifications including hydroxylations on proline and lysine residues, oxidation of lysines to allysines, and attachments of glucose and galactose moieties to hydroxylysines were identified in a simple system such as ex vivo cultures of human articular cartilage (HAC) explants as well as in more complex biological fluids such as human urine and plasma. A competitive ELISA assay has been developed and applied to urine, plasma, and synovial fluid matrices in human, rat and dog samples., Conclusion: A novel NPII assay has been developed and applied to OA and normal human subjects to understand the changes in collagen type II synthesis related to the pathology of OA.

Objectives: To map by magnetic resonance imaging (MRI) and quantitative MRI (qMRI) concomitant fractures and meniscal injuries, and location and volume of traumatic bone marrow lesions (BMLs) in the acutely anterior cruciate ligament (ACL) injured knee. To relate BML location and volume to cortical depression fractures, meniscal injuries and patient characteristics., Methods: One hundred and twenty-one subjects (26% women, mean age 26 years) with an ACL rupture to a previously un-injured knee were studied using a 1.5T MR imager within 3 weeks from trauma. Meniscal injuries and fractures were classified by type, size and location. BML location and volume were quantified using a multi-spectral image data set analyzed by computer software, edited by an expert radiologist., Results: Fractures were found in 73 (60%) knees. In 67 (92%) of these knees at least one cortical depression fracture was found. Uni-compartmental meniscal tears were found in 44 (36%) subjects and bi-compartmental in 24 (20%). One hundred and nineteen (98%) knees had at least one BML, all but four (97%) located in the lateral compartment. Knees with a cortical depression fracture had larger BML volumes (P<0.001) than knees without a cortical depression fracture, but no associations were found between meniscal tears and BML volume or fractures. Older age at injury was associated with smaller BML volumes (P<0.01)., Conclusion: A majority of the ACL injured knees had a cortical depression fracture, which was associated with larger BML volumes. This indicates strong compressive forces to the articular surface and cartilage at the time of injury, which may constitute an additional risk factor for later knee osteoarthritis development.

Objective: To evaluate the effect of medial tibial plateau (MTP) alignment of serial radiographs on the capacity to detect associations between baseline characteristics and progression of joint space narrowing (JSN) in knee osteoarthritis (OA)., Methods: Standardised posteroanterior weight-bearing knee radiographs of 83 knee OA patients were obtained at baseline and after 24 months using the non-fluoroscopic fixed-flexion protocol. Minimum joint space width (JSW) of the medial tibiofemoral joint spaces was measured manually in paired radiographs. Progression of JSN was defined by a change in JSW larger than the smallest detectable difference (0.4mm). Satisfactory MTP alignment was present if the distance between the anterior and posterior margins of the MTP was < or = 1mm. Standardised questionnaires were used to record age, sex and body mass index. Medial tibiofemoral JSN and osteophyte severity at baseline were graded with the Osteoarthritis Research Society International (OARSI) atlas., Results: Progression of JSN was observed in 31 (28.4%) of 109 OA knees. In the sub sample of 48 (44%) OA knees with satisfactory MTP alignment on baseline and 24-month radiographs, 18 (37.5%) knees progressed. Stronger (statistically significant) associations were found between sex, generalised OA, JSN and osteophyte severity at baseline and progression of JSN in the sub sample of radiographs with serial satisfactorily MTP alignment than in all radiographs together., Conclusion: Insufficient quality of MTP alignment on serial radiographs could prevent detection of associations between baseline characteristics and progression of JSN in knee OA. These findings may have implications for longitudinal knee OA studies using the fixed-flexion protocol.

Objective: To evaluate the validity of using the conventional anteroposterior (AP) radiograph of the knee in order to identify joint space narrowing (JSN) at an early stage of osteoarthritis (OA)., Methods: Grading of JSN using a 0-5 score and quantitative measurement of joint space width (JSW) of the medial and lateral compartments of the tibiofemoral joint in AP and fluoroscopically assisted posteroanterior Lyon schuss (LS) radiographs of 202 patients with knee OA., Results: Knees without definite JSN (score <2) were twice as common in AP than in LS radiographs (36.1% vs 18.8%). The number of knees showing definite medial JSN was identical in both views but four knees showing a medial OA in AP view were classified differently in the LS radiographs (three bicompartmental OA and one lateral OA). The frequency of lateral JSN was approximately twice as great in the LS view as in the AP view. JSN score was significantly higher (p<0.001) and JSW was significantly smaller (p<0.01) in the LS view than in the AP view. In knees with definite JSN, JSW of the compartment with no narrowing was significantly (p<0.04) larger than in knees that did not exhibit definite JSN. Medial JSW and lateral JSW were inversely correlated (p<0.001)., Conclusions: The standing AP radiograph performed poorly in identifying both the location of JSN in patients with early tibiofemoral OA (especially, lateral OA) and the severity of JSN. The LS radiographs are preferable to standing AP views for the selection of patients for therapeutic trials of structure-modifying OA drugs.

Objective: To assess the relationship of biochemical markers and radiographic signs of osteoarthritis (ROA) in the subjects with symptomatic osteoarthritis (OA) at multiple sites of the Genetics osteoARthritis and Progression (GARP) study., Methods: We have measured eight biochemical markers, representing tissue turnover of cartilage, bone, synovium, and inflammation. ROA was assessed in the knees, hips, hands, vertebral facet joints and spinal disc degeneration (DD) by using the Kellgren score. A proportionate score was subsequently made for each joint location based on the number of joints with ROA. Principal component and linear mixed model analyses were applied to analyze the data., Results: Three different clusters of markers were identified that may reflect different pathophysiological processes of OA. The first component appeared to be reflected by structural markers of cartilage and bone turnover and associated especially in subjects with hip ROA. The second component was reflected by a marker of inflammation and was associated with knee ROA, high Western Ontario and McMaster Universities (WOMAC) scores and body mass index (BMI). The third component included markers of cartilage turnover and was associated with ROA at hands, spine as well as age. High familial aggregation was observed for serum cartilage oligomeric matrix protein (S-COMP) (70%) and serum N-propeptide of collagen type IIA (S-PIIANP) (62%)., Conclusion: Using a large well-characterized study and eight biochemical markers, we were able to observe three components that may reflect different molecular mechanisms (bone, cartilage, synovium turnover and inflammation). Our data suggested that these components contribute differently to ROA at different joint sites.

Objectives: Independent reports on the longitudinal performance of non-fluoroscopic fixed-flexion knee radiography have not been published. Therefore, we evaluated the sensitivity of fixed-flexion radiography to detect knee joint space narrowing (JSN) over 2 years in patients with osteoarthritis (OA) and compared the effect of reproducibility and quality of medial tibial plateau (MTP) alignment on sensitivity to JSN., Methods: Fixed-flexion radiographs of both knees of 193 OA patients were obtained at baseline and after 24 months. Minimum joint space width (JSW) of the medial tibiofemoral joint spaces was measured manually in paired digitised radiographs without knowledge of the chronology. The degree of MTP alignment was assessed by measuring the distance between the anterior and posterior margins of the MTP (intermargin distance [IMD]). Accurate repositioning was achieved if, in the 24-month radiograph, the IMD was reproduced to within 1mm. The quality of MTP alignment was satisfactory if the IMD was

Objective: To examine whether urine concentrations of type II collagen neoepitope (uTIINE) distinguish subjects with progressive radiographic and/or symptomatic knee osteoarthritis (OA) from those with stable disease., Methods: Subjects were 120 obese middle-aged women with unilateral knee OA who participated in a 30-month randomized-controlled trial of structure modification with doxycycline, in which a standardized semiflexed anteroposterior view of the knee was obtained at baseline, 16 months and 30 months. Subjects were selected from a larger sample to permit a priori comparisons between 60 OA progressors and 60 nonprogressors, as defined by joint space narrowing (JSN) in the medial tibiofemoral compartment. Each group contained 30 subjects who exhibited clinically significant increases in knee pain over 30 months and 30 who did not. Urine samples were obtained every 6 months for determination of the creatinine (Cr)-adjusted uTIINE concentration., Results: Baseline uTIINE levels were unrelated to JSN in the placebo group. However, among subjects in the active treatment group, a 1-standard deviation increment in baseline uTIINE (68 ng/mM Cr) was associated with a marginally significant, two-fold increase in the odds of progression of JSN (odds ratio 2.04, 95% confidence interval 0.98-4.28). The within-subject mean of uTIINE values at baseline, 6 months and 12 months was associated with concurrent JSN measured at 16 months (0.10mm of JSN per 69 ng/mM Cr, P=0.008). Similar results were seen in the interval between months 16 and 30 and in analyses using the maximum of intercurrent uTIINE levels., Conclusion: Baseline uTIINE was not a consistent predictor of JSN in subjects with knee OA. However, serial measurements of uTIINE reflect concurrent JSN.

Purpose: To prospectively evaluate the association between clinical features and structural abnormalities found at magnetic resonance (MR) imaging in patients with osteoarthritis (OA) of the knee., Materials and Methods: The study was approved by the institutional medical ethics review board. Written informed consent was obtained from each patient. MR images of the knee were obtained from 205 (42 [20%] men, 163 [80%] women; median age, 60 years; range, 43-77 years) patients in whom symptomatic OA at multiple joint sites was diagnosed. MR images were analyzed for various abnormalities of OA. All patients were interviewed concerning pain and stiffness in the knee that was imaged. Odds ratios (ORs) with 99% confidence intervals (CIs) were used to determine the association between the imaging findings and clinical features of OA., Results: A large joint effusion was associated with pain (OR, 9.99; 99% CI: 1.28, 149) and stiffness (OR, 4.67; 99% CI: 1.26, 26.1). The presence of an osteophyte in the patellofemoral compartment (OR, 2.25; 99% CI: 1.06, 4.77) was associated with pain. All other imaging findings, including focal or diffuse cartilaginous abnormalities, subchondral cysts, bone marrow edema, subluxation of the meniscus, meniscal tears, or Baker cysts, were not associated with symptoms., Conclusion: Findings of this study indicate that only two associations exist between clinical symptoms and structural findings found on MR images in patients with OA of the knee., (Copyright (c) RSNA, 2006.)

Objective: To assess the relation between the urinary concentrations of type II collagen C-telopeptide (UCTX-II) and radiographic signs of osteoarthritis (ROA) in the GARP (Genetics, Arthrosis and Progression) study., Methods: UCTX-II levels were measured in GARP study participants, who are sibling pairs predominantly with symptomatic osteoarthritis at multiple sites. Kellgren and Lawrence scores were used to assess ROA in the knees, hips, hands, and vertebral facet joints, and spinal disc degeneration. A proportionate score was made for each joint location, based on the number of joints with ROA. The sum total ROA score represents a measure of cartilage abnormalities within each patient. By using linear mixed models the total ROA score and the joint site specific ROA scores were correlated with the UCTX-II level., Results: In 302 subjects the mean (SD) and median (range) for UCTX-II were 265 (168) and 219 (1346) ng/mmol creatine, respectively. There was a significant association between the total ROA score and UCTX-II levels. Subsequent multivariate analysis showed that the joint site specific ROA score at all joint sites, except for spinal disc degeneration, contributed independently to this association., Conclusions: The total ROA score of GARP patients, representing cartilage abnormalities at the most prevalent ROA joint locations, showed an excellent correlation with UCTX-II levels. The specific ROA scores at the hip, hand, facet, and knee joints additively and independently explained this association. Even in patients with osteoarthritis at multiple sites, UCTX-II may be a sensitive quantitative marker of ROA.

Objective: To evaluate whether familial aggregation of osteoarthritis differs by joint site in a sibling pair study (GARP) of patients with osteoarthritis at multiple sites., Subjects: White Dutch probands aged 40 to 70 years and their siblings with primary osteoarthritis at multiple sites., Methods: The diagnosis of knee, hip, and spine osteoarthritis was based on a combination of pain or stiffness on most days of the previous month and osteophytes or joint space narrowing on x ray. Hand osteoarthritis was defined by ACR criteria. Odds ratios (OR) were calculated for siblings and probands sharing disease in the same joints., Results: 191 sibling pairs were included (85% women; mean age 60 years). In the probands, osteoarthritis was present in spine (76%), hands (77%), knees (37%), and hips (26%). The most common combinations in probands were spine-hand (59%), spine-knee (27%), and hand-knee (25%). The OR adjusted for age, sex, and body mass index for siblings to be affected in the same joint sites as the proband were increased in osteoarthritis of the hand (OR = 4.4 (95% confidence interval, 2.0 to 9.5)), hip (OR = 3.9 (1.8 to 8.4)), spine (OR = 2.2 (1.0 to 5.1)), hip-spine (OR = 4.7 (2.1 to 10.4)), and hand-hip (OR = 3.4 (1.1 to 10.4)). Siblings of probands with osteoarthritis in the knee did not have an increased likelihood of knee osteoarthritis., Conclusions: In middle aged patients with familial osteoarthritis at multiple sites, familial aggregation of osteoarthritis was most striking for hand and hip but remarkably absent for the knee.

Objective: To determine the histologic changes that accompany the formation of cell clusters during the early stages of osteoarthritis development in the meniscus, and to characterize the expression phenotype of these cells., Methods: Histologic sections of medial menisci from normal and anterior cruciate ligament (ACL)-deficient rabbit knees were immunolabeled with monoclonal antibodies for vimentin to highlight the cytoskeleton of meniscal cells, Ki-67 to identify proliferating cells, and type X collagen to evaluate changes in the cell expression phenotype. Tissue mineralization was assessed by specific staining with alizarin red., Results: Following ACL transection, there was an alteration in the normal interconnected network of meniscal cells in the fibrocartilaginous region of the tissue. This led to isolation of islands of cells within the extracellular matrix of the meniscal tissue. These islands of cells displayed 3 different morphologies based on cell composition: 1) stellate cells, 2) stellate as well as round cells, and 3) round cells. Islands composed solely of round cells were more prominent in the latter stages following ACL transection, and the size of these islands increased with time, apparently as the result of cell proliferation. These islands of cells corresponded to the "clusters" previously described in osteoarthritic cartilage. Strong expression of type X collagen colocalized with the deposition of calcium within the meniscal regions enriched with cell clusters., Conclusion: Based on the observed changes in cell distribution, morphology, and cell proliferation as well as the previous detection of apoptosis in similar studies of rabbit knee joints, we propose a model for the development of cell clusters in the osteoarthritic meniscus. The morphologic appearance as well as the type X collagen expression phenotype of the meniscal cells forming the clusters is similar to that of hypertrophic chondrocytes. These findings provide a basis for understanding the origin of cell clusters in other joint connective tissues, such as osteoarthritic cartilage.

Four major morphologically distinct classes of cells were identified within the adult rabbit meniscus using antibodies to cytoskeletal proteins. Two classes of cell were present in the fibrocartilage region of the meniscus. These meniscal cells exhibited long cellular processes that extended from the cell body. A third cell type found in the inner hyaline-like region of the meniscus had a rounded form and lacked projections. A fourth cell type with a fusiform shape and no cytoplasmic projections was found along the superficial regions of the meniscus. Using a monoclonal antibody to connexin 43, numerous gap junctions were observed in the fibrocartilage region, whereas none were seen in cells either from the hyaline-like or the superficial zones of the meniscus. The majority of the cells within the meniscus exhibited other specific features such as primary cilia and 2 centrosomes. The placement of the meniscal cell subtypes as well as their morphology and architecture support the supposition that their specific characteristics underlie the ability of the meniscus to respond to different types of environmental mechanical loads.

Objective: Osteoarthritis (OA) is the most common form of arthritis and patients with meniscal and ligament injuries of the knee are at high risk to develop the disease. The purpose of this study was to evaluate changes occurring in both medial and lateral menisci from the knees of anterior cruciate ligament (ACL) transected rabbits at 3 and 8 weeks post-surgery. This study describes both molecular and cellular alterations in menisci during the early stages of OA development., Design: Rabbit meniscal tissues were processed for molecular analysis: DNA and RNA concentrations were assessed, as well as semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis for a subset of relevant molecules was performed. In situ DNA fragmentation was evaluated using the TUNEL assay., Results: Total RNA yields from the medial meniscus were significantly elevated at both 3 and 8 weeks post-ACL transection, while in the lateral meniscus total RNA levels were unchanged following ACL transection. DNA concentrations were significantly decreased in the medial menisci only at 8 weeks post-ACL transection. Following ACL transection, analysis of in situ DNA fragmentation using the TUNEL assay demonstrated an increase in the number of apoptotic cells in the medial meniscus only, in particular at 3 weeks post-ACL transection, a finding which correlates with declines in DNA content. Analysis of specific mRNA levels by RT-PCR demonstrated complex changes in both menisci following ACL transection. At 3 and 8 weeks post-ACL transection, in both medial and lateral menisci, mRNA levels for type I collagen and TIMP-1 were significantly increased, while mRNA levels for decorin, TNF-alpha and IGF-2 were significantly depressed. In the medial meniscus, significant increases in mRNA levels for type II collagen, biglycan as well as iNOS and PAI-1 were detected at both time periods, while mRNA levels for aggrecan, type III collagen and COX-2 were significantly elevated at 3 weeks post-ACL transection and mRNA levels for MMP-1 were significantly elevated at 8 weeks post-ACL transection. In contrast, mRNA levels for COL2 and aggrecan were unchanged in the lateral meniscus following ACL transection. In the lateral meniscus, at 3 weeks post-ACL transection, type III collagen mRNA levels were dramatically increased while fibromodulin mRNA levels were significantly depressed. In the lateral meniscus, significant increases in mRNA levels for biglycan were detected at 8 weeks post-ACL transection., Conclusion: These results show that after ACL transection complex molecular changes, as well as apoptosis, occur early, particularly in the medial meniscus.

Objective: Osteoarthritis (OA) is the most common form of arthritis and patients with meniscal and ligament injuries of the knee are at high risk to develop the disease. The purpose of this study was to evaluate changes occurring in both medial and lateral menisci from the knees of anterior cruciate ligament (ACL) transected rabbits during the early stages of OA development., Design: Meniscal tissues from control and experimental rabbits were processed for histology and immunohistochemistry for assessment of matrix organization and composition., Results: At 3 and 8 weeks following ACL transection, histological examination demonstrated extensive extracellular matrix deterioration. Altered cell distribution, areas depleted of cells, and areas of cell clusters were found within the medial but not in the lateral meniscus. Immunohistochemistry of both medial and lateral menisci demonstrated significant changes in collagen distribution. Type I and III collagen staining was increased in both medial and lateral menisci. In contrast, type II collagen staining was overtly increased only in the medial meniscus., Conclusion: These results demonstrate that after ACL transection, extracellular matrix deposition as well as altered matrix organization and altered cell distribution occur early in the medial meniscus.

The hypothesis of the present work was that expression of matrix metalloproteinase-13 (MMP-13, collagenase-3) would be induced during conditions involving important matrix remodeling such as ligament maturation, scar healing and joint instability. Therefore, MMP-13 expression in the medial collateral ligament (MCL) during the variable situations of tissue maturation and healing was assessed. MMP-13 expression in three intra-articular connective tissues of the knee (i.e. articular cartilage, menisci and synovium) following the transection of the anterior cruciate ligament of the knee was evaluated at 3 and 8 weeks post-injury. MMP-13 mRNA (semi-quantitative RT-PCR) and protein (immunohistochemistry and Western blotting) were detected in all of the tissues studied. Significantly higher MCL mRNA levels for MMP-13 were detected during the early phases of tissue maturation (i.e. 29 days in utero and 2-month-old rabbits) compared to later phases (5- and 12-month-old rabbits). This pattern of expression was recapitulated following MCL injury, with very high levels of expression in scar tissue at 3 weeks post-injury and then a decline to levels not significantly different from control values by 14 weeks. Elevated mRNA levels correlated with increased protein levels for MMP-13 in both menisci and synovium following the transection of the anterior cruciate ligament and during medial collateral ligament healing. These results indicate that MMP-13 expression is regulated by a number of variables and that high levels of expression occur in situations when connective tissue remodeling is very active.

Objective: The efficacy of glucosamine sulfate (GS) in the symptomatic treatment of patients with osteoarthritis (OA) is suggested to be mediated by still unknown effects on the altered OA cartilage., Design: Using human OA chondrocytes in culture, the effects of GS on protein synthesis, caseinase, collagenase, phospholipase A2 (PLA2) and protein kinase C (PKC) activities as well as production of nitric oxide and cyclic AMP were studied in both cells and culture medium., Results: GS significantly reduced PLA2 activity, and more modestly collagenase activity, in the OA chondrocytes in a dose-dependent manner. By contrast, PLA2 and collagenase activity of the culture medium was not modified. No effects on caseinase activity was seen. GS significantly and dose-dependently increased protein synthesis. GS did not modify nitric oxide and cAMP production but significantly increased PKC production., Conclusion: GS modified cultured OA chondrocyte metabolism by acting on PKC, cellular PLA2, protein synthesis and possibly collagenase activation. Extrapolation of the effect to the in-vivo situation remains hypothetical but they might represent some possible mechanisms of action of the drug in human.

Objective: The purpose of this study was to evaluate the effect of pregnancy on mRNA levels for several relevant molecules between five articular cartilage surfaces of the rabbit knee joint., Design: Total RNA was extracted from the following five knee joint articular surfaces: the lateral and medial femoral condyles (LFC and MFC); the lateral and medial tibial plateau (LTP and MTP); and the femoral groove (G) from pregnant and age-matched non-pregnant skeletally immature New Zealand White rabbits. The RNA was analysed by the sensitive molecular technique of semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) using rabbit specific primer sets. Two types of comparisons were performed: (i) comparison of mRNA levels between cartilage surfaces and (ii) comparison of mRNA levels between pregnant and non-pregnant rabbits within the same articular surfaces., Results: (i) Total RNA yield from the MFC and G represented 53 and 58% of the total RNA amount from the five cartilage surfaces in both non-pregnant and pregnant rabbits, respectively. Transcript levels for progesterone receptor (PR), aggrecan and biglycan were similar in all of the cartilage surfaces. In contrast, the cartilage surfaces exhibited significantly different transcript levels with a similar pattern for the estrogen receptor (ER), collagenase and urokinase (i.e., MTP

Hsp47 (also termed "colligin") is a 47 kDa protein that is localized in the ER and cis-Golgi vesicles of fibrocytes, chondrocytes, and other collagen-secreting cells. Under stress conditions, Hsp47 expression is upregulated as part of the heat shock/stress response that mitigates cell damage from noxious stimuli such as elevated temperature, heavy metals, and oxidative stress. Under non-stress conditions, Hsp47 functions as a collagen-specific molecular chaperone that facilitates intracellular procollagen polypeptide synthesis, and triple helix assembly in connective tissues. Previously it has been shown that levels of collagen-specific gene expression are significantly altered in ligaments, menisci, and other connective tissues of the rabbit following surgically induced injuries (increased), and during pregnancy (decreased). The present study was undertaken to determine whether expression of mRNA for the Hsp47 collagen-binding stress protein was also influenced in these experimental models. Since no sequence information was available on the rabbit Hsp47 gene, a partial cDNA for rabbit Hsp47 was first isolated and cloned using reverse transcriptase PCR (RT-PCR) with degenerate oligonucleotide primers. Rabbit Hsp47 sequence-specific primers then designed enabled analysis of Hsp47 mRNA expression in rabbit connective tissues using semiquantitative RT-PCR. It was found that Hsp47 expression is affected in a complex, tissue-specific manner by injury and pregnancy. Hsp47 transcript levels were elevated in the medial collateral ligament (MCL) of the rabbit knee following surgical induction of a gap injury. Transection of the anterior cruciate ligament (ACL), which leads to chronic progressive damage to menisci of the rabbit knee joint, was accompanied by an upregulation of Hsp47 expression in the medial and lateral menisci. Hsp47 mRNA levels were depressed during pregnancy in the kidney and ACL of primigravid adolescent rabbits, but were not altered in corneal tissue during pregnancy or in the ACL of skeletally mature multiparous females. The changes in Hsp47 transcript levels within these connective tissues following injury/pregnancy often, but not always, paralleled changes in collagen-specific gene expression.

This study, using the sensitive molecular technique of semiquantitative reverse transcription-polymerase chain reaction, evaluated mRNA levels for several molecules in medial and lateral menisci from the knees of skeletally mature and immature rabbits. Total RNA was extracted from the medial and lateral menisci of New Zealand White rabbits with the TRIspin method. Total RNA and DNA were similar in the two menisci of both immature and mature rabbits. The total RNA was reverse-transcribed and analyzed by semiquantitative polymerase chain reaction using rabbit-specific primer sets; levels of mRNA for a subset of molecules differed between the medial and lateral menisci. These variations in mRNA levels were also influenced by the degree of skeletal maturity of the rabbits. For most of the genes, mRNA levels were generally higher in the medial than in the lateral meniscus. The medial meniscus from immature and mature rabbits had significantly increased levels of mRNA for molecules such as transforming growth factor-beta, cyclooxygenase-2, and tissue inhibitor of metalloprotease-1. In contrast, compared with mRNA in the lateral meniscus, that for types II and III collagen, biglycan, insulin-like growth factor-2, plasminogen activator inhibitor-1, and matrix metalloprotease-1 was significantly increased in the medial meniscus of mature rabbits only and that for versican and type-I collagen was significantly increased in the medial meniscus of immature rabbits only. Levels of mRNA for inducible nitric oxide synthase and basic fibroblast growth factor were similar in both menisci for both age groups. The present study demonstrates that regulation of mRNA levels in medial and lateral menisci is tissue-specific and influenced by the skeletal maturity of the animals.

Recent studies have indicated that pregnancy can affect cellular activity in connective tissues such as cartilage, ligaments, and tendons. However, the impact of pregnancy on cellular activity in the menisci, a critical component in joint function, has not been reported. Therefore,the purpose of this study was to evaluate mRNA levels for several relevant molecules in both medial and lateral menisci from the knees of first-time pregnant immature rabbits (primigravida), third-time pregnant mature rabbits (multiparous), and nonpregnant rabbits (age-matched immature and mature controls) by the sensitive molecular technique of semiquantitative reverse transcription--polymerase chain reaction. Total RNA yields from the medial meniscus of multiparous rabbits were reduced to 66% of age-matched control values; however, yields from medial and lateral menisci from primigravida animals or the lateral meniscus of multiparous animals were not significantly depressed. DNA yields were not affected by pregnancy. Type I collagen mRNA levels were significantly depressed in both menisci only in primigravida rabbits. Versican mRNA levels were significantly elevated in both menisci only in multiparous rabbits. None of the transcripts for the other matrix molecules assessed were influenced by pregnancy. Collagenase mRNA levels were unaffected by pregnancy, but TIMP-1 mRNA levels were significantly decreased in the medial meniscus of primigravida rabbits and in the lateral meniscus of multiparous rabbits. Complex changes in the pattern of mRNA expression were observed for growth factors (TGF-beta bFGF, and IGF2). Inducible nitric oxide synthase mRNA expression was not altered during pregnancy. Transcripts for cyclooxygenase-2 were 61 and 50% of control values in the medial meniscus of primigravida and multiparous animals, respectively, while cyclooxygenase-2 mRNA levels were 150 and 188% of control values in the lateral meniscus from primigravida and multiparous animals, respectively. Such results indicate that pregnancy-induced changes in the pattern of mRNA expression are meniscus specific. Furthermore, the results support the hypothesis that different connective tissues of the knee respond to pregnancy in a unique manner.