Osteoarthritis and Cartilage - Articles in Press

Equivalence and precision of knee cartilage morphometry between different segmentation teams, cartilage regions, and MR acquisitions - Corrected Proof

2012-05-18

Summary: Objective: To compare precision and evaluate equivalence of femorotibial cartilage volume (VC) and mean cartilage thickness over total area of bone (ThCtAB.Me) from independent segmentation teams using identical Magnetic Resonance (MR) images from three series: sagittal 3D Dual Echo in the Steady State (DESS), coronal multi-planar reformat (DESS-MPR) of DESS and coronal 3D Fast Low Angle SHot (FLASH).Design: Nineteen subjects underwent test–retest MR imaging at 3 T. Four teams segmented the cartilage using prospectively defined plate regions and rules. Mixed models analysis of the pooled data were used to evaluate the effect of acquisition, team and plate on precision and Pearson correlations and mixed models were used to evaluate equivalence.Results: Segmentation team differences dominated measurement variability in most cartilage regions for all image series. Precision of VC and ThCtAB.Me differed significantly by team and cartilage plate, but not between FLASH and DESS. Mean values of VC and ThCtAB.Me differed by team (P < 0.05) for DESS, FLASH and DESS-MPR. FLASH VC was 4–6% larger than DESS in the medial tibia and lateral central femur, and FLASH ThCtAB.Me was 5–6% larger in the medial tibia, but 4–8% smaller in the medial central femur. Correlations between DESS and FLASH for VC and ThCtAB.Me were high (r = 0.90–0.97), except for DESS vs FLASH medial central femur ThCtAB.Me (r = 0.81–0.83).Conclusions: Cartilage morphology metrics from different image contrasts had similar precision, were generally equivalent, and may be combined for cross-sectional analyses if potential systematic offsets are accounted for. Data from different teams should not be pooled unless equivalence is demonstrated for cartilage metrics of interest.

Mineralization of articular cartilage in the sprague-dawley rat: characterization and mechanical analysis - Corrected Proof

M.L. Roemhildt, B.D. Beynnon, M. Gardner-Morse — 2012-05-18

The formation of mineralized deposits in human articular cartilage is a common occurrence; however, the relationship between mineral deposition and material properties of the articular cartilage is not well understood nor the relationship between mineral deposition and the development of degenerative joint disease. Several different crystalline structures have been identified in articular cartilage and synovial fluid including monosodium urate, calcium pyrophosphate dihydrate (CPPD), and basic calcium phosphates (BCPs). These distinct mineral phases are associated with specific pathologies and mechanisms of crystal formation such as the development of monosodium urate in gout and CPPD in pseudogout. Less is known regarding the deposition of BCPs, a class of compounds including carbonate-substituted hydroxyapatite (cHA), tricalcium phosphates (TCP), octacalcium phosphate (OCP), and whitlockite, in articular cartilage. The presence of BCP calcification of articular cartilage in humans has been associated with decreased joint function, aging and severity of osteoarthritis. Commonly used methods of crystal detection such as polarized light microscopy of synovial fluid and conventional radiography of the joint can be insensitive to the detection of BCP crystals and more sensitive techniques such as microradiography or electron microscopy of articular cartilage sections are required to detect areas of BCP mineralization. It is not yet known how regions of mineralization may influence the tribological properties (friction, wear, and lubrication) of the articulating surfaces and the material and structural properties of articular cartilage. Animal models with which to study the mechanisms of mineralization of articular cartilage are limited.

Symptomatic and chondroprotective treatment with collagen derivatives in osteoarthritis: a systematic review - Corrected Proof

2012-05-17

Summary: Objective: Osteoarthritis (OA) is one of the most prevalent musculoskeletal diseases. Collagen derivatives are candidates for disease-modifying OA drugs. This group of derivatives can be divided into undenatured collagen (UC), gelatine and collagen hydrolysate (CH). Collagen derivatives are marketed as having direct chondroprotective action and reducing complaints of OA. This review summarizes the evidence for the effectiveness of symptomatic and chondroprotective treatment with collagen derivatives in patients with OA.Methods: Eligible randomised controlled trials (RCTs) and quasi-RCTs were identified by searching PubMed, Embase and the Cochrane Central Register of Controlled Trials until November 2011. Methodological quality was assessed using methods of the Cochrane Back Review Group.Results: Eight studies were identified: six on CH, two on gelatine, and one on UC. The pooled mean difference based on three studies for pain reduction measured with the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index comparing CH with placebo was −0.49 (95% CI −1.10–0.12). However, some studies report significant between-group differences in pain when measured with a visual analogical scale (VAS) or other instruments, or when CH is compared with glucosamine sulphate. For disability no significant between-group mean differences were found when comparing CH with placebo. Gelatine compared with placebo and with alternative therapies was superior for the outcome pain. UC compared with glucosamine+chondroitin showed no significant between-group differences for pain and disability. The most reported adverse events of collagen derivatives were mild to moderate gastro-intestinal complaints. The overall quality of evidence was moderate to very low.Conclusions: There is insufficient evidence to recommend the generalized use of CHs in daily practice for the treatment of patients with OA. More independent high-quality studies are needed to confirm the therapeutic effects of collagen derivatives on OA complaints.

Musculoskeletal changes following non-invasive knee injury using a novel mouse model of post-traumatic osteoarthritis - Corrected Proof

2012-05-17

Summary: Objective: Post-traumatic osteoarthritis (PTOA) is a common consequence of traumatic joint injury, with 50% of anterior cruciate ligament (ACL) rupture patients developing PTOA within 10–20years. Currently accepted mouse models of PTOA initiate symptoms using various methods, none of which faithfully mimic clinically-relevant injury conditions. In this study we characterize a novel non-invasive mouse model of PTOA that injures the ACL with a single load of tibial compression overload. We utilize this model to determine the time course of articular cartilage and subchondral bone changes following knee injury.Design: Mice were euthanized 1, 3, 7, 14, 28, or 56days after non-invasive knee injury. Knees were scanned using micro-computed tomography (μCT) in order to quantify subchondral trabecular bone, subchondral bone plate, and non-native bone formation (heterotopic ossification). Development of osteoarthritis (OA) was graded using the osteoarthritis research society international (OARSI) scale on histological sections of injured and uninjured knees.Results: Following injury we observed a rapid loss of trabecular bone in injured knees compared to uninjured knees by 7days post-injury, followed by a partial recovery of trabecular bone to a new steady state by 28days post-injury. We also observed considerable non-native bone formation by 56days post-injury. Grading of histological sections revealed deterioration of articular cartilage by 56days post-injury, consistent with development of mild OA.Conclusions: This study establishes a novel mouse model of PTOA, and describes the time course of musculoskeletal changes following knee injury, helping to establish the window of opportunity for preventative treatment.

Response to Letter to the Editor: ‘Morphological changes in the lateral meniscus in end stage lateral compartment osteoarthritis: translating to clinical practice’ - Corrected Proof

2012-05-14

We appreciate the opportunity to respond to the thoughtful and supportive letter by Dr. R. Sakthiswary et al. on our paper “Morphological changes of the lateral meniscus in end stage lateral compartment osteoarthritis of the knee”. As we mentioned in our paper, because our cross sectional study included a highly selected sample of persons with severe symptomatic lateral osteoarthritis (OA), the majority of lateral menisci demonstrated a complete maceration or destruction. Therefore, our study is unable to answer whether a damaged meniscus is the cause or consequence of the lateral OA. As Dr. R. Sakthiswary suggested, we agree that a prospective study would be able to answer the pathological process of lateral OA while recognizing the great design challenges this new longitudinal study would have. Also, the answer may guide us on where we should pay more attention; either between cartilage and meniscus, or potentially both regarding prevention of lateral compartment OA. Even with this limitation, our belief is that the damaged meniscus may have a significant contribution in the development of lateral OA, based on the fact that meniscal tears play a prominent role in the risk of developing OA.

First insights into human acetabular labrum cell metabolism - Corrected Proof

2012-05-14

Summary: Objective: Hip labrum pathology has only begun to emerge as a significant source of groin pain in the last decade since the development of hip arthroscopy. Few data are available on the anatomy, histology and function of this structure. Moreover, no metabolic data exist at cellular level. The aim of this study was to characterize extracellular matrix (ECM) genes and pro-inflammatory mediators expressed by these cells.Methods: Isolated human acetabular labrum cells were cultured in alginate beads for 10days and additionally stimulated with interleukin (IL)-1 for 24h. Gene expression levels and secretion of different ECM genes, enzymes and cytokines were examined by quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA) to assess the metabolic characteristics of labrum cells. Articular chondrocytes and meniscus cells served as controls.Results: Labrum cells expressed high levels of COL1A1 and low levels of COL2A1, aggrecan and SOX-9 compared to chondrocytes. However, COL2A1 was more expressed by labrum cells than by meniscus cells. The expression of matrix metalloproteinase (MMP)-1/-2/-9, ADAMTS-4 and IL-6 was significantly higher in labrum cells than in chondrocytes. IL-1 suppressed the ECM gene expression levels of labrum cells, but increased the expression levels and release of MMP-1/-3/-9/-13 and ADAMTS-4 and IL-6 by these cells. Remarkably, MMP-9 was only significantly upregulated in acetabular labrum cells.Conclusions: The findings in this study demonstrated that the acetabular labrum is populated with unique highly active fibrochondrocyte-like cells. These cells are capable of expressing and releasing pro-inflammatory enzymes and cytokines and react to a pro-inflammatory stimulus. In this way, they contribute obviously to disturbed tissue function in hip labrum pathology.

Why the P-value culture is bad and confidence intervals a better alternative - Corrected Proof

J. Ranstam — 2012-05-14

Summary: In spite of frequent discussions of misuse and misunderstanding of probability values (P-values) they still appear in most scientific publications, and the disadvantages of erroneous and simplistic P-value interpretations grow with the number of scientific publications. Osteoarthritis and Cartilage prefer confidence intervals. This is a brief discussion of problems surrounding P-values and confidence intervals.

IL-4 alone and in combination with IL-10 protects against blood-induced cartilage damage - Corrected Proof

2012-05-14

Summary: Objective: It has been reported that interleukin (IL)-10 limits blood-induced cartilage damage. Our aim was to study the effect of IL-4 alone and in combination with IL-10 on blood-induced cartilage damage.Design: Healthy human full thickness cartilage explants were cultured for 4 days in the presence of 50% v/v blood. IL-4, IL-10, or a combination of both cytokines was added during blood exposure. Cartilage matrix turnover was determined after a recovery period; additionally cytokine production, chondrocyte apoptosis, and expression of the IL-4 and IL-10 receptors were analyzed directly after exposure.Results: Blood-induced damage to the cartilage matrix was limited by IL-4 in a dose-dependent way (P<0.05). Also IL-10 limited this damage, although to a lesser extent (P<0.03). The effect of IL-4 plus IL-10 was more pronounced and protective than IL-10 alone (P<0.05). Production of IL-1β and tumor necrosis factor (TNF)-α was limited by both IL-4 and IL-10 (P<0.05), but more strongly by IL-4. Blood-induced apoptosis of chondrocytes was limited by IL-4 and the combination, and not by IL-10 alone. No direct beneficial effect of IL-4 or IL-10 on cartilage was found, however, the chondrocyte receptor expression of both cytokine receptors was upregulated by exposure to blood.Conclusions: This study demonstrates that IL-4 alone and in combination with IL-10 prevents blood-induced cartilage damage. Expectedly, anti-inflammatory effects on monocytes in the blood fraction and protective effects on chondrocytes are both involved. IL-4 in combination with IL-10 might be used to prevent blood-induced joint damage as a result of trauma or surgery.

Baseline mean and heterogeneity of MR cartilage T2 are associated with morphologic degeneration of cartilage, meniscus, and bone marrow over 3years – data from the Osteoarthritis Initiative - Corrected Proof

2012-05-14

Summary: Objective: The purpose of this study is to determine whether the mean and heterogeneity of magnetic resonance (MR) knee cartilage T2 relaxation time measurements at baseline are associated with morphologic degeneration of cartilage, meniscus, and bone marrow tissues over 3years in subjects with risk factors for osteoarthritis (OA).Design: Subjects with risk factors for OA (n=289) with an age range of 45–55years were selected from the Osteoarthritis Initiative (OAI) database. 3.0 Tesla MR images were analyzed using morphological gradings of cartilage, bone marrow and menisci whole-organ magnetic resonance imaging scores (WORMS scoring). A T2 mapping sequence was used to assess the mean and heterogeneity of cartilage T2 (gray level co-occurrence matrix texture analysis). Regression models were used to assess the relationship between baseline T2 parameters and changes in morphologic knee WORMS scores over 3years.Results: The prevalence of knee abnormalities in the cartilage (P<0.0005), meniscus (P<0.00001), and bone marrow significantly (P<0.00001) increased from baseline to 3years in all compartments combined. The baseline mean and heterogeneity of cartilage T2 were significantly (P<0.05) associated with morphologic joint degeneration in the cartilage, meniscus and bone marrow over 3years.Conclusions: The prevalence of knee abnormalities significantly increased over 3years; increased cartilage T2 at baseline predicted longitudinal morphologic degeneration in the cartilage, meniscus, and bone marrow over 3years in subjects with risk factors for OA.

Clusters within a wide spectrum of biochemical markers for osteoarthritis: data from CHECK, a large cohort of individuals with very early symptomatic osteoarthritis - Corrected Proof

2012-05-14

Summary: Objective: To assess a wide spectrum of biochemical markers (biomarkers) in a large cohort of individuals with (very) early symptomatic knee and/or hip osteoarthritis (OA). Secondly, to investigate associations between biomarkers and between biomarkers and demographics to demonstrate validity of the obtained dataset and further investigate the involvement and/or role of these biomarkers in OA.Design: Fourteen biomarkers (uCTX-II, uCTX-I, uNTX-I, sCOMP, sPIIANP, sCS846, sC1,2C, sOC, sPINP, sHA, sPIIINP, pLeptin, pAdiponectin, pResistin) were assessed by ELISA or RIA in CHECK (Cohort Hip and Cohort Knee), a 10-year prospective cohort of 1,002 individuals with early symptomatic knee and/or hip OA.Results: Quality controls revealed that gathered data were technically reliable. The majority of biomarkers showed relevant associations with demographic variables, which were expectedly different between genders and/or menopausal status for some. Principal component analysis enabled identification of five clusters, consecutively designated as ‘bone-CTX-II’, ‘inflammation’, ‘synovium’, ‘C1,2C-adipokines’, and ‘cartilage synthesis’ cluster. Notably, uCTX-II clustered with biomarkers of bone metabolism, while sCOMP clustered with biomarkers of synovial activity.Conclusions: The identified clusters extended knowledge on individual biomarkers from mostly smaller studies as did the observed associations between biomarker levels and demographics, from which validity of our data was deduced. uCTX-II may not only reflect articular cartilage but also bone metabolism and sCOMP may reflect synovial rather than cartilage metabolism. Major involvement of adipokines in joint metabolism was not identified.

Osteoarthritis and the metabolic syndrome: more evidence that the etiology of OA is different in men and women - Corrected Proof

K.M. Huffman, W.E. Kraus — 2012-05-14

Projections by the Centers for Disease Control (CDC) suggest that if current trends continue, by 2030, 20% of the US population will be over age 65, and 86% or the population will be overweight or obese. As our population ages and becomes more obese, prevalence is increasing for diseases related to aging and obesity, such as osteoarthritis (OA) and the metabolic syndrome—a cluster of cardio-metabolic risks secondary to impaired insulin action including hypertension, increased abdominal girth, hypertriglyceridemia, low high density lipoprotein (HDL-cholesterol), and elevated fasting glucose.

Incidence and risk factors for radiographic lumbar spondylosis and lower back pain in japanese men and women: the ROAD study - Corrected Proof

2012-05-10

Summary: Objective: To determine the incidence of radiographic lumbar spondylosis (LS)and lower back pain, and their risk factors in Japan using a large-scale population from the nationwide cohort Research on Osteoarthritis/osteoporosis Against Disability (ROAD) Study.Methods: Participants in the ROAD study who had been recruited between 2005 and 2007 were followed up with lumbar spine radiography for 3 years. A total of 2,282 paired radiographs (75% of the original sample) were scored using Kellgren and Lawrence (KL) grades, and the incidence and progression rate of radiographic LS was analyzed. The incidence of lower back pain was also examined. In addition, associations between risk factors and incident and progressive radiographic LS as well as incident lower back pain were tested.Results: Given a 3.3-year follow-up, the incidence of KL≥2 radiographic LS was 50.0% and 34.4% (15.3% and 10.5% per year), while that of KL≥3 LS was 15.3% and 23.7% (4.6% and 7.2% per year) in men and women, respectively. The progression rate of LS was 20.5% and 27.4% (6.2% and 8.3% per year) in men and in women, respectively. In addition, the incidence of lower back pain was 28.3% and 31.2% (8.6% and 9.5% per year) in men and women. Lower back pain was not significantly associated with incident radiographic LS, while a more severe KL grade at baseline was associated with incident lower back pain.Conclusion: The present longitudinal study revealed a high incidence of radiographic LS in Japan.

Potential mechanism of alendronate inhibition of osteophyte formation in the rat model of post-traumatic osteoarthritis: evaluation of elemental strontium as a molecular tracer of bone formation - Corrected Proof

A. Panahifar, W.P. Maksymowych, M.R. Doschak — 2012-05-07

Summary: Objective: To employ elemental Strontium as a tracer of bone turnover, in the presence (or absence) of the bisphosphonate drug Alendronate, in order to spatially map osteophytogenesis and other bone turnover in rats developing post-traumatic secondary osteoarthritis (PTOA).Methods: PTOA was induced in rats by medial meniscectomy surgery. We utilized in-vivo microfocal computed tomography (CT) to follow bony adaptations in groups for 8weeks after surgery, either with or without alendronate treatment. Electron probe microanalysis (EPMA) was used to detect Strontium incorporation in mineralizing tissues. Histologic studies were conducted on the same samples using Safranin-O/fast green and Tetrachrome staining of decalcified sections to examine articular cartilage health and osteophyte formation at the sites of elemental Strontium deposition.Results: EPMA revealed uniform incorporation of Strontium over actively remodeling trabecular surfaces in normal control rats. That pattern was significantly altered after meniscectomy surgery resulting in greater Strontium signal at the developing osteophyte margins. Alendronate treatment inhibited osteophyte development by 40% and 51% quantified by micro-CT volumetric measurements at 4 and 8weeks after surgery, respectively. Osteophytes in the alendronate group were more cartilaginous in composition [i.e., lower bone mineral density (BMD)] compared to the untreated group. Histological analysis confirmed the osteophyte inhibitory effect of alendronate, and also verified reduced degeneration of the articular cartilage compared to untreated rats.Conclusion: Our study confirmed that alendronate administration will reduce osteophyte formation in a rat model of post-traumatic osteoarthritis, partially through the inhibition of secondary remodeling of osteophytes. Our study is the first to employ elemental Strontium as a tracer of bone turnover in the pathogenesis of osteoarthritis and to assess the efficacy of bisphosphonate antiresorptive drug interventions on osteophytogenesis.

T2∗ mapping of hip joint cartilage in various histological grades of degeneration - Corrected Proof

2012-05-03

Summary: Objective: To evaluate T2∗ values in various histological severities of osteoarthritis (OA).Method: Magnetic resonance imaging (MRI) and T2∗ mapping including a three-dimensional (3D) double-echo steady-state (DESS) sequence for morphological cartilage assessment and a 3D multiecho data image combination (MEDIC) sequence for T2∗ mapping were conducted in 21 human femoral head specimens with varying severities of OA. Subsequently, histological assessment was undertaken in all specimens to correlate the observations of T2∗ mapping with histological analyses. According to the Mankin score, four grades of histological changes were determined: grade 0 (Mankin scores of 0–4), grade I (scores of 5–8), grade II (scores of 9–10), and grade III (scores of 11–14). For reliability assessment, cartilage T2∗ measurements were repeated after 4 weeks in 10 randomly selected femoral head specimens.Results: T2∗ values decreased significantly with increasing cartilage degeneration (total P-values <0.001) ranging from 36.3 ± 4.3 ms in grade 0 regions to 22.8 ± 4.3 ms in regions with grade III changes. Pearson correlation analysis proved a fair correlation between T2∗ values and Mankin score (correlation coefficient = −0.362) that was statistically significant (P-value <0.001). Intra-class correlation (ICC) analysis demonstrated high intra-observer reproducibility for the T2∗ measurement (ICC: 0.949, P < 0.001).Conclusions: Given the advantages of the T2∗ mapping technique with no need for contrast medium, high image resolution and ability to perform 3D biochemically sensitive imaging, T2∗ mapping may be a strong addition to the currently evolving era of cartilage biochemical imaging.

Acute inflammation with induction of anaphylatoxin C5a and terminal complement complex C5b-9 associated with multiple intra-articular injections of hylan G-F 20: a case report - Corrected Proof

C.L. Dragomir, J.L. Scott, G. Perino, R. Adler, S. Fealy, M.B. Goldring — 2012-05-03

Summary: Objective: The purpose of this case report was to investigate local immune mechanisms present during an acute inflammatory flare initiated by viscosupplementation with hylan G-F 20 in a patient with osteoarthritis (OA) and past meniscectomy.Experimental design: A patient with a history of bilateral OA and partial left knee meniscectomy, who had received three injections of hylan G-F 20, was diagnosed with an acute flare reaction in the left knee. Her chart was evaluated for clinical, radiological, and laboratory findings and for clinical follow-up. Histopathological synovial examination and real-time polymerase chain reaction (RT-PCR) for genes with major roles in local inflammation and enzyme-linked immunosorbent assays (ELISAs) for markers of complement activation and cytokines were performed. To study the impact of the inflammatory and immune features we compared the case patient with groups of three representative OA and three rheumatoid arthritis (RA) patients.Results: The patient exhibited evidence of highly increased acute phase reactant C-reactive protein (CRP) in the blood. The pathological examination of the synovial membrane identified abundant fibrinous exudate with numerous particles of hyaluronan surrounded by a dense infiltrate of neutrophils and eosinophils. The synovium had moderate hypertrophy and sclerosis as well as an inflammatory infiltrate predominantly composed of T lymphocytes and macrophages with scattered perivascular eosinophils and neutrophils. Immunoperoxidase staining identified numerous deposits of C5b-9 in the fibrinous exudates and the synovial membrane of the patient. Similar findings were observed in the RA patients, whereas deposits were rare in OA synovial samples. In addition, both anaphylatoxin C5a and the terminal complement complex C5b-9 were present at high levels, comparable to those in RA patients. The levels of mRNA for interleukin-1 beta (IL-1β), IL-6, and the neutrophil marker myeloperoxidase (MPO) were markedly increased compared to those in the RA and OA patients.Conclusions: This present study is indicative of a pseudo-septic acute inflammatory reaction in response to local accumulation of hylan G-F 20 with the activation of complement and local invasion of pro-inflammatory cells.

MaryFran R. Sowers, MS PhD, May 30, 1947–July 17, 2011 - Corrected Proof

2012-05-01

Dr MaryFran R. Sowers, the John G Searle Professor of Public Health at the University of Michigan (UM) School of Public Health and Director of the UM Center for Integrated Approaches to Complex Diseases, died July 17, 2011. She was 64 years old. Dr. Sowers was an epidemiologist nationally and internationally renowned for her unique insights into the ways that different diseases can arise from variations of the same underlying physiological process and whose research contributed substantially to the science of women's health. Her multifaceted research has characterized ovarian aging and other major hormonal transitions across women's lifecourse as well as their influence on bone health, osteoarthritis, physical functioning and aging.

Consequences of handling missing data for treatment response in osteoarthritis: a simulation study - Corrected Proof

I.C. Olsen, T.K. Kvien, T. Uhlig — 2012-04-30

Summary: Objective: To understand how handling of missing data influences the statistical power and bias of treatment effects in randomised controlled trials of painful knee osteoarthritis (OA).Methods: We simulated trials with missing data (withdrawals) due to lack-of-efficacy. Outcome measures were response/non-response according to the Outcome Measures in Rheumatology–Osteoarthritis Research Society International (OMERACT–OARSI) set of responder criteria, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and physical function from the WOMAC questionnaire, and patient global assessment. We used five methods for managing missing data: ignoring the missing data, last and baseline observation carried forward (LOCF and BOCF), and multiple imputation with two different strategies. The treatment effect was then analysed by appropriate univariate and longitudinal statistical methods, and power, bias and mean squared error (MSE) was assessed by comparing the estimated treatment effect in the trials with missing data with the estimated treatment effect on the trials without missing data.Results: The best imputation method in terms of high power and low bias/MSE was our implementation of regression multiple imputation. The most conservative method was the data augmentation Markov chain Monte Carlo (MCMC) multiple imputation. The LOCF, BOCF and the complete-case methods were not particularly conservative and gave relatively low power and high bias. The analysis on the WOMAC pain scale gave less bias and higher power than the OMERACT–OARSI responder outcome measure.Conclusions: Multiple imputation of missing data may be used to decrease bias/MSE and increase power in OA trials. These results can guide investigators in the choice of outcome measures and especially how missing data can be handled.

Enhanced levels of non-enzymatic glycation and pentosidine crosslinking in spontaneous osteoarthritis progression - Corrected Proof

T.L. Willett, R. Kandel, J.N.A. De Croos, N.C. Avery, M.D. Grynpas — 2012-04-30

Summary: Objective: To test the hypothesis that heightened advanced glycation endproducts (AGEs) content in cartilage accelerates the progression of spontaneous osteoarthritis (OA) in the Hartley guinea pig (HGP) model.Methods: Twenty-eight male, 3-month-old HGPs were used. Eight were left untreated as a baseline control group and sacrificed at 3 months of age (n = 4) and 9 months of age (n = 4; age-matched controls). The other 20 HGPs received intra-articular knee injections in the right knee whereas the left knees acted as contra-lateral non-injected controls. Injections consisted of 100 μl phosphate buffered saline (PBS; n = 10) or PBS+2.0 M d-(−)-Ribose (n = 10). Injections were given once weekly for 24 weeks. At the end of the treatment period, the tibiae were fixed with formalin, scanned with microCT for sub-chondral bone mineral density, and then histological slides were prepared, stained with Safranin-O with Fast Green counter stain and scored using the OARSI-HISTOgp scheme. Cartilage pentosidine (established biomarker for AGEs) content, collagen content (% dry mass), glucosaminoglycan GAG-to-collagen ratio (μg/μg), GAG-to-DNA ratio and DNA-to-collagen ratio were measured.Results: Pentosidine content increased greatly due to PBS + Ribose injection (P < 0.0001) and reached levels found in cartilage from 80-year-old humans. Surprisingly, mean OARSI-HISTOgp scores for both the injected and contra-lateral controls in the PBS + Ribose group were not detectably different, nor were they different from the mean score for the age-matched control group.Conclusion: AGEs accumulation due to intra-articular ribose-containing injections in the HGP model of spontaneous knee OA did not enhance disease progression.

Three-dimensional patterns of early acetabular cartilage damage in hip dysplasia; a high-resolutional CT arthrography study - Corrected Proof

S. Tamura, T. Nishii, T. Shiomi, Y. Yamazaki, K. Murase, H. Yoshikawa, N. Sugano — 2012-04-30

Summary: Objective: The purpose of this study was to examine the three-dimensional (3D) progression patterns of early acetabular cartilage damage in hip dysplasia using high-resolutional computed tomography (CT) arthrography.Design: Thirty-two dysplastic hips of 26 Japanese symptomatic females including 21 hips in pre-stage of osteoarthritis (Kellgren–Lawrence (K–L) grade 0; mean patient age, 32.0years) and 11 hips in early stage of osteoarthritis (K–L grade 1 or 2; mean patient age, 32.8years) were examined. Isotropic high-resolutional CT arthrography with an image resolution of 0.5 mm in any orthogonal direction was performed. A 3D acetabular cartilage model was generated and we evaluated distribution of cartilage thickness in 12 zones after dividing the weight-bearing area of the hip joint in radial and lateral/medial directions.Results: In pre-stage of osteoarthritis, significant differences in cartilage thickness were observed between the lateral and medial zones in all radial regions, most prominently in the antero-superior region. In early stage of osteoarthritis, no significant differences in cartilage thickness were observed, except in the most posterior region. The lateral–medial (LM) ratio was defined as cartilage thickness in the lateral zone divided by that in the medial zone, and hips with the LM ratio in the antero-superior region of <1.4 had significantly more extensive involvement of labral tears than hips with the LM ratio of ≥1.4.Conclusions: In hip dysplasia, acetabular cartilage damage was probably occurred in the antero-superior lateral area. The LM ratio may be a sensitive index to quantify early cartilage damage associated with extent of labral disorders.

Morphological changes in the lateral meniscus in end stage lateral compartment osteoarthritis: translating to clinical practice - Corrected Proof

S. Das, R. Sakthiswary — 2012-04-30

We congratulate Hwang et al. for venturing into an area of research, which was underexplored. It is well established that lateral compartment osteoarthritis (OA) is less common than the medial compartment and as such this area has not generated much interest among researchers. Although this study highlighted the association between the end stage lateral OA and macerated lateral meniscus, the chronology of the pathological processes involved, still remains unaddressed. Is the damaged meniscus, more of the cause or the consequence of the lateral OA? We believe, a prospective study would be able to answer this. Ascertaining this may be helpful for planning therapeutic strategies to halt the progression of OA.

Ultrasonic evaluation of acute impact injury of articular cartilage in vitro - Corrected Proof

T. Virén, M. Timonen, H. Tyrväinen, V. Tiitu, J.S. Jurvelin, J. Töyräs — 2012-04-27

Summary: Objective: The aim of the study was to investigate whether high frequency ultrasound technique, originally designed for arthroscopic use can be utilized to detect traumatic cartilage injuries.Methods: A total of four intact osteochondral plugs were prepared from eight patellas for parallel comparison (total of 32 plugs). The plugs were injured by dropping an impactor on them from heights of 2.5 cm, 5.0 cm, 10.0 cm and 15.0 cm (corresponding to impact energies of 0.12, 0.25 0.50 and 0.74 J, respectively), in a custom made dropping tower. The samples were imaged with a high frequency (40 MHz) ultrasound device before and after the injury. Reflection coefficient (R), integrated reflection coefficient (IRC), apparent integrated backscattering (AIB) and ultrasound roughness index (URI) were determined for each sample.Results: Injuries invisible to the naked eye could be sensitively detected via the decreased values of the ultrasound reflection parameters (P < 0.05). Furthermore, a decreasing trend was detected in the values of R and IRC as the momentum of the impactor increased. The values of AIB were significantly lower for samples injured by dropping the impactor on the cartilage from heights of 2.5 cm and 15 cm but the URI values were similar in intact and injured cartilage. Histological analysis of the cartilage samples revealed that the injured cartilage exhibited depletion of the cartilage surface proteoglycans but the structure of collagen network was almost normal.Conclusions: Quantitative ultrasound imaging enables the detection of minor visually non-detectable cartilage injuries. As the present technique is feasible for arthroscopic use it might have clinical value in the evaluation of cartilage lesions during arthroscopy e.g., after tear of the anterior cruciate ligament.

The early outcome of surgical treatment for femoroacetabular impingement: success depends on how you measure it - Corrected Proof

F.M. Impellizzeri, A.F. Mannion, F.D. Naal, O. Hersche, M. Leunig — 2012-04-27

Summary: Objective: To evaluate the proportion of “successes” after surgery for femoroacetabular impingement (FAI) using different external criteria, “feeling better” and “feeling good”, and to determine the corresponding cut-off scores indicating “success” for the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) (0–10-point response scale), Oxford Hip Score (OHS) and EuroQoL-5D (EQ-5D and EQ-VAS).Design: Prospective, observational study based in an orthopaedic hospital. Ninety-nine consecutive patients with FAI completed the questionnaires before and 6 months after surgery (arthroscopy or mini-open surgical dislocation). Patient-ratings of change in state (“feeling better”) were assessed using a global treatment outcome (GTO) item. Acceptability of the current health state was assessed using the symptom-specific well-being (SSWB) item. Cut-off (threshold) scores for the different instruments indicating the minimal clinically important change (MCIC) and acceptable symptom state were calculated using Receiver Operating Characteristics (ROC) analyses.Results: Significant improvements in all scores (P < 0.001) were recorded 6 months after surgery. The proportion of good outcomes measured with GTO was 60%; 55% of patients reported having achieved an acceptable symptom state. The MCIC scores for improvement were ≥6 for the OHS (0–48 total score range), ≥15 for EQ-VAS, ≥0.16 for EQ-5D index, and ≥22 for the WOMAC-total score (0–100 total score range); absolute scores of ≥40, ≥80, ≥0.682 and ≤8, respectively, were associated with an acceptable symptom state.Conclusions: The results show that feeling better does not always equate to feeling good, and that improvements in outcome scores, even large, do not necessarily indicate acceptability of the current state. The cut-off values may help in the interpretation of trial results and individual change-scores recorded in clinical practice.

Chondroitin sulfate and/or glucosamine hydrochloride for Kashin-Beck disease: a cluster-randomized, placebo-controlled study - Corrected Proof

J. Yue, M. Yang, S. Yi, B. Dong, W. Li, Z. Yang, J. Lu, R. Zhang, J. Yong — 2012-04-26

Summary: Objective: To evaluate the efficacy and safety of chondroitin sulfate and/or glucosamine hydrochloride in alleviating symptoms and improving the dysfunction of Kashin-Beck disease (KBD) patients.Methods: We undertook a cluster-randomized, placebo-controlled trial in 251 patients with KBD. Participants were randomly allocated to comparing (1) chondroitin sulfate, (2) glucosamine hydrochloride, (3) a combination of chondroitin sulfate and glucosamine hydrochloride, or (4) placebo, for 6 months duration. The primary outcome measures of interest were 20% and 50% reductions in pain from baseline, measured by pain subscale in the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index. Secondary outcome measures included parameters in the WOMAC Index such as pain, stiffness, and physical function, as well as patients’ quality of life by the 12-item Short-Form General Health Survey. The trial registration number is ChiCTR-TRC-11001480 (http://www.chictr.org/).Results: A combination therapy of chondroitin sulfate and glucosamine hydrochloride was effective in reducing WOMAC pain by 20% (differences of 23.4%, P=0.006) and 50% (differences of 15.7%, P=0.016), WOMAC pain (P=0.032), WOMAC stiffness (P=0.043), and WOMAC total score (P=0.035). Chondroitin sulfate used alone was also found to be effective in reducing WOMAC total score and stiffness score (P=0.038 and P=0.023, respectively). No significant positive effects in improving WOMAC Index scores were observed with glucosamine hydrochloride alone.Conclusion: The findings of this study indicate that a combination of chondroitin sulfate and glucosamine hydrochloride was more effective than placebo in treating KBD.

Patterns of joint damage seen on MRI in early hip osteoarthritis due to structural hip deformities - Corrected Proof

2012-04-26

Summary: Objective: The aim of this study was to evaluate differences in damage patterns assessed using magnetic resonance imaging (MRI) between hips with femoroacetabular impingement (FAI) and developmental dysplasia of the hip (DDH) as well as to correlate MRI findings with delayed Gadolinium enhanced MRI of cartilage (dGEMRIC) and with patient pain.Design: This retrospective study included 40 patients (mean age 28.6 ± 11.2years) who underwent dGEMRIC and morphological MRI of the hip. Twenty-one hips with FAI and 19 with DDH were investigated. A self-developed morphological grading (MRI score) and dGEMRIC evaluation were done on seven radial reformats obtained from an isotropic 3D True-fast imaging with steady state precession (FISP) sequence and an isotropic T1-mapping sequence. The observed damage patterns were summed up into sub-scores and a total MRI score.Results: Labrum damage, paralabral cysts, and acetabular rim bone cysts were more common in DDH patients than in FAI patients. No significant differences were seen in the occurrence of cartilage damage, bone cysts, or osteophytes. In DDH (but not in FAI), the dGEMRIC index demonstrated a tendency for lower values in areas next to cartilage defects. There was no association between labrum damage and dGEMRIC index. A moderate correlation was seen between Western Ontario and McMaster Universities (WOMAC) pain score and cartilage damage, paralabral cysts, and the total MRI score.Conclusions: This study confirms a higher prevalence of labrum damage but not cartilage damage in patients with DDH in comparison to patients with FAI. In addition, our data suggests an association of cartilage damage and paralabral cysts with patient reported pain.

Cross-sectional DXA and MR measures of tibial periarticular bone associate with radiographic knee osteoarthritis severity - Corrected Proof

2012-04-23

Summary: Objective: We evaluated the relationship of medial proximal tibial periarticular areal bone mineral density (paBMD) and trabecular morphometry and determined whether these bone measures differed across radiographic medial joint space narrowing (JSN) scores.Methods: 482 participants of the Osteoarthritis Initiative (OAI) Bone Ancillary Study had knee dual X-ray absorptiometry (DXA) and trabecular bone 3T magnetic resonance imaging (MRI) exams assessed at the same visit. Medial proximal tibial paBMD was measured on DXA and apparent trabecular bone volume fraction (aBV/TV), thickness (aTb.Th), number (aTb.N), and spacing (aTb.Sp) were determined from MR images. Radiographs were assessed for medial JSN scores (0–3). We evaluated associations between medial paBMD and trabecular morphometry. Whisker plots with notches of these measures versus medial JSN scores were generated and presented.Results: Mean age was 63.9 (9.2) years, BMI 29.6 (4.8) kg/m2, and 53% were male. The Spearman correlation coefficients between DXA-measured medial paBMD and aBV/TV was 0.61 [95% confidence interval (CI) 0.55–0.66]; between paBMD and aTb.Th was 0.38 (95%CI 0.30–0.46); paBMD and aTb.N was 0.65 (95%CI 0.60–0.70); paBMD and aTb.Sp was −0.65 (95%CI −0.70 to −0.59). paBMD and the trabecular metrics were associated with medial JSN scores.Conclusion: The moderate associations between periarticular trabecular bone density and morphometry and their relationship with greater severity of knee OA support hypotheses of remodeling and/or microscopic compression fractures in the natural history of OA. Longitudinal studies are needed to assess whether knee DXA will be a predictor of OA progression. Further characterization of the periarticular bone in OA utilizing complementary imaging modalities will help clarify OA pathophysiology.

Activation of Indian hedgehog promotes chondrocyte hypertrophy and upregulation of MMP-13 in human osteoarthritic cartilage - Corrected Proof

2012-04-23

Summary: Objective: The objectives of this study were to (1) determine the correlation between osteoarthritis (OA) and Indian hedgehog (Ihh) expression, and (2) establish the effects of Ihh on expression of markers of chondrocyte hypertrophy and matrix metalloprotease (MMP)-13 in human OA cartilage.Design: OA cartilage and synovial fluid samples were obtained during total knee arthroplasty. Normal cartilage samples were obtained from intra-articular tumor resections, and normal synovial fluid samples were obtained from healthy volunteers and the contralateral uninjured knee of patients undergoing anterior cruciate ligament reconstruction. OA was graded using the Mankin score. Expression of Ihh in synovial fluid was determined by Western blot. Ihh, type X collagen and MMP-13 mRNA were determined by real time PCR. Protein expression of type X collagen and MMP-13 in cartilage samples was analyzed with immunohistochemistry. Chondrocyte size was measured using image analysis.Results: Ihh expression was increased 2.6 fold in OA cartilage and 37% in OA synovial fluid when compared to normal control samples. Increased expression of Ihh was associated with the severity of OA and expression of markers of chondrocyte hypertrophy: type X collagen and MMP-13, and chondocyte size. Chondrocytes were more spherical with increasing severity of OA. There was a significant correlation between Mankin score and cell size (r2 = 0.80) and Ihh intensity (r2 = 0.89). Exogenous Ihh induced a 6.8 fold increase of type X collagen and 2.8 fold increase of MMP-13 mRNA expression in cultured chondrocytes. Conversely, knockdown of Ihh by siRNA and Hh inhibitor cyclopamine had the opposite effect.Conclusions: Ihh expression correlates with OA progression and changes in chondrocyte morphology and gene expression consistent with chondrocyte hypertrophy and cartilage degradation seen in OA cartilage. Thus, Ihh may be a potential therapeutic target to prevent OA progression.

Usefulness of specific OA biomarkers, Coll2-1 and Coll2-1NO2, in the anterior cruciate ligament OA canine model - Corrected Proof

Y. Henrotin, J. Martel-Pelletier, P. Msika, G.B. Guillou, M. Deberg — 2012-04-23

Osteoarthritis (OA) is a frequent and disabling rheumatic condition. Its diagnosis relies mainly on clinical examination and imaging. Most of the time, there is a discrepancy between patient symptoms and the appearance of the joint structural changes on either X-ray or magnetic resonance imaging (MRI). There is an obvious need for specific biomarkers that could be useful for diagnostic purposes, detectable at an early disease stage, and that could predict and follow disease progression. In addition, specific biomarkers could also be useful tools to evaluate treatment efficacy of disease modifying OA drugs (DMOAD).

Measurement of matrilin-3 levels in human serum and synovial fluid using a competitive enzyme-linked immunosorbent assay - Corrected Proof

2012-04-23

Matrilin-3 (MATN3) is a skeletal-specific, tetrameric pericellular protein, localizing to the pericellular matrix of chondrocytes. It accumulates in higher amounts in osteoarthritic cartilage in human. Indeed, in vitro characterization of MATN3 identified anti-anabolic and pro-catabolic functions, although it was also found to favour chondrogenesis of synovial fibroblasts. As MATN3 is virtually specifically expressed in cartilage, over-expressed upon osteoarthritis and as its functions may participate in the mechanisms of the disease, it may constitute a useful marker to diagnose osteoarthritis or to evaluate its progression, not only from synovial fluids (SF), but also from circulating fluids. However, methods to quantify MATN3 from complex solutions are lacking. Here, we report the establishment of a direct, competitive Enzyme-Linked Immunosorbent Assay (ELISA) method prepared from commercially available antibodies and reagents, which allows reproducible determination of MATN3 levels in the nanogramm to microgramm per millilitre range. The method will be useful to conclude whether MATN3 will be a useful marker to diagnose osteoarthritis and/or to follow its progression using a non-invasive and financially affordable technique.

CT arthrography of the human knee to measure cartilage quality with low radiation dose - Corrected Proof

2012-04-19

Summary: Objective: Recently, CT arthrography (CTa) was introduced as a non-destructive technique to quantitatively measure cartilage quality in human knees. This study investigated whether this is also possible using lower radiation dose CT protocols. Furthermore, we studied the ability of (lower radiation) CTa to distinguish between local sulphated glycosaminoglycan (sGAG) content differences.Design: Of ten human cadaveric knee joints, six CT scans using different radiation doses (81.33–8.13 mGy) were acquired after intra-articular ioxaglate injection. The capability of CTa to measure overall cartilage quality was determined in seven anatomical regions of interest (ROIs), using equilibrium partitioning of an ionic contrast agent using (EPIC)-microCT (μCT) as reference standard for sGAG content. To test the capability of CTa to spatially distinguish between local differences in sGAG content, we calculated the percentage of pixels incorrectly predicted as having high or low sGAG content by the different CTa protocols.Results: Low radiation dose CTa correlated well with EPIC-μCT in large ROIs (R = 0.78; R2 = 0.61; P < 0.0001). CTa can also distinguish between high and low sGAG content within a single slice. However, the percentage of incorrectly predicted quality pixels increases (from 35% to 41%) when less radiation is used. This makes is hard or even impossible to differentiate between spatial differences in sGAG content in the lowest radiation scans.Conclusions: CTa acquired using low radiation exposure, comparable to a regular knee CT, is able to measure overall cartilage quality. Spatial sGAG distribution can also be determined using CTa, however for this purpose a higher radiation dose is necessary. Nevertheless, radiation dose reduction makes CTa suitable for quantitative analysis of cartilage in clinical research.

Assessment of articular cartilage repair tissue after matrix-associated autologous chondrocyte transplantation or the microfracture technique in the ankle joint using diffusion-weighted imaging at 3 Tesla - Corrected Proof

2012-04-19

Summary: Objective: The objective was to compare patients after matrix-associated autologous chondrocyte transplantation (MACT) and microfracture therapy (MFX) of the talus using diffusion-weighted imaging (DWI), with morphological and clinical scoring.Materials and methods: Twenty patients treated with MACT or MFX (10 per group) were examined using 3 T magnetic resonance imaging (MRI) at 48 ± 21.5 and 59.6 ± 23months after surgery, respectively. For comparability, patients from each group were matched by age, body mass index, and follow-up. American Orthopaedic Foot and Ankle Society (AOFAS) score served as clinical assessment tool pre- and postoperatively. DWI was obtained using a partially balanced, steady-state gradient echo pulse sequence, as well as the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score, based on a 2D proton density-weighted turbo spin-echo sequence and a 3D isotropic true fast imaging with steady-state precession sequence. Semi-quantitative diffusion quotients were calculated after region of interest analysis of repair tissue (RT) and healthy control cartilage, and compared among both groups.Results: The mean AOFAS score improved significantly (P = 0.001) for both groups (MACT: 48.8 ± 20.4–83.6 ± 9.7; MFX: 44.3 ± 16.5–77.6 ± 13.2). No differences in the AOFAS (P = 0.327) and MOCART (P = 0.720) score were observed between MACT and MFX postoperatively. DWI distinguished between healthy cartilage and cartilage RT in the MFX group (P = 0.016), but not after MACT treatment (P = 0.105). Significant correlations were found between MOCART score and DWI index after MFX (Pearson: −0.648; P = 0.043), and between the diffusivity and longer follow-up interval in MACT group (Pearson: −0.647, P = 0.043).Conclusion: Whereas conventional scores reveal a similar outcome after MACT or MFX treatment in the ankle joint, DWI was able to distinguish between different RT qualities, as reported histologically for these diverse surgical procedures.

Development and validation of a quality of life instrument for Kashin-Beck disease: an endemic osteoarthritis in China - Corrected Proof

H. Fang, X. Guo, U. Farooq, C. Xia, R. Dong — 2012-04-16

Summary: Objectives: To develop and validate a disease-specific Quality of Life (QOL) measure for a specialized osteoarthritis (OA)-Kashin-Beck disease (KBD).Methods: The standard methodology used for developing QOL instruments was employed. In phase 1, initially a group of health care professionals (HCPs) and KBD patient defined the overall concept of KBDQOL. It was followed by generation of an item pool through literature review, in-depth interview of 20 KBD patients and eight KBD HCPs and four focus group discussions. In phase 2, 368 KBD patients were interviewed and the reinterview of 95 participants, 10–14 days later assessed the reproducibility of the KBDQOL instrument.Results: A 37 items draft instrument was devised during phase 1. Principal Component Analysis (PCA) revealed six domains: physical function, activity limitation, social support, economics, mental health, and general health. Cronbach's alphas of six domains ranged from 0.77 to 0.90. The test–retest reliability (intraclass co-relation coefficient) of six domains was satisfactory, and ranged from 0.73 to 0.90. The smallest detectable change ranged from 13.2 to 30.2 points at the individual level and from 1.4 to 3.1 points at the group level for different domains. The construct validity was adequate when co-related with the EQ-5D (spearman co-relation coefficients: 0.49–0.61) and WHOQOL-BREF (spearman co-relation coefficients: 0.53–0.68). This resulted into the final version of KBDQOL instrument having 28 items and six domains.Conclusions: The KBDQOL is a simple and easy to use 28-item six dimensional questionnaire. The measure has been developed as a true patient-based questionnaire and demonstrates good measurement properties.

Sodium selenite for treatment of Kashin-Beck disease in children: a systematic review of randomised controlled trials - Corrected Proof

Y. Jirong, P. Huiyun, Y. Zhongzhe, D. Birong, L. Weimin, Y. Ming, S. Yi — 2012-03-23

Summary: Objective: To assess the effectiveness and safety of sodium selenite in treatment of patients with Kashin-Beck disease (KBD).Methods: We searched for all publications between January 1966 and October 2011 using seven electronic databases. All randomized controlled trials (RCTs) assessing the effects of sodium selenite on KBD vs no treatment or placebo were included. For dichotomous data, odds ratios (OR) and 95% confidence intervals (CI) were estimated according to the intention-to-treat principles. For continuous data, mean difference (MD) was used for outcomes pooled on the same scale.Results: A total of 10 RCTs involving 2244 patients were included. The methodological quality of the included studies was low. When comparing the outcome of sodium selenite treatment group vs the control group, the OR of repairing rate of metaphyseal lesions was 5.63 (95% CI: 3.67–8.63) and repairing rate at the distal end of phalanges was 2.98 (95% CI: 1.32–6.70) based on X-ray assessment, which was statistically significant difference in favour of sodium selenite. In one RCT which reported data on clinical improvement, no statistically significant difference was observed in the treatment vs control group (OR 1.50, 95% CI: 0.43–5.30). Se content in hair was (MD 0.11, 95% CI: 0.09–0.13) which was statistically significant higher in selenium group.Conclusions: Current evidence suggests that sodium selenite is more effective than placebo or no treatment in patients with KBD. However, the evidence was limited by potential biases; thus, further high quality large-scale RCTs are still needed to evaluate the short term and long term effects of selenium.

WITHDRAWN: Assessment of clinical outcomes 10–20 years after autologous chondrocyte implantation - Corrected Proof

H. Vasiliadis, G. Salanti, A. Georgoulis, A. Lindahl, L. Peterson — 2010-05-06

This article has been withdrawn at the request of the Editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.

WITHDRAWN: Characteristic markers of the WNT signalling pathway are differentially expressed in osteoarthritic cartilage - Corrected Proof

2010-04-30

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.

REMOVED: Generation of cartilage microtissues by hanging drops: effect of different culture conditions - Corrected Proof

I. Martinez — 2007-04-28

This article has been removed, consistent with Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). The Publisher apologizes for any inconvenience this may cause.