Ursula Heilmeier

Early T2 changes predict onset of radiographic knee osteoarthritis: data from the osteoarthritis initiative

Objective To evaluate whether T2 relaxation time measurements obtained at 3 T MRI predict the onset of radiographic knee osteoarthritis (OA). Materials and methods We performed a nested case–control study of incident radiographic knee OA in the Osteoarthritis Initiative cohort. Cases were 50 knees with baseline Kellgren–Lawrence (KL) grade of 0 that developed KL grade of 2 or more over a 4-year period. Controls were 80 knees with KL grade of 0 after 4 years of follow-up. Baseline T2 relaxation time measurements and laminar analysis of T2 in deep and superficial layers were performed in all knee compartments. The association of T2 values with incident OA was assessed with logistic regression and differences in T2 values by case–control status with linear regression, adjusting for age, sex, body mass index (BMI) and other covariates. Results Baseline T2 values in all compartments except the medial tibia were significantly higher in knees that developed OA compared with controls and were particularly elevated in the superficial cartilage layers in all compartments. There was an increased likelihood of incident knee OA associated with higher baseline T2 values, particularly in the patella, adjusted OR per 1 SD increase in T2 (3.37 (95% CI 1.72 to 6.62)), but also in the medial femur (1.90 (1.07 to 3.39)), lateral femur (2.17 (1.11 to 4.25)) and lateral tibia (2.23 (1.16 to 4.31)). Conclusions These findings suggest that T2 values assessed when radiographic changes are not yet apparent may be useful in predicting the development of radiological tibiofemoral OA.

Serum miRNA Signatures Are Indicative of Skeletal Fractures in Postmenopausal Women With and Without Type 2 Diabetes and Influence Osteogenic and Adipogenic Differentiation of Adipose Tissue-Derived Mesenchymal Stem Cells In Vitro

Standard DXA measurements, including Fracture Risk Assessment Tool (FRAX) scores, have shown limitations in assessing fracture risk in Type 2 Diabetes (T2D), underscoring the need for novel biomarkers and suggesting that other pathomechanisms may drive diabetic bone fragility. MicroRNAs (miRNAs) are secreted into the circulation from cells of various tissues proportional to local disease severity and were recently found to be crucial to bone homeostasis and T2D. Here, we studied, if and which circulating miRNAs or combinations of miRNAs can discriminate best fracture status in a well‐characterized study of diabetic bone disease and postmenopausal osteoporosis (n = 80 postmenopausal women). We then tested the most discriminative and most frequent miRNAs in vitro. Using miRNA‐qPCR‐arrays, we showed that 48 miRNAs can differentiate fracture status in T2D women and that several combinations of four miRNAs can discriminate diabetes‐related fractures with high specificity and sensitivity (area under the receiver‐operating characteristic curve values [AUCs], 0.92 to 0.96; 95% CI, 0.88 to 0.98). For the osteoporotic study arm, 23 miRNAs were fracture‐indicative and potential combinations of four miRNAs showed AUCs from 0.97 to 1.00 (95% CI, 0.93 to 1.00). Because a role in bone homeostasis for those miRNAs that were most discriminative and most present among all miRNA combinations had not been described, we performed in vitro functional studies in human adipose tissue–derived mesenchymal stem cells to investigate the effect of miR‐550a‐5p, miR‐188‐3p, and miR‐382‐3p on osteogenesis, adipogenesis, and cell proliferation. We found that miR‐382‐3p significantly enhanced osteogenic differentiation (p < 0.001), whereas miR‐550a‐5p inhibited this process (p < 0.001). Both miRNAs, miR‐382‐3p and miR‐550a‐5p, impaired adipogenic differentiation, whereas miR‐188‐3p did not exert an effect on adipogenesis. None of the miRNAs affected significantly cell proliferation. Our data suggest for the first time that miRNAs are linked to fragility fractures in T2D postmenopausal women and should be further investigated for their diagnostic potential and their detailed function in diabetic bone.

Circulating microRNAs as novel biomarkers for bone diseases – Complex signatures for multifactorial diseases?

Biomarkers are essential tools in clinical research and practice. Useful biomarkers must combine good measurability, validated association with biological processes or outcomes, and should support clinical decision making if used in clinical practice. Several types of validated biomarkers have been reported in the context of bone diseases. However, because these biomarkers face certain limitations there is an interest in the identification of novel biomarkers for bone diseases, specifically in those that are tightly linked to the disease pathology leading to increased fracture-risk. MicroRNAs (miRNAs) are the most abundant RNA species to be found in cell-free blood. Encapsulated within microvesicles or bound to proteins, circulating miRNAs are remarkably stable analytes that can be measured using gold-standard technologies such as quantitative polymerase-chain-reaction (qPCR). Nevertheless, the analysis of circulating miRNAs faces several pre-analytical as well as analytical challenges. From a biological view, there is accumulating evidence that miRNAs play essential roles in the regulation of various biological processes including bone homeostasis. Moreover, specific changes in miRNA transcription levels or miRNA secretory levels have been linked to the development and progression of certain bone diseases. Only recently, results from circulating miRNAs analysis in patients with osteopenia, osteoporosis and fragility fractures have been reported. By comparing these findings to studies on circulating miRNAs in cellular senescence and aging or muscle physiology and sarcopenia, several overlaps were observed. This suggests that signatures observed during osteoporosis might not be specific to the pathophysiology in bone, but rather integrate information from several tissue types. Despite these promising first data, more work remains to be done until circulating miRNAs can serve as established and robust diagnostic tools for bone diseases in clinical research, clinical routine and in personalized medicine.

A reference database of cartilage 3 T MRI T2 values in knees without diagnostic evidence of cartilage degeneration: data from the osteoarthritis initiative.

OBJECTIVE 1) To establish a gender- and BMI-specific reference database of cartilage T2 values, and 2) to assess the associations between cartilage T2 values and gender, age, and BMI in knees without radiographic osteoarthritis or MRI-based (WORMS 0/1) evidence of cartilage degeneration. DESIGN 481 subjects aged 45-65 years with Kellgren-Lawrence Scores 0/1 in the study knee were selected. Baseline morphologic cartilage 3T MRI readings (WORMS scoring) and T2 measurements (resolution = 0.313 mm × 0.446 mm) were performed in the medial and lateral femurs, medial and lateral tibias, and patella compartments. To create a reference database, a logarithmic transformation was applied to the data to obtain the 5th-95th percentile values for T2. RESULTS Significant differences in mean cartilage T2 values were observed between joint compartments. Although females had slightly higher T2 values than males in a majority of compartments, the differences were only significant in the medial femur (P < 0.0001). A weak positive association was seen between age and T2 in all compartments, most pronounced in the patella (3.27% increase in median T2/10 years, P = 0.009). Significant associations between BMI and T2 were observed, most pronounced in the lateral tibia (5.33% increase in median T2/5 kg/m(2) increase in BMI, P < 0.0001), and medial tibia (4.81% increase in median T2 /5 kg/m(2) increase in BMI, P < 0.0001). CONCLUSIONS This study established the first reference database of T2 values in a large sample of morphologically normal cartilage plates in knees without radiographic knee osteoarthritis (OA). While cartilage T2 values were weakly associated with age and gender, they had the highest correlations with BMI.

In vitro assessment of knee MRI in the presence of metal implants comparing MAVRIC-SL and conventional fast spin echo sequences at 1.5 and 3 T field strength.

To assess lesion detection and artifact size reduction of a multiacquisition variable‐resonance image combination, slice encoding for metal artifact correction (MAVRIC‐SEMAC) hybrid sequence (MAVRIC‐SL) compared to standard sequences at 1.5T and 3T in porcine knee specimens with metal hardware.

High-temporospatial-resolution dynamic contrast-enhanced (DCE) wrist MRI with variable-density pseudo-random circular Cartesian undersampling (CIRCUS) acquisition: evaluation of perfusion in rheumatoid arthritis patients

This study is to evaluate highly accelerated three‐dimensional (3D) dynamic contrast‐enhanced (DCE) wrist MRI for assessment of perfusion in rheumatoid arthritis (RA) patients. A pseudo‐random variable‐density undersampling strategy, circular Cartesian undersampling (CIRCUS), was combined with k–t SPARSE‐SENSE reconstruction to achieve a highly accelerated 3D DCE wrist MRI. Two healthy volunteers and 10 RA patients were studied. Two patients were on methotrexate (MTX) only (Group I) and the other eight were treated with a combination therapy of MTX and anti‐tumor necrosis factor (TNF) therapy (Group II). Patients were scanned at baseline and 3 month follow‐up. DCE MR images were used to evaluate perfusion in synovitis and bone marrow edema pattern in the RA wrist joints. A series of perfusion parameters was derived and compared with clinical disease activity scores of 28 joints (DAS28). 3D DCE wrist MR images were obtained with a spatial resolution of 0.3 × 0.3 × 1.5 mm3 and temporal resolution of 5 s (with an acceleration factor of 20). The derived perfusion parameters, most notably transition time (dT) of synovitis, showed significant negative correlations with DAS28‐ESR (r = −0.80, p < 0.05) and DAS28‐CRP (r = −0.87, p < 0.05) at baseline and also correlated significantly with treatment responses evaluated by clinical score changes between baseline and 3 month follow‐up (with DAS28‐ESR r = −0.79, p < 0.05, and DAS28‐CRP r = −0.82, p < 0.05). Highly accelerated 3D DCE wrist MRI with improved temporospatial resolution has been achieved in RA patients and provides accurate assessment of neovascularization and perfusion in RA joints, showing promise as a potential tool for evaluating treatment responses. Copyright

Association of Physical Activity Measured by Accelerometer, Knee Joint Abnormalities, and Cartilage T2 Measurements Obtained From 3T Magnetic Resonance Imaging: Data From the Osteoarthritis Initiative

To study the cross‐sectional association between physical activity measured with an accelerometer, structural knee abnormalities, and cartilage T2 values assessed with 3T magnetic resonance imaging (MRI).

Racial differences in biochemical knee cartilage composition between African-American and Caucasian-American women with 3 T MR-based T2 relaxation time measurements - data from the Osteoarthritis Initiative

OBJECTIVE To determine whether knee cartilage composition differs between African-American and Caucasian-American women at risk for Osteoarthritis (OA) using in vivo 3 T MRI T2 relaxation time measurements. METHODS Right knee MRI studies of 200 subjects (100 African-American women, and 100 closely matched Caucasian-American women) were selected from the Osteoarthritis Initiative (OAI). Knee cartilage was segmented in the patellar (PAT), medial and lateral femoral (MF/LF), and medial and lateral tibial compartments (MT/LT)). Mean T2 relaxation time values per compartment and per whole joint cartilage were generated and analyzed spatially via laminar and grey-level co-occurrence matrix (GLCM) texture methods. Presence and severity of cartilage lesions per compartment were graded using a modified WORMS grading. Statistical analysis employed paired t- and McNemar testing. RESULTS While African-American women and Caucasian-Americans had similar WORMS cartilage lesion scores (P = 0.970), African-Americans showed significantly lower mean T2 values (∼1 ms difference; ∼0.5SD) than Caucasian-Americans in the whole knee cartilage (P < 0.001), and in the subcompartments (LF: P = 0.001, MF: P < 0.001, LT: P = 0.019, MT: P = 0.001) and particularly in the superficial cartilage layer (whole cartilage: P < 0.001, LF: P < 0.001, MF: P < 0.001, LT: P = 0.003, MT: P < 0.001). T2 texture parameters were also significantly lower in the whole joint cartilage of African-Americans than in Caucasian-Americans (variance: P = 0.001; contrast: P = 0.018). In analyses limited to matched pairs with no cartilage lesions in a given compartment, T2 values remained significantly lower in African-Americans. CONCLUSION Using T2 relaxation time as a biomarker for the cartilage collagen network, our findings suggest racial differences in the biochemical knee cartilage composition between African-American and Caucasian-American women.

Tool for osteoarthritis risk prediction (TOARP) over 8 years using baseline clinical data, X-ray, and MRI: Data from the osteoarthritis initiative

Osteoarthritis (OA), a multifactorial disease causing joint degeneration, often leads to severe disability. The rising rates of disability highlight the need for implementing preventative measures at early stages of the disease, which would especially benefit subjects at high risk for OA development.

Association of diabetes mellitus and biochemical knee cartilage composition assessed by T2 relaxation time measurements: Data from the osteoarthritis initiative

To investigate the association of the presence and severity of diabetes mellitus (DM) with articular cartilage composition, using magnetic resonance imaging (MRI)‐based T2 relaxation time measurements, and structural knee abnormalities.