Cartilage Composition Research Articles

Radiographically normal knees with contralateral joint space narrowing display greater change in cartilage transverse relaxation time than those with normal contralateral knees: a model of early OA? – data from the Osteoarthritis Initiative (OAI)

To develop a model of early osteoarthritis, by examining whether radiographically normal knees with contralateral joint space narrowing (JSN), but without contralateral trauma history, display greater longitudinal cartilage composition change (transverse relaxation time; T2) than subjects with bilaterally normal knees. 120 radiographically normal knees (Kellgren Lawrence grade [KLG] 0) from the Osteoarthritis Initiative were studied. 60 case knees displayed definite contralateral radiographic knee osteoarthritis (KLG≥2) whereas 60 reference subjects were bilaterally KLG0, and were matched 1:1 to cases based on age, sex, and BMI. All had multi-echo spin-echo MRI acquired at year (Y) 1 and 4 follow-up, with cartilage T2 being determined in superficial and deep cartilage layers across 16 femorotibial subregions. T2 across all regions was considered the primary analytic focus. Of 60 KLG0 case knees (30 female, age: 65.0±8.8y, BMI: 27.6±4.4kg/m2), 21/22/13/4 displayed contralateral JSN 0/1/2/3, respectively. The longitudinal increase in the deep layer cartilage T2 between Y1 and Y4 was significantly greater (P=0.03; Cohen's D 0.50) in the 39 KLG0 case knees with contralateral JSN (1.2ms; 95% confidence interval [CI] [0.4, 2.0]) than in matched KLG0 reference knees (0.1ms; 95% CI [-0.5, 0.7]). No significant differences were identified in superficial T2 change. T2 at Y1 was significantly greater in case than in reference knees, particularly in the superficial layer of the medial compartment. Radiographically normal knees with contralateral, non-traumatic JSN represent an applicable model of early osteoarthritis, with deep layer cartilage composition (T2) changing more rapidly than in bilaterally normal knees. CLINICALTRIALS. NCT00080171.

Defective WNT signaling may protect from articular cartilage deterioration – a quantitative MRI study on subjects with a heterozygous WNT1 mutation

WNT signaling is of key importance in chondrogenesis and defective WNT signaling may contribute to the pathogenesis of osteoarthritis and other cartilage diseases. Biochemical composition of articular cartilage in patients with aberrant WNT signaling has not been studied. Our objective was to assess the knee articular cartilage in WNT1 mutation-positive individuals using a 3.0T MRI unit to measure cartilage thickness, relaxation times, and texture features. Cohort comprised mutation-positive (N=13; age 17-76 years) and mutation-negative (N=13; 16-77 years) subjects from two Finnish families with autosomal dominant WNT1 osteoporosis due to a heterozygous missense mutation c.652T>G (p.C218G) in WNT1. All subjects were imaged with a 3.0T MRI unit and assessed for cartilage thickness, T2 and T1ρ relaxation times, and T2 texture features contrast, dissimilarity and homogeneity of T2 relaxation time maps in six regions of interest (ROIs) in the tibiofemoral cartilage. All three texture features showed opposing trends with age between the groups in the medial tibiofemoral cartilage (P=0.020-0.085 for the difference of the regression coefficients), the mutation-positive individuals showing signs of cartilage preservation. No significant differences were observed in the lateral tibiofemoral cartilage. Cartilage thickness and means of T2 relaxation time did not differ between groups. Means of T1ρ relaxation time were significantly different in one ROI but the regression analysis displayed no differences. Our results show less age-related cartilage deterioration in the WNT1 mutation-positive than the mutation-negative subjects. This suggests, that the WNT1 mutation may alter cartilage turnover and even have a potential cartilage-preserving effect.

Walking Biomechanics Six and Twelve Months Following Anterior Cruciate Ligament Reconstruction Compared to Healthy Controls

Vertical ground reaction force (vGRF) during walking is associated with cartilage metabolism, cartilage composition, and patient symptoms in individuals with anterior cruciate ligament reconstruction (ACLR). However, it is unclear how vGRF changes throughout stance between 6- and 12-months following ACLR compared to an uninjured control group. PURPOSE: Compare vGRF between the uninvolved and involved limbs 6- and 12-months following ACLR, as well as to a healthy control limb. METHODS: vGRF normalized to body weight (BW) was collected at 6- and 12-months following surgery in individuals with ACLR and at one time point in healthy controls. 2 x 2 functional analyses of variance were used to evaluate the effects of limb (involved and uninvolved) and time (6- and 12-months) on time-normalized vGRF waveforms in individuals with ACLR. Pairwise comparison functions were used to compare time-normalized vGRF waveforms in controls and the involved and uninvolved limbs at 6- and 12-months. RESULTS: Thirty individuals with ACLR (50% female, 21.6±3.4 years, body mass index (BMI)=24.2±3.2 kg/m2) and 48 controls (67% female, 20.3±1.6 years, BMI=23.1±3.3 kg/m2) completed the current study. At 12-months, both the involved and uninvolved limbs demonstrated lesser vGRF (-3% BW) during the first peak (13-28% of stance) and greater vGRF (+2% BW) during mid-stance (46-66% of stance) compared to 6-months.Over time,the involved limb demonstrated lesser vGRF (-2 to -4% BW) at the first (13-28% of stance) and second (77-87% of stance) peaks compared to the uninvolved limb. Healthy controls demonstrated greater vGRF at the first (6-months: +8% BW, 1-32% of stance; 12-months: +10% BW, 1-33% of stance) and second peaks (6-months: +5% BW, 69-91% of stance; 12-months: +4% BW, 72-92% of stance) and lesser vGRF in mid-stance (6-months: -2% BW, 39-54% of stance; 12-months: -3% BW, 38-64% of stance) compared to the involved limb at both 6- and 12-months. CONCLUSIONS: Individuals may achieve more symmetrical loading over time by lowering vGRF of the uninvolved limb between 6- and 12-months following ACLR. Future gait retraining programs may seek to achieve optimal loading in both the involved and uninvolved limbs,as well as symmetrical loading between limbs in individuals with an ACLR.

Conventional and Arthrographic Magnetic Resonance Techniques for Hip Evaluation: What the Radiologist Should Know.

Over the last 2 decades, the definition of pathomechanical concepts that link osseous deformities to chondrolabral damage and expose young and active patients to the risk of early osteoarthritis has led to a tremendous increase in the number of joint-preserving surgeries performed. The rise in arthroscopic procedures has led to an increasing demand for comprehensive preoperative magnetic resonance imaging (MRI) assessment of the hip joint. This includes conventional MRI for the assessment of extra-articular and periarticular pathologies such as greater trochanteric pain, deep gluteal pain syndrome, and sports injuries. Magnetic resonance arthrography with or without traction is reserved for the accurate evaluation of deformities associated with impingement and hip instability and for detecting the resulting intra-articular lesions. This article summarizes the current standard imaging techniques that the radiologist should know. It also explores the potential of computer-assisted analysis of three-dimensional MRI for virtual impingement simulation and volumetric analysis of cartilage composition and geometry.

Automatic MRI-based Three-dimensional Models of Hip Cartilage Provide Improved Morphologic and Biochemical Analysis.

The time-consuming and user-dependent postprocessing of biochemical cartilage MRI has limited the use of delayed gadolinium-enhanced MRI of cartilage (dGEMRIC). An automated analysis of biochemical three-dimensional (3-D) images could deliver a more time-efficient and objective evaluation of cartilage composition, and provide comprehensive information about cartilage thickness, surface area, and volume compared with manual two-dimensional (2-D) analysis. (1) How does the 3-D analysis of cartilage thickness and dGEMRIC index using both a manual and a new automated method compare with the manual 2-D analysis (gold standard)? (2) How does the manual 3-D analysis of regional patterns of dGEMRIC index, cartilage thickness, surface area and volume compare with a new automatic method? (3) What is the interobserver reliability and intraobserver reproducibility of software-assisted manual 3-D and automated 3-D analysis of dGEMRIC indices, thickness, surface, and volume for two readers on two time points? In this IRB-approved, retrospective, diagnostic study, we identified the first 25 symptomatic hips (23 patients) who underwent a contrast-enhanced MRI at 3T including a 3-D dGEMRIC sequence for intraarticular pathology assessment due to structural hip deformities. Of the 23 patients, 10 (43%) were male, 16 (64%) hips had a cam deformity and 16 (64%) hips had either a pincer deformity or acetabular dysplasia. The development of an automated deep-learning-based approach for 3-D segmentation of hip cartilage models was based on two steps: First, one reader (FS) provided a manual 3-D segmentation of hip cartilage, which served as training data for the neural network and was used as input data for the manual 3-D analysis. Next, we developed the deep convolutional neural network to obtain an automated 3-D cartilage segmentation that we used as input data for the automated 3-D analysis. For actual analysis of the manually and automatically generated 3-D cartilage models, a dedicated software was developed. Manual 2-D analysis of dGEMRIC indices and cartilage thickness was performed at each "full-hour" position on radial images and served as the gold standard for comparison with the corresponding measurements of the manual and the automated 3-D analysis. We measured dGEMRIC index, cartilage thickness, surface area, and volume for each of the four joint quadrants and compared the manual and the automated 3-D analyses using mean differences. Agreement between the techniques was assessed using intraclass correlation coefficients (ICC). The overlap between 3-D cartilage volumes was assessed using dice coefficients and means of all distances between surface points of the models were calculated as average surface distance. The interobserver reliability and intraobserver reproducibility of the software-assisted manual 3-D and the automated 3-D analysis of dGEMRIC indices, thickness, surface and volume was assessed for two readers on two different time points using ICCs. Comparable mean overall difference and almost-perfect agreement in dGEMRIC indices was found between the manual 3-D analysis (8 ± 44 ms, p = 0.005; ICC = 0.980), the automated 3-D analysis (7 ± 43 ms, p = 0.015; ICC = 0.982), and the manual 2-D analysis.Agreement for measuring overall cartilage thickness was almost perfect for both 3-D methods (ICC = 0.855 and 0.881) versus the manual 2-D analysis. A mean difference of -0.2 ± 0.5 mm (p < 0.001) was observed for overall cartilage thickness between the automated 3-D analysis and the manual 2-D analysis; no such difference was observed between the manual 3-D and the manual 2-D analysis.Regional patterns were comparable for both 3-D methods. The highest dGEMRIC indices were found posterosuperiorly (manual: 602 ± 158 ms; p = 0.013, automated: 602 ± 158 ms; p = 0.012). The thickest cartilage was found anteroinferiorly (manual: 5.3 ± 0.8 mm, p < 0.001; automated: 4.3 ± 0.6 mm; p < 0.001). The smallest surface area was found anteroinferiorly (manual: 134 ± 60 mm; p < 0.001, automated: 155 ± 60 mm; p < 0.001). The largest volume was found anterosuperiorly (manual: 2343 ± 492 mm; p < 0.001, automated: 2294 ± 467 mm; p < 0.001). Mean average surface distance was 0.26 ± 0.13 mm and mean Dice coefficient was 86% ± 3%. Intraobserver reproducibility and interobserver reliability was near perfect for overall analysis of dGEMRIC indices, thickness, surface area, and volume (ICC range, 0.962-1). The presented deep learning approach for a fully automatic segmentation of hip cartilage enables an accurate, reliable and reproducible analysis of dGEMRIC indices, thickness, surface area, and volume. This time-efficient and objective analysis of biochemical cartilage composition and morphology yields the potential to improve patient selection in femoroacetabular impingement (FAI) surgery and to aid surgeons with planning of acetabuloplasty and periacetabular osteotomies in pincer FAI and hip dysplasia. In addition, this validation paves way to the large-scale use of this method for prospective trials which longitudinally monitor the effect of reconstructive hip surgery and the natural course of osteoarthritis. Level III, diagnostic study.

Longitudinal assessment of cartilage composition by high-field MRI in patients with low-grade knee cartilage injury

Purpose: If left untreated, early-stage articular cartilage lesions may progress to full-thickness, higher-grade lesions, possibly leading to further degeneration of the joint surface. This process is typically associated with the breakdown of extracellular matrix macromolecules, such as collagen type 2 and proteoglycans. This makes collagen and glycosaminoglycans (GAG) as biomarkers to monitor the status of the articular cartilage and for studies on cartilage repair. The aim of this study was to evaluate the sensitivity of a comprehensive Magnetic Resonance Imaging (MRI) approach in detecting changes in cartilage composition in ICRS grade I/II focal lesions over a 12-month period. Methods: MRI was performed at baseline, 8-day, 3, 6 and 12-month, both at 7T and 3T, on 20 subjects with ICRS Grade I/II cartilage defects. Collagen bi-layer organization was assessed by T2 mapping, and GAG content was measured both by 23Na and gagCEST-MRI (7T only) (Fig. 1). Regions-of-interest were defined in both defective and normal appearing cartilage (weight bearing [WBR] and non-weight bearing [NWBR] regions), and transferred to T2 maps, 23Na and gagCEST images for quantitative analysis. Patient functional status was assessed via the Knee injury and Osteoarthritis Outcome Score (KOOS) questionnaire. Results: Higher T2 values were measured at baseline in deep and superficial layers of the defective vs healthy WBR and NWBR, both at 3T and 7T. While T2 values remained unchanged at 7T, a T2 decrease was observed over 12 months at 3T in deep (-15%) and superficial (-17%) layers of the damaged cartilage. 23Na-MRI signal intensities were ∼25% lower in the defective area vs other regions, with no large variation over the 12-month follow-up. gagCEST measurements at 7T appeared in good agreement with 23Na-MRI results. KOOS values remained stable over the 12-month time period. Conclusions: These results point to a progressive alteration of collagen structure in the defective region (despite stable KOOS), without large changes in GAG levels over 1 year in this population. These data support the use of MRI as a noninvasive alternative to cartilage biopsy for the detection of subtle changes in cartilage composition.

Associations between Vitamin C and D intake and MR-based cartilage composition and knee joint morphology over 4 years: data from the osteoarthritis initiative

Purpose: The purpose of this study was to determine the cross-sectional and longitudinal associations of Vitamin C and D intake with MR imaging measures of cartilage composition (T2) and joint structure (cartilage, meniscus, and bone marrow), using data from the Osteoarthritis Initiative (OAI). Methods: 1785 subjects were selected with radiographic Kellgren Lawrence knee grades 0-3 from the OAI database and with available MRI data in UCSF Radiology database. For a cross-sectional analysis, three measurements of Vitamin C and Vitamin D intake from the baseline Block Brief 2000 questionnaire were assessed: (a) daily intake from food of Vitamin C (mg) and Vitamin D (IU), (b): mean daily intake from supplements of Vitamin C (mg) or Vitamin D (IU) estimated over the past 12 months, and (c) total Vitamin C or Vitamin D intake from food and from supplements (sum of a + b). For a longitudinal analysis of Vitamin C supplement intake, 612 subjects with available data were categorized into those that had consistent intake of Vitamin C (at least 750 mg) at least 4-6 days per week at years 1, 2, 3, and 4, and those that did not take Vitamin C over the same time period. For the longitudinal analysis of Vitamin D, 516 subjects with available data were categorized into those that had consistent intake of Vitamin D (at least 400 IU) at least 4-6 days per week at years 1, 2, 3, and 4, and those that did not take Vitamin D over the same time period. Subjects with varying vitamin intake over 4 years were not included in the longitudinal analysis. The MR imaging analysis protocol included region-specific baseline 3T MRI cartilage, meniscus and bone marrow semi-quantitative WORMS gradings and cartilage T2 quantification. For the cross-sectional analysis, linear regression models were used to assess the associations between baseline Vitamin C and D intake and baseline cartilage T2 and WORMS scores. Standardized vitamin predictors and T2 outcomes were quantified by subtracting the mean of all predictors from the value for each subject and dividing by the standard deviation. For the longitudinal analysis, logistic regression models were used to quantify the associations between consistent Vitamin C or D intake over 4 years and worsening of joint morphology over 4 years. Worsening of joint morphology was designated as binary variable, and positive if the WORMS score at year 4 was greater than the WORMS score at baseline. All models were adjusted for baseline age, gender, BMI, race, education, and total calorie intake. Results: The 1785 participants in this study had a mean age of 59.8±9.0 years and a mean BMI of 28.6±4.4 kg/m2 at baseline. Overall, higher Vitamin C intake was associated with lower cartilage T2 and WORMS scores, particularly in the medial cartilage regions. Daily total Vitamin C intake (food +supplements) had significant negative associations with cartilage T2 in the average of all regions (coeffstandardized=-0.05, p=0.04, 95% CI=-0.09 to -0.002) and in the medial tibia (coeffstandardized=-0.05, p=0.03, 95% CI=-0.09 to -0.01). Also, daily supplement Vitamin C intake had a significant negative association with baseline medial tibia cartilage WORMS score (coeffstandardized= -0.07, p=0.04, 95% CI = -0.14 to -0.001). Daily dietary Vitamin D intake had a significant negative association with baseline cartilage WORMS sum score (coeffstandardized=-0.24, p=0.03, 95% CI=-0.46 to -0.02), and daily Vitamin D supplement intake had a significant negative association with cartilage WORMS score in the medial femur (coeffstandardized=-0.09, p=0.04, 95% CI=-0.18 to -0.003). For the longitudinal analysis, subjects with a consistent Vitamin C supplement intake over 4 years (n=39) did not have significantly different odds of WORMS progression over 4 years (p>0.05) compared to subjects that did not consistently take Vitamin C supplements (n=573). However, subjects with consistent Vitamin D supplement intake over 4 years (n=75) had significantly lower odds of WORMS progression in the cartilage, meniscus, and bone marrow over 4 years compared to those that did not (n=441), Table 1.Table 1Logistic regression models testing the associations between consistent intake of Vitamin D over 4 years (at least 4-6 days/week with a dose of at least 400 IU) and worsening of WORMS scores over 4 years. Conclusions: The cross-sectional results for both Vitamin C and D show that a higher intake is associated with less cartilage degeneration. While Vitamin C supplementation over 4 years did not have a significant association on changes in joint morphology, supplementation with Vitamin D (at least 4-6 days per week and 400 IU) over four years had significantly less progression of knee joint abnormalities in the meniscus, cartilage, and bone marrow. Given the retrospective nature of this study, future randomized control studies with advanced MRI outcomes would be useful for further analysis.

GagCEST MRI at 3T can detect cartilage differences between healthy and osteoarthritic subjects

Purpose: Evaluation of osteoarthritis (OA) is hampered by a lack of non-invasive tools to effectively detect early and reversible changes associated with the disease. Early OA is characterized by cartilage proteoglycan depletion related to an increase in enzymatic degradation. GagCEST is a promising quantitative MR technique for assessing content of Glycosaminoglycan (GAG) side chains attached to proteoglycans at 7T and is of particular interest due to its specificity to GAG content without the use of exogenous contrast agents or specialized hardware. While gagCEST has been shown to be a useful biomarker for cartilage composition at 7T, there is limited evidence of its utility at 3T. In this study, we assess the utility of an optimized gagCEST protocol at 3T by comparing gagCEST asymmetry in subjects with established OA to healthy controls. Methods: Ten healthy subjects (5 female and 5 male, ages 20-30) and twenty-four subjects with medial compartment OA were scanned on a 3T MRI system. The OA cohort (ages 60-70) was grouped by Kellgren-Lawrence (KL) grade (assessed using radiography) with five subjects with a KL grade of 1 (4 female and 1 male), twelve with a KL grade of 2 (8 female and 4 male), and five with a KL grade of 3 (4 female and 3 male). Other inclusion criteria included no previous ACL reconstruction surgery and BMI < 35. GagCEST images were acquired with a magnetization prepared 3D spoiled gradient-echo sequence (imaging parameters in Table 1). After correcting for magnetic field inhomogeneities, gagCEST asymmetry (%) was calculated using the B0-field corrected signal intensity at ±1.0 ppm, and the chemical shift of GAG hydroxyl protons, using the equation: gagCESTasym= [S(-1.0 ppm)-S(+1.0 ppm)]/ S0]. Femoral cartilage was manually segmented and subdivided into medial and lateral subregions. Statistical comparisons between cartilage compartments and healthy vs OA subjects were made using an ANOVA 2-way test with a Tukey HSD Test for multiple comparisons. Results: Subjects with OA showed a reduced gagCEST asymmetry compared to healthy controls. Further, there was a trend of an inverse relationship between GagCEST asymmetry and KL grade. There was a statistically significant difference in gagCEST asymmetry among KL grade values (p = 0.019). Further analysis comparing healthy subjects to the different OA KL grade subjects, showed a significant difference between healthy and OA KL-2 subjects and OA KL-3 subjects (p = 0.022 and p = 0.046 respectively). The comparison between healthy and KL-1 subjects did not show a significant difference (p = 0.536), which may be due to insufficient power in this cohort. There was no statistically significant difference between medial and lateral compartments in the femoral cartilage (p = 0.977). Additionally, a negative correlation of GagCEST with KL grade was observed (r= -0.404, p=0.01). The results show that optimized gagCEST methods at 3T were able to detect a statistically significant reduction in gagCEST asymmetry in osteoarthritic subjects, known to have cartilage degeneration and lower biochemical GAG composition, compared to healthy controls. Further analysis showed a significant difference in gagCEST asymmetry between the healthy and OA KL-2 and KL-3 subjects. This decrease can be seen in the unrolled gagCEST asymmetry maps, especially in the medial compartment of the knee, which corresponds well with the diagnosis in our cohort of medial compartment OA. Further, at a total acquisition time of 8:76 minutes for whole joint coverage, these methods offer translational potential. Conclusions: Our results demonstrate promise for the application of gagCEST at 3T to detect differences between healthy cartilage and cartilage in subjects with OA. Taken together, our results show that GagCEST could be a viable tool to assess early degenerative changes in cartilage in clinical trials. A strength of MRI over X-ray is that it is more sensitive to early changes in cartilage composition that occur due to OA. GagCEST has the potential for distinguishing these changes that are unseen in X-rays because it may be sensitive to signs of changes in GAG content that radiographs are not able to visualize.View Large Image Figure ViewerDownload Hi-res image Download (PPT)View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Patient characteristics associated with benefits from weight loss to prevent progression of knee osteoarthritis: data from the osteoarthritis initiative

Purpose: The effect of weight loss on knee osteoarthritis (OA) development and severity has been subject to a number of previous studies that found significantly less progression of cartilage degeneration in subjects with weight loss compared to those with stable weight or weight gain. However, little is known about the extent to which subgroups with certain demographic characteristics and imaging findings benefit from weight loss, and if some groups could benefit more from weight loss compared to others. Since OA and overweight are both frequent disorders with a rising prevalence, identifying those that would particularly benefit from weight loss would be highly useful in clinical practice. Our aim was therefore to assess how different baseline subject characteristics influence the protective effect of weight loss on morphological knee joint degeneration over 4 years. Methods: In this study, 592 subjects (age 62.2 ± 8.9 years, sex: 39.5% females, BMI: 30.1 ± 3.6 kg/m2) from the Osteoarthritis Initiative (OAI) were included who were overweight or obese (BMI ≥ 25 kg/m2) and showed either weight loss or stable weight over 4 years. Weight loss was defined as ≥ 5% decrease in BMI over 4 years (n = 367), while stable weight was defined as a weight change of < 3% in BMI over 4 years (n = 225). Morphological knee abnormalities were assessed on 3T MRIs at baseline and 4 year follow-up in the right knee using the Whole-Organ Magnetic Resonance Imaging Score (WORMS). In addition Kellgren-Lawrence (KL) scores were assessed from weight bearing fixed flexion radiographs. Cartilage composition was obtained by measuring T2 relaxation time using 3T MRI and available in a subset of 370 knees. To identify the characteristics of subjects who would benefit most from weight loss, in a multivariable linear regression model we tested for the interaction of baseline demographics (age, sex, BMI), baseline radiographic findings (KL scores), and cartilage T2 with weight loss in predicting WORMS sum score changes over 4 years. Results: Our data showed that progression of WORMS sum scores over 4 years was significantly associated with weight loss (effect size -1.09; 95% confidence interval (CI) -2.00, - 0.18; p = 0.019) and KL scores at baseline (effect size 0.79; 95% CI 0.37, 1.2; p < 0.001). However, no significant interaction with weight loss was found for any of the subject demographics (age, sex, BMI), baseline radiographic imaging findings (KL score), and cartilage T2 at baseline (p>0.05 for all interaction terms). Overall, we could not identify a subcohort with specific baseline subject characteristics that were associated with significantly more benefits from weight loss as measured by progression of WORMS scores. Conclusions: Our findings highlight the importance of weight loss for the overweight and obese population to prevent progression of morphological knee joint degeneration as measured by WORMS. Moreover, our results suggest that weight loss is beneficial for all individuals suffering from obesity or overweight. We could not identify specific baseline characteristics that significantly influenced the protective effect of weight loss on morphologic knee joint degeneration over 4 years.

Building physiologically‐relevant models of developing cartilage

Perlecan, or heparan sulfate proteoglycan (Hspg2), is an extracellular matrix (ECM) protein localized to the pericellular matrix (PCM). When Hspg2 is knocked down, the phenotype mimics the skeletal defects observed in human Schwartz‐Jampel syndrome. We previously demonstrated, using atomic force microscopy, that perlecan knockdown significantly decreased the stiffness of the ECM and chondrocytes in developing cartilage; however, it is not clear what changes occur in ECM structure and organization to cause this decrease. To address this question, our goal is to develop computational models that incorporate geometries and material properties that will enable us to analyze the mechanical response of cells in situ. Therefore, we created 3D physiologically‐derived geometries that can generate repeatable simulations of cartilage mechanics. In parallel, we are using mass spectrometry (LC‐MS/MS) and transmission electron microscopy (TEM) to define how cartilage composition and organization changes as a function of development and perlecan knockdown.Multi‐cellular geometries from embryonic day (E)16.5 and postnatal day (P)3 murine cartilage were imaged in 3D using confocal microscopy. Image stacks were processed using MATLAB to create multicellular geometries for finite element analysis using ANSYS (Fig 1A,B). Geometries based on confocal images and isolated, single cell models were compressed 5% and cells and ECM strain were compared (Fig 1C,D). Our simulations indicated that cells had similar strains at both time points, even though cell and ECM stiffness at P3 was significantly higher than at E16.5. In addition, the ECM at P3 took on more strain than at E16.5. The isolated, single cell geometries underestimated both cell and ECM strain and were not able to capture the similarity in cell strain observed with physiologically‐derived geometries.A limitation of the current model is that cells and ECM were treated as homogenous materials, whereas native cartilage is a biphasic material comprised of type II collagen fibrils embedded in an amorphous proteoglycan matrix. To identify how ECM composition and organization changes, cartilage from distal humeri or femurs were dissected from E16.5 and P3 wildtype, heterozygous, and homozygous Hspg2 mice for analysis via LC‐MS/MS or TEM. Proteins were extracted with guanidine‐HCl and processed for LC‐MS/MS. Relative increases in the abundance of ECM and associated proteins, including collagen types II &amp; IX and aggrecan highlighted expected developmental changes between E16.5 and P3. Multiple proteins were significantly more abundant in homozygous vs. wildtype P3 mice, including collagens type II &amp; IX, fibronectin and matrilin‐3. Surprisingly, TEM studies indicate that collagen fibril density and diameter decreased between wildtype and homozygous mice, suggesting that perlecan knockdown leads to a decrease in cross‐linking and increased ECM extractability. We aim to integrate these changes in material properties with our simulations to generate a computational model that can describe and predict the mechanics of developing cartilage.Support or Funding InformationThis work was supported by the National Institutes of Health [R21 AR069248, R01 AR071359 and DP2 AT009833 to S.C.].This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Impact of contralateral radiographic status on longitudinal change of cartilage transverse relaxation time (T2) in radiographically normal knees, a model of early OA? – data from the osteoarthritis initiative

Purpose: Evaluating treatment for modifying structural progression at an early stage of OA requires models that display subtle synovial tissue alterations that occur early in the disease process, but still have a reasonable likelihood of progression. We have previously shown that radiographically normal (KLG0) knees with definite contralateral (CL) radiographic OA had a greater likelihood of incident ROA, and that KLG0 knees with CL radiographic joint space narrowing (JSN) displayed greater cartilage loss than those with radiographically normal CL knees. The purpose of this study was to use this model of “early” OA of a KLG0 case knee in a person with CL (non-posttraumatic) ROA, to determine whether baseline values and longitudinal change in cartilage composition differ compared with those with radiographically normal CL knees (controls). Methods: The data were obtained from the Osteoarthritis Initiative (OAI). 150 KLG0 case knees displayed CL ROA (KLG2-4; central readings vs.0.7), without reporting previous injury to that knee. Of those, 63 (50.8% female, age: 64.2±8.8 y, BMI: 27.6±4.4 kg/m2) were right knees with multi-echo spin-echo (MESE) MRIs (Fig.1) to support analysis of the cartilage transverse relaxation time (T2), a method previously shown to be related to cartilage composition and mechanical properties. 23 were CL KLG2 without JSN, 22 KLG2 with JSN grade1, 13 KLG3, and 5 KLG 4. The 63 case knees were matched 1:1 with 63 KLG0 controls of persons who were bilaterally KLG0 and had the same sex, similar age (64.3±8.7 y), and BMI (27.3±4.0 kg/m2). The 3-year change in cartilage T2 (between year 1 and 4 [Y1/4] follow-up) was determined from sagittal MESE MRIs (Fig.), analyzing the superficial and deep 50% of the cartilage in each of 16 femorotibial joint (FTJ) subregions. The mean T2-values across the superficial and deep cartilage layers of the entire FTJ were the primary analytic focus. Exploratory measures included T2 of the medial and lateral femorotibial compartment (MFTC/LFTC) and location-independent T2 shortening and lengthening scores (i.e. the sum of all negative / positive femorotibial subregion T2 changes). Results: The baseline T2 (Y1) was significantly greater in the case than in control KLG0 knees, both in the superficial and deep FTJ cartilage layers (paired t-test: p=0.01; Cohen’s D=0.40; and p=0.04; Cohen’s D=0.34, respectively). In the superficial layer, the effect tended to be stronger in the medial than in the lateral, and in the deep layer stronger in the lateral than in the medial compartment (Table 1).Table 1Cartilage T2 at the beginning of the observation intervalCase KLG0 kneesControl KLG0 kneesDifferenceSuperficial LayerMeanSD95% CIMeanSD95% CIPCohen DFTJ48.73.447.849.547.42.846.748.10.010.40MFTC49.24.248.150.347.73.746.848.60.020.37LFTC48.13.747.249.147.13.046.347.90.050.31Deep LayerFTJ37.72.337.238.337.02.036.537.50.040.34MFTC38.22.637.538.937.82.537.238.40.320.16LFTC37.32.636.637.936.22.235.736.80.010.44 Open table in a new tab When restricting analysis to those with CL JSN, the effect size (Cohen’s D) was 0.49 in the superficial and to 0.36 in the deep layer (data not shown). The longitudinal increase in medial and lateral T2 from Y1 to Y4 of the case knees was significantly different from zero; it also tended to be greater in case than in control KLG0 knees, but the case-control differences did not reach statistical significance (data not shown). Only when restricting the analysis to those with CL JSN, we observed a significantly (p<0.05) greater increase in deep layer T2 in the case than in the control knees in the FTJ, and also in the lateral compartment and location-independent lengthening score (Cohen’s D 0.45-0.46). No significant differences were observed in the longitudinal changes of the superficial layer (Table 2).Table 2Longitudinal change in T2 over 3 years of observationKLG0 with CL JSNKLG0 with CL KLG0DifferenceSuperficial LayerMeanSD95% CIMeanSD95% CIPCohen DFTJ1.01.90.41.60.91.50.41.40.850.04MFTC1.42.50.62.21.42.20.72.10.950.01LFTC0.62.2-0.21.30.41.9-0.21.00.820.06Decrease-15.316.1-20.4-10.1-15.110.2-18.4-11.80.96-0.01Increase31.717.726.037.429.717.824.035.40.610.11Deep LayerFTJ1.12.50.31.90.11.7-0.40.70.040.46MFTC1.33.30.22.40.32.4-0.41.10.140.34LFTC0.92.50.11.7-0.11.8-0.60.50.040.45Decrease-13.413.5-17.7-9.0-18.217.0-23.7-12.80.150.32Increase32.329.522.941.721.812.717.725.80.050.46 Open table in a new tab The increase in deep layer T2 was significantly correlated with location-independent measures of cartilage thickness loss in the FT joint (r=-0.27, p<0.01). Conclusions: This is the first study to explore whether cartilage T2 is sensitive to identifying compositional changes in cartilage in a model of “early” knee OA, i.e. a KLG0 knee with a CL non-posttraumatic ROA knee. Significant differences in superficial and deep layer cartilage T2 were observed at the beginning of the longitudinal observation interval. Similar to previous observations for the change in location-independent measures of cartilage thickness, significant longitudinal differences in T2 lengthening between case and control knees were observed in knees with CL JSN. These differences were limited to the deep layer, and were most prominent in the lateral femorotibial compartment. KLG0 knees with CL JSN hence may represent a model of early OA in which structure modification can be studied at an early disease stage.

18F]-sodium fluoride PET-MR imaging reveals bone-cartilage interactions in hip osteoarthritis

18F]-sodium fluoride PET-MR imaging reveals bone-cartilage interactions in hip osteoarthritis

Comparison of talar cartilage thickness between those with and without chronic ankle instability: a ultrasonography study

Purpose: Chronic ankle instability (CAI) has been linked with the development of ankle post-traumatic osteoarthritis. Individuals with CAI demonstrate early degenerative changes in talar cartilage composition using advanced MR techniques. However, MR-based imaging techniques are not clinically accessible or cost effective. Ultrasonography (US) has emerged as an alternative to MR to assess femoral cartilage morphology, but it remains unknown if US is able to assess between group differences in cartilage thickness at ankle joint. Therefore, the purpose of this study is to determine if US measures of talar cartilage thickness at rest differ between those with CAI and uninjured healthy individuals. Methods: Fifteen individuals with CAI (age: 21.2±1.8 years, height: 1.7±.8m, mass: 67.0±7.7kg) and fifteen uninjured controls (age: 21.0±2.5 years, height: 1.7±.8m, weight: 69.6±13.2kg) volunteered to participate. As recommended by the International Ankle Consortium, individuals with CAI demonstrated a history of at least one lateral ankle sprain and at least two episodes of giving way within the past 6 months; an Identification of Functional Ankle Instability (IdFAI) >11, a Foot and Ankle Ability Measure Activities of Daily Living subscale (FAAM-ADL) < 90%, and a FAAM-Sport subscale (FAAM-S) < 80%. Controls demonstrated no history of ankle sprains and giving way episodes; an IdFAI of < 11, a FAAM-ADL of ≥98%, a FAAM-S of ≥98%. Relative to the controls, CAI participants had a history of multiple lateral ankle sprains (4.0±2.1 vs. 0.0±0.0 sprains), multiple giving way episodes within the past 6 months (6.6±5.1 vs. 0.0±0.0 episodes), higher IdFAI scores (22.9±2.8 vs. 0.1±0.5), and greater limitations in self-reported function based on the FAAM-ADL (85.9±9.7% vs. 100.0±0.0%) and FAAM-S (68.4±20.6% vs. 100.0±0.0%). The US images of talar cartilage thickness were acquired using a LOGIQe system with a 12 MHz linear probe after unloading the cartilage for 30 minutes. For US imaging, participants were positioned supine with the knee in 90 degrees of flexion and the ankle plantar flexed so that the foot was flat on the support surface. The US probe was placed transversely in line with the medial and lateral malleolus and rotated to maximize reflection of the talar articular cartilage surface. Talar cartilage images were manually segmented using ImageJ software to identify the medial, lateral, and overall cross-sectional area (mm2). Cross-sectional area was then normalized to the length of the cartilage-bone interface to obtain an average thickness (mm). Average thickness in each region of interest (i.e. medial, lateral, overall) were compared between CAI patients and healthy controls using independent sample t-tests and an a priori alpha level of 0.05. Results: The CAI and controls groups were similar in terms of their age, height, and weight (p≥0.433). Measures of injury history and self-reported function differed between the groups (p<0.001) as expected. There is no significant difference between the CAI and control groups in the medial (CAI: 0.394±0.089mm, control: 0.435±0.112mm, p=0.276), lateral (CAI: 0.441±0.131mm, control: 0.458±0.117mm, p=0.717), or overall (CAI: 0.427±0.094mm, control: 0.450±0.083mm, p=0.493) regions of interest. Conclusions: Previous studies showed that CAI patients had worse compositional changes (i.e. higher T1rho and T2 mapping relaxation times) of the talar cartilage compared to healthy individuals without morphological degradation (i.e. no decline in cartilage volume). Our results indicate that US thickness measures at rest did not differ between CAI and control groups. This finding supports the existing literature that illustrates no morphological changes in talar cartilage in the early stage of joint degeneration. US appears to be a feasible method for evaluating ankle cartilage morphology, but future research is needed to determine if US based measures of cartilage deformation or resiliency following a standardized loading protocol, which may provide information regarding cartilage composition, differ between CAI and uninjured individuals.

Investigating the association of serum lipid biomarkers with biochemical cartilage composition using quantitative MRI – a pilot study

Purpose: There has been considerable interest in the association between osteoarthritis (OA) and metabolic syndrome (MS), whose components include abdominal obesity, diabetes, hypertension and dyslipidemia. OA is increasingly understood as a metabolic disease and recent epidemiologic studies suggest that OA pathogenesis could be linked to altered lipid metabolism. While there is evidence suggesting that the MS-associated OA phenotype is biochemically and structurally distinct from standard OA, the few studies that explored the relationship between serum lipid profile and OA utilized radiographic measurements which are insensitive for early and mild OA. Magnetic resonance imaging (MRI)-based T2 and T1ρ mapping are techniques that measure early degenerative changes of the whole cartilage layer while ultrashort (UTE) T2* mapping focuses on early degenerative changes of the deep calcified cartilage layer. Therefore, the goal of this study was to investigate the association of serum lipid levels with knee cartilage composition, assessed using T2, T1ρ and UTE T2* mapping. Methods: Fourteen study participants were recruited using the following inclusion criteria: 40-70 years of age, Kellgren Lawrence grade (KLG) 0-2 in at least one knee, no previous diagnosis of an inflammatory arthropathy, no knee pain most days of the month, no history of knee injury or knee surgery and no metal implants. Serum lipid biomarkers included total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), non-HDL cholesterol (sum of vLDL and LDL) and triglycerides. All subjects underwent bilateral standing anterior-posterior knee radiographs and 3 Tesla MRI imaging of the knee with the lower KL score using 3D multiecho T2, T1ρ and UTE sequences. Cartilage was segmented semi-automatically into five regions (patella, medial/lateral femur, medial/lateral tibia) for T2*UTE maps and six regions (patella, medial/lateral femur, medial/lateral tibia, trochlea) for T2 and T1ρ maps. T2, T1ρ and T2*UTE maps were computed after segmentation. Global values were calculated as the mean of all knee regions. Partial correlations and linear regression analyses were performed using standardized serum lipid biomarkers as predictors and global T2, T1ρ and UTE as outcomes adjusting for BMI. Results: The mean age of all subjects was 54.4 years (SD ± 4.0) with a higher proportion of males (71.4%), mean body mass index (BMI) was 29.4 (SD ± 2.8) and mean total WOMAC was 1.4 (SD ± 2.5). For serum lipid levels, the mean total cholesterol was 159.9 (SD ± 43.0) mg/dl, mean HDL was 44.8 (SD ± 11.0) mg/dl, mean LDL was 94.2 (SD ± 35.8) mg/dl, mean non-HDL cholesterol was 115.1 (SD ± 40.6) mg/dl and mean triglycerides was 104.7 (SD ± 69.0) mg/dl. As shown in Table 1, higher total cholesterol was significantly associated with higher global higher global UTE T2* (0.82 ms [0.07,1.57], r = 0.59, P = 0.035), higher LDL was significantly associated with higher global UTE T2* (0.80 ms [0.06,1.54], r = 0.58, P = 0.037) and higher non-HDL cholesterol was significantly associated with higher global UTE T2* (0.95 ms [0.27,1.63], r = 0.68, P = 0.011). No significant associations were found between serum lipid levels and global T2 and T1ρ. Conclusions: This cross-sectional study demonstrates that higher total cholesterol, LDL and non-HDL cholesterol were associated with higher UTE T2*, suggesting increased degeneration of the deep calcified cartilage layer. This layer may, therefore, have an important role in dyslipidemia-associated early cartilage degeneration. Potential pathophysiological mechanisms underlying these relationships include oxidized LDL’s role in cartilage destruction and ectopic bone formation, subchondral ischemia secondary to lipid deposits in cartilage and disrupted lipid metabolism leading to upregulation of pro-inflammatory signaling within cartilage and chondrocytes. Mechanisms through which dyslipidemia could contribute to OA development must still be fully elucidated. This study was supported by the National Center for Advancing Translational Sciences, NIH, through UCSF-CTSI Grant Number TL1 TR001871. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.Tabled 1Association of serum lipid biomarkers with cartilage UTE T2*. P-values < 0.05 are in bold.Coefficient[95% Conf. Interval]CorrelationP-valueGlobal UTE T2*Total cholesterol0.82[0.07,1.57]0.590.035HDL-0.29[-1.17,0.60]-0.210.491LDL0.80[0.06,1.54]0.580.037Non-HDL cholesterol0.95[0.27,1.63]0.680.011Triglycerides0.68[-0.15,1.51]0.480.101 Open table in a new tab

Does radiographic knee OA status impact age-related reduction of thigh muscle specific strength - data from the osteoarthritis initiative

Does radiographic knee OA status impact age-related reduction of thigh muscle specific strength - data from the osteoarthritis initiative

Less femoral cartilage deformation following walking associates with clinically relevant symptoms in individuals with anterior cruciate ligament reconstruction

Purpose: Approximately one-third of individuals with an anterior cruciate ligament reconstruction (ACLR) develop post-traumatic knee osteoarthritis (PTOA) within the first decade following ACLR. Currently there is a need to develop methods of early detection of PTOA, as articular cartilage damage is irreversible. Diagnostic brightness-mode (B-mode) ultrasound has been used to evaluate femoral cartilage deformation, evidenced by a decrease in cross-sectional area (CSA), following 30 minutes of treadmill walking in healthy uninjured individuals. Additionally, femoral cartilage CSA is greater in the ACLR limb compared to the uninjured limb in a resting state, which is similar to results from magnetic resonance imaging studies hypothesized to demonstrate cartilage swelling following joint injury. It remains unknown if the magnitude of femoral cartilage deformation following a standardized walking protocol is related to clinically relevant symptoms (CRS) in those with an ACLR. Persistent CRS, measured with the Knee Osteoarthritis and Injury Outcome Score (KOOS), have been reported in 39% of individuals six years following ACLR. The purpose of the current study was to determine the magnitude of femoral cartilage deformation following a standardized walking protocol which best-identified individuals with CRS. We hypothesized that individuals with this magnitude of femoral cartilage deformation would also be more likely to demonstrate CRS. Methods: Thirty-two individuals (56% female, 22±4 years old, 23.8±2.8 kg/m2body mass index, 50±37 months since ACLR) with a history of primary unilateral ACLR were recruited for a cross-sectional descriptive laboratory experiment. Femoral cartilage CSA was measured with B-mode ultrasound immediately prior to and following 3,000 steps of walking on a treadmill at a self-selected comfortable speed. Prior to the pre-walking ultrasound images, individuals rested in the long-sit position for 45 minutes to allow the cartilage rebound for a baseline CSA assessment. Individuals moved their knee into 140° of flexion to capture the anterior portion of the femur on the ultrasound during imaging. Femoral cartilage was segmented using ImageJ software, and cartilage deformation on the involved limb was calculated as a percent change (%Δ)from baseline, with negative %Δ indicating deformation following walking. All individuals were classified as symptomatic or asymptomatic based on previously defined cutoff values for the KOOS. A symptomatic individual was defined as scoring ≤ 87.5 on the quality of life portion of the KOOS as well as scoring below the cutoff of at least two other subscales of the KOOS questionnaire (KOOS Symptoms ≤ 85.7; KOOS Pain ≤ 86.1; KOOS ADL ≤ 86.8, KOOS Sports ≤ 85.0). Fourteen of the 32 individuals were classified as symptomatic. Area under the curve (AUC) values were calculated using receiver operator characteristic curve analysis to determine the capacity of femoral cartilage deformation to identify symptomatic individuals. If a significant AUC was determined (i.e. AUC 95% confidence intervals [CI] did not cross 0.5), we identified the cutoff value maximizing sensitivity and specificity. Lastly, an odds ratio was calculated to demonstrate the association between the cartilage deformation cutoff score and symptoms. Results: Femoral cartilage deformation -0.15±4.47%Δ, range: -8.18 - 13.87%Δ) displayed fair accuracy (AUC = 0.70; 95% CI, 0.51 - 0.89) for identifying symptomatic individuals. A femoral cartilage deformation cutoff of -0.29% was found to maximize sensitivity (0.79) and specificity (0.67). Individuals whose femoral cartilage did not deform by at least -0.29%Δ (meaning cartilage CSA stayed the same or increased during walking) displayed 7.33 (1.47 - 36.66) times higher odds of being symptomatic. Conclusions: Contrary to our hypothesis, individuals who did not demonstrate deformation of at least -0.29%Δ in the involved limb during 3,000 steps were more likely to report CRS. Sixteen individuals (50%) did not demonstrate deformation and experienced an increase in CSA during walking. Overall, while the mean is small and the standard deviation is large, this reflects half of participants increased CSA while the other half decreased CSA during walking. Individuals who demonstrated an increase in femoral cartilage CSA following walking were more likely to be symptomatic. Preliminary data demonstrates femoral cartilage in uninjured controls deforms (-1.33±1.65%) following 3,000 steps, which may indicate that femoral cartilage deformation is a healthy response to walking. The mechanism leading to an increase in CSA following 3,000 steps in these ACLR individuals remains unknown. It is possible increased CSA following walking is due to altered cartilage composition or aberrant biomechanics, which may promote cartilage swelling or altered fluid shifts within the tissue during movement.

3414 Association of blood pressure and biochemical knee cartilage composition assessed by T2 relaxation time measurements: Data from the Osteoarthritis Initiative

OBJECTIVES/SPECIFIC AIMS: The goal of this study was to investigate the associations of systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse pressure (PP) with knee articular cartilage composition using magnetic resonance imaging (MRI)-based T2 relaxation time measurements in study participants from the Osteoarthritis Initiative (OAI). METHODS/STUDY POPULATION: In this longitudinal study, 1,139 participants from the OAI, a multi-center, observational study of the evolution of knee OA, were selected using the following inclusion criteria: right knee Kellgren Lawrence (KL) score (radiographic classification of OA severity) 0-2 indicating no to mild radiographic OA at baseline, no history of rheumatoid arthritis at baseline, available blood pressure measurements at baseline, available T2 measurements in at least three knee compartments at baseline and 48-month follow-up. Linear regression models were performed using standardized values for SBP, DBP and PP as primary predictors and change in cartilage T2 over 48 months, a measure of cartilage matrix quality and degeneration, as the primary outcome. PP was defined as SBP minus DBP. Change in superficial layer and deep layer cartilage T2, which reflect differences in the laminar organization of knee cartilage T2, were also included as outcomes. Statistical models were adjusted for common risk factors for knee OA (baseline age, sex, BMI, KL score) as well as number of currently used anti-hypertensive medications (AHM) reported at baseline. We included AHMs whose primary indication was the treatment of hypertension including beta blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARB), thiazides, chlorthalidone, dihydropyridine calcium channel blockers (CCB) and aliskiren. All predictors, outcomes and covariates (except sex) were analyzed as continuous variables. We included interaction terms in the models to evaluate whether the covariates (age, sex, BMI, KL score, number of AHMs) modified the association of SBP, DBP and PP with cartilage T2. RESULTS/ANTICIPATED RESULTS: The average age of all study participants was 58.8 years (SD ± 8.6) with a higher proportion of men (59.4%), average body mass index (BMI) was 28.3 (SD ± 4.5), average SBP was 122.4 (SD ± 15.4) mmHg, average DBP was 75.5 (SD ± 9.6) mmHg and 469 (38.1%) study participants were taking at least one AHM. Higher baseline DBP was significantly associated with a faster increase in global T2 (0.22 [0.10,0.35], P &lt; 0.001), global deep layer T2 (0.20 [0.03,0.36], P &lt; 0.022) and global superficial layer T2 (0.39 [0.20,0.58], P &lt; 0.001). These associations were significant in both unadjusted and the models adjusted for age, sex, BMI and KL score. No significant associations were found between SBP or PP and cartilage T2 and no significant interactions were found between SBP, DBP, PP and the covariates. DISCUSSION/SIGNIFICANCE OF IMPACT: Higher baseline DBP was associated with a faster increase in knee cartilage T2, suggesting accelerated cartilage degeneration. This association was stronger for the superficial layer of knee cartilage T2 compared to the deep layer. Although further basic mechanistic studies are needed to elucidate the underlying pathophysiology of this relationship, these results suggest lowering DBP may influence knee OA.

Weight loss regimen in obese and overweight individuals is associated with reduced cartilage degeneration: 96-month data from the Osteoarthritis Initiative

To investigate change in knee cartilage composition over 96 months in overweight and obese participants with constant weight compared to those with weight loss (WL), and to assess how different WL regimens are associated with these changes. We studied right knees of 760 participants (age 62.6±9.0y; 465 females) with a baseline body mass index (BMI) >25 kg/m2 from the Osteoarthritis Initiative with mild to moderate or with risk factors for knee osteoarthritis. Participants losing weight (>5% of baseline BMI over 72 months; N=380) were compared to controls with stable weight (SW, N=380). Participants losing weight were categorized based on WL method (diet and exercise, diet only, exercise only) and compared to those with stable weight. Magnetic resonance imaging (MRI) at 3T was performed at baseline, 48- and 96-months. The association of WL and WL method with change in cartilage composition, measured with T2 mapping, was analyzed using mixed random effects models. Compared to SW, WL was associated with a significantly slower increase in global (averaged over all compartments) cartilage T2 (adjusted mean difference of change in T2 ms/year [95% CI] between the groups: 0.24 [0.20, 0.41] ms/year; P<0.001) and global deep layer cartilage T2 0.35 [0.20, 0.42] ms/year; P<0.001), suggesting slower cartilage deterioration. Compared to the SW group, slower increases in global T2 were observed in the diet and diet and exercise groups, but not in the exercise only group (P=0.042, P=0.003 and P=0.85, respectively). Our results suggest that WL may slow knee cartilage degeneration over 96 months, and that these potential benefits may differ by method of WL.

Spatial distribution and temporal progression of T2 relaxation time values in knee cartilage prior to the onset of cartilage lesions – data from the Osteoarthritis Initiative (OAI)

To investigate compositional changes of knee cartilage at the site of newly appearing cartilage lesions and the surrounding cartilage 1-4 years prior to lesion onset using quantitative T2-measurements. Fifty-seven cartilage plates with newly appearing cartilage lesions from 45 knees (cases) and 52 plates from 26 control knees from the Osteoarthritis Initiative (OAI) cohort (controls) were evaluated. Using MRI T2-mapping, composition of local (the site of future lesions) and surrounding cartilage (remainder of the cartilage plate) was assessed 1-4 years prior to lesion onset. Analogous cartilage ROIs in control plates without cartilage lesions were assessed over 1-4 years. Mixed models were used to compare T2-means and change rates between local and surrounding cartilage within cases and controls, and to compare change rates in local and surrounding cartilage between cases and controls, adjusting for covariates. Four years prior to lesion onset, we found that local cartilage ROIs had higher T2-values compared to the surrounding cartilage. No such differences were found in control plates. In cases mean local T2-values were persistantly elevated compared to the surrounding cartilage prior to lesion onset reaching significance 1 year prior (+2.94ms, p=0.012). T2-values of the surrounding cartilage were also persistantly higher in cases compared to controls, reaching significance 2 years prior to lesion onset (+3.61ms, p=0.003). The findings of our study support the concept of compositional cartilage changes as a mechanism for cartilage degradation and that both diffuse and focal changes of cartilage composition within a cartilage plate precede the development of cartilage lesions.

New advances in MRI diagnosis of degenerative osteoarthropathy of the peripheral joints.

Degenerative osteoarthropathy is one of the leading causes of the pain and disability from musculoskeletal disease in the adult population. Magnetic resonance imaging (MRI) allows optimal visualization of all tissues involved in degenerative osteoarthritis disease process, mainly the articular cartilage. In addition to qualitative and semiquantitative morphologic assessment, several MRI-based advanced techniques have been developed to allow characterization and quantification of the biochemical cartilage composition. These include quantitative analysis and several compositional techniques (T1 and T2 relaxometry measurements and mapping, sodium imaging, delayed gadolinium-enhanced MRI of cartilage dGEMRIC, glycosaminoglycan-specific chemical exchange saturation transfer gagCEST, diffusion-weighted imaging DWI and diffusion tensor imaging DTI). These compositional MRI techniques may have the potential to serve as quantitative, reproducible, noninvasive and objective endpoints for OA assessment, particularly in diagnosis of early and pre-radiographic stages of the disease and in monitoring disease progression and treatment effects over time.