Prevalence and progression of arterial calcifications on computed tomography in humans with knee osteoarthritis.

OBJECTIVES: Ectopic bone deposition plays an important role in osteoarthritis (OA) and in arterial wall disease. We aimed to investigate the prevalence and progression of arterial calcifications on whole-body computed tomography (CT) in persons with knee OA. METHODS: We included 118 (36 male) participants who satisfied the clinical American College of Rheumatology classification criteria for knee OA. Baseline investigations included Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Kellgren-Lawrence grading. At baseline and after two years, a whole-body CT was performed using the same scanner and protocol. Calcifications were quantified in the carotid, brachiocephalic, coronary, thoracic aortic, abdominal aortic, iliac, femoropopliteal and crural arteries. Multivariable linear and logistic regression modeling was used for analyses. RESULTS: At baseline males were 66.9 ± 7.7 and females were 68.0 ± 5.6 years old. Calcifications were common, all participants except two females had some calcification, and prevalence ranged between 41.8% and 94.4% for various arterial beds. Baseline femoropopliteal calcifications were associated with a higher Kellgren-Lawrence grade (more severe knee OA). Median annual progression rate was 13.1% in males and 15.7% in females. Structural OA severity was not associated with progression, but a five points lower (worse) WOMAC was associated with 1% faster progression of arterial calcifications (p= 0.008). CONCLUSION: Around age 70 nearly all persons with knee OA have arterial calcifications, which progress substantially. For further investigation into shared causality intervention studies are needed.

Macrophage-Driven Inflammation in Metabolic Osteoarthritis: Implications for Biomarker and Therapy Development.

Osteoarthritis (OA) is a common and debilitating joint disorder that leads to progressive joint breakdown and loss of articular cartilage. Accompanied by a state of low-grade inflammation, its etiology extends beyond that of a wear-and-tear disease, and the immune system might have a role in its initiation and progression. Obesity, which is directly associated with an increased incidence of OA, alters adipokine release, increases pro-inflammatory macrophage activity, and affects joint immune regulation. Studying inflammatory macrophage expression and strategies to inhibit inflammatory macrophage phenotype polarization might provide insights into disease pathogenesis and therapeutic applications. In pre-clinical studies, the detection of OA in its initial stages was shown to be possible using imaging techniques such as SPECT-CT, and advances are made to detect OA through blood-based biomarker analysis. In this review, obesity-induced osteoarthritis and its mechanisms in inducing joint degeneration are summarized, along with an analysis of the current developments in patient imaging and biomarker use for diagnostic and therapeutic strategies.

Evaluating the Targeting of a Staphylococcus-aureus-Infected Implant with a Radiolabeled Antibody In Vivo.

Implant infections caused by Staphylococcus aureus are difficult to treat due to biofilm formation, which complicates surgical and antibiotic treatment. We introduce an alternative approach using monoclonal antibodies (mAbs) targeting S. aureus and provide evidence of the specificity and biodistribution of S.-aureus-targeting antibodies in a mouse implant infection model. The monoclonal antibody 4497-IgG1 targeting wall teichoic acid in S. aureus was labeled with indium-111 using CHX-A"-DTPA as a chelator. Single Photon Emission Computed Tomography/computed tomographyscans were performed at 24, 72 and 120 h after administration of the 111In-4497 mAb in Balb/cAnNCrl mice with a subcutaneous implant that was pre-colonized with S. aureus biofilm. The biodistribution of this labelled antibody over various organs was visualized and quantified using SPECT/CT imaging, and was compared to the uptake at the target tissue with the implanted infection. Uptake of the 111In-4497 mAbs at the infected implant gradually increased from 8.34 %ID/cm3 at 24 h to 9.22 %ID/cm3 at 120 h. Uptake at the heart/blood pool decreased over time from 11.60 to 7.58 %ID/cm3, whereas the uptake in the other organs decreased from 7.26 to less than 4.66 %ID/cm3 at 120 h. The effective half-life of 111In-4497 mAbs was determined to be 59 h. In conclusion, 111In-4497 mAbs were found to specifically detect S. aureus and its biofilm with excellent and prolonged accumulation at the site of the colonized implant. Therefore, it has the potential to serve as a drug delivery system for the diagnostic and bactericidal treatment of biofilm.

Statistical Shape Modeling of US Images to Predict Hip Dysplasia Development in Infants.

Background The current widely applied Graf classification used on US images for developmental dysplasia of the hip in infants does not enable prediction of the development and outcome of well-centered stable dysplastic hips (Graf type II). Purpose To use statistical shape modeling on US images to identify acetabular shape characteristics of Graf type II hips, which enable prediction of the development of Graf type II hips, and to identify which hips benefit from Pavlik harness treatment. Materials and Methods In this secondary analysis of a prospective multicenter randomized trial on treatment of 104 infants aged 3-4 months with Graf type IIb or IIc hip dysplasia conducted between 2009 and 2015, a statistical shape model was developed on baseline US images. With multivariable logistic regression adjusted for infant sex and treatment (Pavlik harness treatment vs active observation), shape modes were correlated with the outcomes of persistent hip dysplasia on US images (α angle <60°) after 12-week follow-up and residual hip dysplasia on pelvic radiographs (Tönnis classification: acetabular index greater than 2 standard deviations) around 1 year of age. An interaction term (treatment with mode) was used to investigate if this result depended on treatment. Results Baseline US images were available in 97 infants (mean age, 3.37 years ± 0.43 [standard deviation]; 89 [92%] girls; 90 cases of Graf type IIb hip dysplasia; 52 cases treated with Pavlik harness). Shape modes 2 and 3 of the statistical shape modeling were associated with persistent hip dysplasia on US images (odds ratio [OR] = 0.43; P = .007 and OR = 2.39; P = .02, respectively). Mode 2 was also associated with residual hip dysplasia on pelvic radiographs (OR = 0.09; P = .002). The interaction term remained significant after multivariable analysis, indicating that Pavlik harness treatment was beneficial in patients with negative mode 2 values (OR = 12.46; P = .01). Conclusion Statistical shape modeling of US images of infants with Graf type II dysplastic hips predicted which hips developed to normal or remained dysplastic and identified hips that benefited from Pavlik harness treatment. © RSNA, 2022.

Predicted and actual 2-year structural and pain progression in the IMI-APPROACH knee osteoarthritis cohort.

OBJECTIVES: The IMI-APPROACH knee osteoarthritis study used machine learning (ML) to predict structural and/or pain progression, expressed by a structural (S) and pain (P) predicted-progression score, to select patients from existing cohorts. This study evaluates the actual 2-year progression within the IMI-APPROACH, in relation to the predicted-progression scores. METHODS: Actual structural progression was measured using minimum joint space width (minJSW). Actual pain (progression) was evaluated using the Knee injury and Osteoarthritis Outcomes Score (KOOS) pain questionnaire. Progression was presented as actual change (Δ) after 2 years, and as progression over 2 years based on a per patient fitted regression line using 0, 0.5, 1 and 2-year values. Differences in predicted-progression scores between actual progressors and non-progressors were evaluated. Receiver operating characteristic (ROC) curves were constructed and corresponding area under the curve (AUC) reported. Using Youden's index, optimal cut-offs were chosen to enable evaluation of both predicted-progression scores to identify actual progressors. RESULTS: Actual structural progressors were initially assigned higher S predicted-progression scores compared with structural non-progressors. Likewise, actual pain progressors were assigned higher P predicted-progression scores compared with pain non-progressors. The AUC-ROC for the S predicted-progression score to identify actual structural progressors was poor (0.612 and 0.599 for Δ and regression minJSW, respectively). The AUC-ROC for the P predicted-progression score to identify actual pain progressors were good (0.817 and 0.830 for Δ and regression KOOS pain, respectively). CONCLUSION: The S and P predicted-progression scores as provided by the ML models developed and used for the selection of IMI-APPROACH patients were to some degree able to distinguish between actual progressors and non-progressors. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT03883568.

Structural tissue damage and 24-month progression of semi-quantitative MRI biomarkers of knee osteoarthritis in the IMI-APPROACH cohort.

BACKGROUND: The IMI-APPROACH cohort is an exploratory, 5-centre, 2-year prospective follow-up study of knee osteoarthritis (OA). Aim was to describe baseline multi-tissue semiquantitative MRI evaluation of index knees and to describe change for different MRI features based on number of subregion-approaches and change in maximum grades over a 24-month period. METHODS: MRIs were acquired using 1.5 T or 3 T MRI systems and assessed using the semi-quantitative MRI OA Knee Scoring (MOAKS) system. MRIs were read at baseline and 24-months for cartilage damage, bone marrow lesions (BML), osteophytes, meniscal damage and extrusion, and Hoffa- and effusion-synovitis. In descriptive fashion, the frequencies of MRI features at baseline and change in these imaging biomarkers over time are presented for the entire sample in a subregional and maximum score approach for most features. Differences between knees without and with structural radiographic (R) OA are analyzed in addition. RESULTS: Two hundred eighty-nine participants had readable baseline MRI examinations. Mean age was 66.6 ± 7.1 years and participants had a mean BMI of 28.1 ± 5.3 kg/m2. The majority (55.3%) of included knees had radiographic OA. Any change in total cartilage MOAKS score was observed in 53.1% considering full-grade changes only, and in 73.9% including full-grade and within-grade changes. Any medial cartilage progression was seen in 23.9% and any lateral progression on 22.1%. While for the medial and lateral compartments numbers of subregions with improvement and worsening of BMLs were very similar, for the PFJ more improvement was observed compared to worsening (15.5% vs. 9.0%). Including within grade changes, the number of knees showing BML worsening increased from 42.2% to 55.6%. While for some features 24-months change was rare, frequency of change was much more common in knees with vs. without ROA (e.g. worsening of total MOAKS score cartilage in 68.4% of ROA knees vs. 36.7% of no-ROA knees, and 60.7% vs. 21.8% for an increase in maximum BML score per knee). CONCLUSIONS: A wide range of MRI-detected structural pathologies was present in the IMI-APPROACH cohort. Baseline prevalence and change of features was substantially more common in the ROA subgroup compared to the knees without ROA. TRIAL REGISTRATION: Clinicaltrials.gov identification: NCT03883568.

Sprague Dawley Rats Show More Severe Bone Loss, Osteophytosis and Inflammation Compared toWistar Han Rats in a High-Fat, High-Sucrose Diet Model of Joint Damage.

In animal models, joint degeneration observed in response to obesogenic diet varies in nature and severity. In this study, we compare joint damage in Sprague Dawley and Wistar-Han rats in response to a high-fat, high-sucrose (HFS) diet groove model of osteoarthritis (OA). Wistar Han (n = 5) and Sprague Dawley (n = 5) rats were fed an HFS diet for 24 weeks. OA was induced 12 weeks after the diet onset by groove surgery in the right knee joint. The left knee served as a control. Outcomes were OARSI histopathology scoring, bone changes by µCT imaging, local (synovial and fat pad) and systemic (blood cytokine) inflammation markers. In both rat strains, the HFS diet resulted in a similar change in metabolic parameters, but only Sprague Dawley rats showed a large, osteoporosis-like decrease in trabecular bone volume. Osteophyte count and local joint inflammation were higher in Sprague Dawley rats. In contrast, cartilage degeneration and systemic inflammatory marker levels were similar between the rat strains. The difference in bone volume loss, osteophytosis and local inflammation suggest that both rat strains show a different joint damage phenotype and could, therefore, potentially represent different OA phenotypes observed in humans.

The role of the femoral component orientation on dislocations in THA: a systematic review.

INTRODUCTION: Dislocation remains a major complication in total hip arthroplasty (THA), in which femoral component orientation is considered a key parameter. New imaging modalities and definitions on femoral component orientation have been introduced, describing orientation in different planes. This study aims to systematically review the relevance of the different orientation parameters on implant stability. METHODS: A systematic review was performed according to the PRISMA guidelines to identify articles in the PubMed and EMBASE databases that study the relation between any femoral component orientation parameters and implant stability in primary THA. RESULTS: After screening for inclusion and exclusion criteria and quality assessment, nine articles were included. Definitions to describe the femoral component orientation and methodologies to assess its relevance for implant stability differed greatly, with lack of consensus. Seven retrospective case-control studies reported on the relevance of the transversal plane orientation: Low femoral- or low combined femoral and acetabular anteversion was statistical significantly related with more posterior dislocations, and high femoral- or combined femoral and acetabular anteversion with anterior dislocations in two studies. There were insufficient data on sagittal and coronal component orientation in relation to implant stability. CONCLUSION: Because of incomparable definitions, limited quality and heterogeneity in methodology of the included studies, there is only weak evidence that the degree of transverse component version is related with implant stability in primary THA. Recommendations about the optimal orientation of the femoral component in all three anatomical planes cannot be provided. Future studies should uniformly define the three-dimensional orientation of the femoral component and systematically describe implant stability.

A mean 4-year evaluation of infection control rates of hip and knee prosthetic joint infection-related revision arthroplasty: an observational study.

BACKGROUND AND PURPOSE: The long-term results of the 1- or 2-stage revision procedure and infection-free prosthesis survival in a tertiary referral center are unknown. In this retrospective observational study, the long-term results of infection control and infection-free prosthesis survival of the periprosthetic joint infection-related 1- and 2-stage revision procedure are evaluated. Furthermore, the merits of performing an antibiotic-free window in the 2-stage revision is evaluated. PATIENTS AND METHODS: All patients who received a 1- or 2-stage revision procedure of the hip or knee between 2010 and 2017 were included. Data was collected on patient and infection characteristics. The primary treatment aim was successful infection control without the use of antibiotic therapy afterwards. Infection-free survival analysis was performed using the Kaplan-Meier method with type of periprosthetic joint infection-related revision as covariate. Within the group of 2-stage revisions, use of an antibioticfree window was selected as covariate. RESULTS: 128 patients were treated for a periprosthetic joint infection-related revision procedure (81 hips and 47 knees). Successful infection control was achieved in 18 of 21 cases for the 1-stage and 89 out of 107 cases for the 2-stage revision procedure (83%) respectively after follow-up of more than 4 years. In addition, 2-stage revision procedure infection control was achieved in 52 of 60 cases with an antibiotic-free interval and 37 of 45 cases without such interval (p = 0.6). The mean infection-free survival of the 1-stage revision was 90 months (95% CI 75-105) and 98 months (CI 90-106) for the 2-stage revision procedure. INTERPRETATION: There seems to be no difference in infection control and infection-free survival between the 1- and 2-stage revision procedure. Second, an antibiotic-free window in the case of a 2-stage revision did not seem to influence treatment outcome. However, one must be cautious when interpreting these results due to confounding by indication and the small study population. Therefore, no definite conclusion can be drawn.

Good long-term outcomes of the hip Chiari osteotomy in adolescents and adults with hip dysplasia: a systematic review.

BACKGROUND AND PURPOSE: The Chiari osteotomy was a regular treatment for developmental hip dysplasia before it became mostly reserved as a salvage therapy. However, the long-term survival of the Chiari osteotomy has not been systematically investigated. We investigated the survival time of the Chiari osteotomy until conversion to total hip arthroplasty (THA) in patients with primary hip dysplasia, and factors which correlated with survival, complications, and the improvement measured in radiographic parameters. PATIENTS AND METHODS: Studies were included when describing patients (> 16 years) with primary hip dysplasia treated with a Chiari osteotomy procedure with 8 years' follow-up. Data on patient characteristics, indications, complications, radiographic parameters, and survival time (endpoint: conversion to THA) were extracted. RESULTS: 8 studies were included. The average postoperative center-edge angle, acetabular head index, and Sharp angle were generally restored within the target range. 3 studies reported Kaplan-Meier survival rates varying from 96% at 10 years to 72% at 20 years' follow-up. Negative survival factors were high age at intervention and pre-existing advanced preoperative osteoarthritis. Moreover, reported complications ranged between 0% and 28.3 %. INTERPRETATION: The Chiari osteotomy has high reported survival rates and is capable of restoring radiographic hip parameters to healthy values. When carefully selected by young age, and a low osteoarthritis score, patients benefit from the Chiari osteotomy with satisfactory survival rates. The position of the Chiari osteotomy in relation to the periacetabular osteotomies should be further (re-)explored.

The Effect of Postural Pelvic Dynamics on the Three-dimensional Orientation of the Acetabular Cup in THA Is Patient Specific.

BACKGROUND: Sagittal pelvic dynamics mainly consist of the pelvis rotating anteriorly or posteriorly while the hips flexes, and this affects the femoroacetabular or THA configuration. Thus far, it is unknown how the acetabular cup of the THA in the individual patient reorients with changing sagittal pelvic dynamics. QUESTIONS/PURPOSES: The aim of this study was to validate a method that establishes the three-dimensional (3-D) acetabular cup orientation with changing sagittal pelvic dynamics and describe these changes during functional pelvic dynamics. METHODS: A novel trigonometric mathematical model, which was incorporated into an easy-to-use tool, was tested. The model connected sagittal tilt, transverse version, and coronal inclination of the acetabular cup during sagittal pelvic tilt. Furthermore, the effect of sagittal pelvic tilt on the 3-D reorientation of acetabular cups was simulated for cups with different initial positions. Twelve pelvic CT images of patients who underwent THA were taken and rotated around the hip axis to different degrees of anterior and posterior sagittal pelvic tilt (± 30°) to simulate functional pelvic tilt in various body positions. For each simulated pelvic tilt, the transverse version and coronal inclination of the cup were manually measured and compared with those measured in a mathematical model in which the 3-D cup positions were calculated. Next, this model was applied to different acetabular cup positions to simulate the effect of sagittal pelvic dynamics on the 3-D orientation of the acetabular cup in the coronal and transverse plane. After pelvic tilt was applied, the intraclass correlation coefficients of 108 measured and calculated coronal and transverse cup orientation angles were 0.963 and 0.990, respectively, validating the clinical use of the mathematical model. RESULTS: The changes in 3-D acetabular cup orientation by functional pelvic tilt differed substantially between cups with different initial positions; the change in transverse version was much more pronounced in cups with low coronal inclination (from 50° to -29°) during functional pelvic tilt than in cups with a normal coronal inclination (from 39° to -11°) or high coronal inclination (from 31° to 2°). However, changes in coronal inclination were more pronounced in acetabular cups with high transverse version. CONCLUSION: Using a simple algorithm to determine the dynamic 3-D reorientation of the acetabular cup during functional sagittal pelvic tilt, we demonstrated that the 3-D effect of functional pelvic tilt is specific to the initial acetabular cup orientation and thus per THA patient. CLINICAL RELEVANCE: Future studies concerning THA (in)stability should not only include the initial acetabular cup orientation, but also they need to incorporate the effect of sagittal pelvic dynamics on the individual 3-D acetabular cup orientation. Clinicians can also use the developed tool, www.3d-hip.com, to calculate the acetabular cup's orientation in other instances, such as for patients with spinopelvic imbalance.

Deep learning-based MR-to-CT synthesis: The influence of varying gradient echo-based MR images as input channels.

PURPOSE: To study the influence of gradient echo-based contrasts as input channels to a 3D patch-based neural network trained for synthetic CT (sCT) generation in canine and human populations. METHODS: Magnetic resonance images and CT scans of human and canine pelvic regions were acquired and paired using nonrigid registration. Magnitude MR images and Dixon reconstructed water, fat, in-phase and opposed-phase images were obtained from a single T1 -weighted multi-echo gradient-echo acquisition. From this set, 6 input configurations were defined, each containing 1 to 4 MR images regarded as input channels. For each configuration, a UNet-derived deep learning model was trained for synthetic CT generation. Reconstructed Hounsfield unit maps were evaluated with peak SNR, mean absolute error, and mean error. Dice similarity coefficient and surface distance maps assessed the geometric fidelity of bones. Repeatability was estimated by replicating the training up to 10 times. RESULTS: Seventeen canines and 23 human subjects were included in the study. Performance and repeatability of single-channel models were dependent on the TE-related water-fat interference with variations of up to 17% in mean absolute error, and variations of up to 28% specifically in bones. Repeatability, Dice similarity coefficient, and mean absolute error were statistically significantly better in multichannel models with mean absolute error ranging from 33 to 40 Hounsfield units in humans and from 35 to 47 Hounsfield units in canines. CONCLUSION: Significant differences in performance and robustness of deep learning models for synthetic CT generation were observed depending on the input. In-phase images outperformed opposed-phase images, and Dixon reconstructed multichannel inputs outperformed single-channel inputs.

Long-term outcomes of the hip shelf arthroplasty in adolescents and adults with residual hip dysplasia: a systematic review.

Background and purpose - The shelf arthroplasty was the regular treatment for residual hip dysplasia before it was substituted by the peri-acetabular osteotomy. Yet, evidence regarding the survival of shelf arthroplasty surgery has never been systematically documented. Hence, we investigated the survival time of the shelf procedure until revision to THA in patients with primary hip dysplasia. Factors that influenced survival and complications were also examined, along with the accuracy of correcting radiographic parameters to characterize dysplasia.Material and methods - The inclusion criteria were studies of human adolescents and adults (> 16 years) with primary or congenital hip dysplasia who were treated with a shelf arthroplasty procedure. Data were extracted concerning patient characteristics, survival time, complications, operative techniques, and accuracy of correcting radiographic parameters.Results - Our inclusion criteria were applicable to 9 studies. The average postoperative Center-Edge Angle and Acetabular Head Index were mostly within target range, but large variations were common. Kaplan-Meier curves (endpoint: conversion to THA) varied between 37% at 20 years' follow-up and 72% at 35 years' follow-up. Clinical failures were commonly associated with pain and radiographic osteoarthritis. Only minor complications were reported with incidences between 17% and 32%.Interpretation - The shelf arthroplasty is capable of restoring normal radiographic hip parameters and is not associated with major complications. When carefully selected on minimal osteoarthritic changes, hip dysplasia patients with a closed triradiate cartilage may benefit from the shelf procedure with satisfactory survival rates. The importance of the shelf arthroplasty in relation to peri-acetabular osteotomies needs to be further (re)explored.

Three-dimensional analysis of shape variations and symmetry of the fibula, tibia, calcaneus and talus.

The bones forming the talocrural joint (TCJ) and subtalar joint (STJ) are often assumed to be bilaterally symmetric. Therefore, the contralateral limb (i.e. the fibula, tibia, calcaneus and talus) is used as a template or an intra-subject control in clinical and research practice. However, the validity of the symmetry assumption is controversial, because insufficient information is available on the shape variations and bilateral (a)symmetry of the fibula, tibia, calcaneus and talus. Using three-dimensional spatially dense sampled representations of bone shapes extracted from bilateral computed tomography scans of 66 individuals (55 male, mean age: 61 ±â€…10 years; 11 female, mean age: 53 ±â€…15 years), we analyzed whether: (i) similar shape patterns exist in the left and right bones of the same type; (ii) gender has an effect on bone shape variations; (iii) intra-subject shape variation is smaller than that of inter-subject for a given shape variance direction. For the first set of analyses, all left and right instances of the same type of bone were considered as two separate groups, and statistically compared with each other on multiple aspects including group location (central tendency), variance-covariance scale (dispersion) and orientation (covariance structure) using distance-based permutational tests. For the second and third sets of analyses, all left and right bones of the same type were pooled into one group, and shape variations in the TCJ and STJ bones were extracted using principal component analysis. The effects of gender on age-adjusted bone shape differences were assessed using an analysis of covariance. Moreover, intra-class correlation was employed to evaluate intra- and inter-subject bone shape variations. For each bone type, both sides had similar shape patterns (Ppermutational -values > 0.05). After Bonferroni adjustment, gender led to shape differences, which were mainly in the lateral and medial condyles of the tibia (P = 0.003), the length and height of the calcaneus (P < 0.001), the posterior and anterior talar articular surfaces of the calcaneus (P = 0.001), and in the posterior aspect of the talus (P = 0.001). Intra-subject shape variations in the tibial tuberosity together with the diameter of the tibia, and the curvature of the fibula shaft and the diameter of the fibula were as high as those of inter-subject. This result suggests that the shape symmetry assumption could be violated for some specific shape variations in the fibula and tibia.

Increased TGF-ß and BMP Levels and Improved Chondrocyte-Specific Marker Expression In Vitro under Cartilage-Specific Physiological Osmolarity.

During standard expansion culture (i.e., plasma osmolarity, 280 mOsm) human articular chondrocytes dedifferentiate, making them inappropriate for autologous chondrocyte implantation to treat cartilage defects. Increasing the osmolarity of culture media to physiological osmolarity levels of cartilage (i.e., 380 mOsm), increases collagen type II (COL2A1) expression of human articular chondrocytes in vitro, but the underlying molecular mechanism is not fully understood. We hypothesized that TGF-ß superfamily signaling may drive expression of COL2A1 under physiological osmolarity culture conditions. Human articular chondrocytes were cultured in cytokine-free medium of 280 or 380 mOsm with or without siRNA mediated TGF-ß2 knockdown (RNAi). Expression of TGF-ß isoforms, and collagen type II was evaluated by RT-qPCR and immunoblotting. TGF-ß2 protein secretion was evaluated using ELISA and TGF-ß bioactivity was determined using an established reporter assay. Involvement of BMP signaling was investigated by culturing human articular chondrocytes in the presence or absence of BMP inhibitor dorsomorphin and BMP bioactivity was determined using an established reporter assay. Physiological cartilage osmolarity (i.e., physosmolarity) most prominently increased TGF-ß2 mRNA expression and protein secretion as well as TGF-ß bioactivity. Upon TGF-ß2 isoform-specific knockdown, gene expression of chondrocyte marker COL2A1 was induced. TGF-ß2 RNAi under physosmolarity enhanced TGF-ß bioactivity. BMP bioactivity increased upon physosmotic treatment, but was not related to TGF-ß2 RNAi. In contrast, dorsomorphin inhibited COL2A1 mRNA expression in human articular chondrocytes independent of the osmotic condition. Our data suggest a role for TGF-ß superfamily member signaling in physosmolarity-induced mRNA expression of collagen type II. As physosmotic conditions favor the expression of COL2A1 independent of our manipulations, contribution of other metabolic, post-transcriptional or epigenetic factors cannot be excluded in the underlying complex and interdependent regulation of marker gene expression. Dissecting these molecular mechanisms holds potential to further improve future cell-based chondral repair strategies.

Is T1ρ Mapping an Alternative to Delayed Gadolinium-enhanced MR Imaging of Cartilage in the Assessment of Sulphated Glycosaminoglycan Content in Human Osteoarthritic Knees? An in Vivo Validation Study.

PURPOSE: To determine if T1ρ mapping can be used as an alternative to delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) in the quantification of cartilage biochemical composition in vivo in human knees with osteoarthritis. MATERIALS AND METHODS: This study was approved by the institutional review board. Written informed consent was obtained from all participants. Twelve patients with knee osteoarthritis underwent dGEMRIC and T1ρ mapping at 3.0 T before undergoing total knee replacement. Outcomes of dGEMRIC and T1ρ mapping were calculated in six cartilage regions of interest. Femoral and tibial cartilages were harvested during total knee replacement. Cartilage sulphated glycosaminoglycan (sGAG) and collagen content were assessed with dimethylmethylene blue and hydroxyproline assays, respectively. A four-dimensional multivariate mixed-effects model was used to simultaneously assess the correlation between outcomes of dGEMRIC and T1ρ mapping and the sGAG and collagen content of the articular cartilage. RESULTS: T1 relaxation times at dGEMRIC showed strong correlation with cartilage sGAG content (r = 0.73; 95% credibility interval [CI] = 0.60, 0.83) and weak correlation with cartilage collagen content (r = 0.40; 95% CI: 0.18, 0.58). T1ρ relaxation times did not correlate with cartilage sGAG content (r = 0.04; 95% CI: -0.21, 0.28) or collagen content (r = -0.05; 95% CI = -0.31, 0.20). CONCLUSION: dGEMRIC can help accurately measure cartilage sGAG content in vivo in patients with knee osteoarthritis, whereas T1ρ mapping does not appear suitable for this purpose. Although the technique is not completely sGAG specific and requires a contrast agent, dGEMRIC is a validated and robust method for quantifying cartilage sGAG content in human osteoarthritis subjects in clinical research.

Distinct subtypes of knee osteoarthritis: data from the Osteoarthritis Initiative.

OBJECTIVE: OA is suspected to be a collection of distinct subtypes, each with different aetiology and clinical characteristics. We aimed to explore the existence of different subtypes of knee OA, using cluster analysis of the data of the OA Initiative. METHODS: We used latent class cluster analysis (LCA) to cluster baseline data of 518 subjects of the OA Initiative progression cohort. Data included radiographic scores of OA features per compartment, regional quantitative MRI measures of cartilage quantity and denuded bone, and self-reported clinical scores on knee symptoms. To ensure that the clusters were found independently of OA severity, the LCA model was corrected with a measure of OA severity. The resulting clusters were compared with respect to the presence of risk factors and progression. RESULTS: LCA resulted in four clusters containing 47%, 27%, 15% and 12% of the subjects. Clusters 1, 2 and 4 showed OA features at the medial compartment, while cluster 3 only showed lateral OA features. Clusters 3 and 4 showed severe increases in areas of denuded bone, whereas no denuded bone was present in cluster 1. Prevalence of OA progression over 24 months was highest in clusters 3 and 4 and lowest in cluster 1. The clusters also differed significantly in BMI, knee alignment and prevalence of reported trauma. CONCLUSION: LCA confirmed the existence of distinct subtypes of knee OA with clear differences in structural degradation and symptoms. The fact that subtypes also differed in risk factors suggests that different causes lead to different types of knee OA.

Validation of statistical shape modelling to predict hip osteoarthritis in females: data from two prospective cohort studies (Cohort Hip and Cohort Knee and Chingford).

OBJECTIVES: To prospectively investigate whether hip shape variants at baseline are associated with the need for future total hip replacement (THR) in women and to validate the resulting associated shape variants of the Cohort Hip and Cohort Knee (CHECK) cohort and the Chingford cohort. METHODS: Female participants from the CHECK cohort without radiographic OA (Kellgren-Lawrence score <2) at baseline were included (1100 hips); 22 hips had a THR within 5 years of follow-up. For the Chingford cohort, with only female participants, hips without radiographic OA at baseline were selected and a nested case-control design was used, with 19 THR cases within 19 years of follow-up and 95 controls matched 5 to 1 for age and BMI. Hip shape on baseline anteroposterior pelvic radiographs was assessed by statistical shape modelling (SSM) using the same model for both cohorts. RESULTS: In the CHECK and Chingford cohorts, the respective mean age was 55.8 (s.d. 5.1) and 53.6 (s.d. 5.4) and the BMI was 26.14 (s.d. 4.3) and 25.7 (s.d. 3.3), respectively. Multiple shape variants of the hip were significantly (P < 0.05) associated with future THR in both the CHECK (modes 4, 11, 15, 17 and 22) and Chingford (modes 2 and 17) cohorts. Mode 17 [odds ratio (OR) 0.51 (95% CI 0.33, 0.80) in the CHECK cohort], representing a flattened head-neck junction and flat greater trochanter, could be confirmed in the Chingford cohort [OR 0.41 (95% CI 0.23, 0.82)]. Modes 4 and 15 of the CHECK cohort also showed non-significant trends in the Chingford cohort. CONCLUSION: Several baseline shape variants are associated with the future need for THR within a cohort. Despite differences in participant characteristics, radiographic protocol and follow-up time, we could validate at least one shape variant, suggesting that SSM is reasonably transferable between cohorts.