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ObjectiveTo assess (i) the impact of changes in body weight on changes in joint-adjacent subcutaneous fat (SCF) and cartilage thickness over 4 years and (ii) the relation between changes in joint-adjacent SCF and knee cartilage thickness.DesignIndividuals from the Osteoarthritis Initiative (total=399) with > 10% weight gain (n=100) and > 10% weight loss (n=100) over 4 years were compared to a matched control cohort with less than 3% change in weight (n=199). 3.0T Magnetic Resonance Imaging (MRI) of the right knee was performed at baseline and after 4 years to quantify joint-adjacent SCF and cartilage thickness. Linear regression models were used to evaluate the associations between the (i) weight change group and 4-year changes in both knee SCF and cartilage thickness, and (ii) 4-year changes in knee SCF and in cartilage thickness. Analyses were adjusted for age, sex, baseline body mass index (BMI), tibial diameter (and weight change group in analysis (ii)).ResultsIndividuals who lost weight over 4-years had significantly less joint-adjacent SCF (beta range, medial/lateral joint sides: 2.2-4.2 mm, p

ObjectiveTo determine the longitudinal changes of patellofemoral joint (PFJ) contact pressure following anterior cruciate ligament reconstruction (ACLR). To identify the associations between PFJ contact pressure and cartilage health.DesignForty-nine subjects with hamstring autograft ACLR (27 males; age 28.8 [standard deviation, 8.3] years) and 19 controls (12 males; 30.7 [4.6] years) participated. A sagittal plane musculoskeletal model was used to estimate PFJ contact pressure. A combined T1ρ/T2 magnetic resonance sequence was obtained. Assessments were performed preoperatively, at 6 months, 1, 2, and 3 years postoperatively in ACLR subjects and once for controls. Repeated Analysis of Variance (ANOVA) was used to compare peak PFJ contact pressure between ACLR and contralateral knees, and t-tests to compare with control knees. Statistical parametric mapping was used to evaluate the associations between PFJ contact pressure and cartilage relaxation concurrently and longitudinally.ResultsNo changes in peak PFJ contact pressure were found within ACLR knees over 3 years (preoperative to 3 years, 0.36 [CI, -0.08, 0.81] MPa), but decreased over time in the contralateral knees (0.75 [0.32, 1.18] MPa). When compared to the controls, ACLR knees exhibited lower PFJ contact pressure at all time points (at baseline, -0.64 [-1.25, -0.03] MPa). Within ACLR knees, lower PFJ contact pressure at 6 months was associated with elevated T2 times (r = -0.47 to -0.49, p = 0.021-0.025).ConclusionsUnderloading of the PFJ following ACLR persists for up to 3 years and has concurrent and future consequences in cartilage health. The non-surgical knees exhibited normal contact pressure initially but decreased over time achieving limb symmetry.

OBJECTIVE: The aim of this work was to report the prevalence of computed tomography (CT)-detected intra-articular mineralization. DESIGN: We included participants from the Multicenter Osteoarthritis (MOST) Study. At the 12th year visit of the MOST study, bilateral knee CTs were first obtained. All participants also had posteroanterior and lateral radiographs of bilateral knees and completed standard questionnaires. Knee radiographs were assessed for Kellgren & Lawrence grade (KLG) and radiographic evidence of intra-articular mineralization. CT images were scored using the Boston University Calcium Knee Score (BUCKS) for cartilage, menisci, ligaments, capsule, and vasculature. Prevalence of intra-articular mineralization was computed for the total sample, and stratified by age, sex, race, Body Mass Index (BMI), presence of frequent knee pain, and KLG. We also determined distribution of mineralization in the cartilage and meniscus, and co-localization. RESULTS: 4140 bilateral knees from 2070 participants were included (56.7% female, mean age 61.1 years, mean BMI: 28.8 kg/m2). On radiographs 240 knees (5.8%) had intraarticular mineralization, while CT-detected mineralization was present in 9.8% of knees. Prevalence of hyaline articular and meniscus mineralization increased with age and KL grade, and was similar by sex, BMI categories, and comparable in subjects with and without frequent knee pain. Mineralization tended to be ubiquitous in the joint, most commonly involving all three (medial/lateral tibiofemoral and patellofemoral) compartments (3.1%), while the patellofemoral compartment was the most involved compartment in isolation (1.4%). CONCLUSIONS: CT of the knee provides greater visualization of intra-articular mineralization than radiographs and allows better localization of the crystal deposition within the joint. Further studies should focus on the co-localization of intra-articular crystal deposition and corresponding magnetic resonance imaging (MRI)-features of knee osteoarthritis (OA).

ObjectiveThis study aimed to determine longitudinal associations, including sex-specific differences, between greater knee flexor antagonist coactivation and worsening cartilage morphology in knees with or at risk for osteoarthritis (OA).DesignBaseline measurements were collected at the 60-month visit of a longitudinal osteoarthritis study following community-dwelling participants (MOST). Knee flexor and extensor muscle activity were measured with surface electromyography during a maximal isokinetic knee extension task. MRI analyzed knee cartilage morphology at baseline and 24-month follow-up. Multivariable adjusted logistic regression models were used to assess associations between coactivation level and cartilage morphology worsening.ResultsAnalysis of 373 women (mean ± SD age 67.4 ± 7.3 years and BMI 29.7 ± 5.0 kg/m2) and 240 men (66.5 ± 7.8 years and 29.9 ± 4.5 kg/m2) revealed that women had greater medial (P

ObjectiveEligibility for clinical trials in osteoarthritis (OA) is usually limited to Kellgren-Lawrence (KL) grades 2 and 3 knees. Our aim was to describe the prevalence and severity of cartilage damage in KL 2 and 3 knees by compartment and articular subregion.DesignThe Multicenter Osteoarthritis (MOST) study is a cohort study of individuals with or at risk for knee OA. All baseline MRIs with radiographic disease severity KL2 and 3 were included. Knee MRIs were read for cartilage damage in 14 subregions. We determined the frequencies of no, any and widespread full-thickness cartilage damage by knee compartment, and the prevalence of any cartilage damage in 14 articular subregions.Results665 knees from 665 participants were included (mean age 63.8 ± 7.9 years, 66.5% women). 372 knees were KL2 and 293 knees were KL3. There was no cartilage damage in 78 (21.0%) medial tibio-femoral joint (TFJ), 157 (42.2%) lateral TFJ and 62 (16.7%) patello-femoral joint (PFJ) compartments of KL2 knees, and 17 (5.8%), 115 (39.3%) and 35 (12.0%) compartments, respectively, of KL3 knees. There was widespread full-thickness damage in 94 (25.3%) medial TFJ, 36 (9.7%) lateral TFJ and 176 (47.3%) PFJ compartments of KL2 knees, and 217 (74.1%), 70 (23.9%) and 104 (35.5%) compartments, respectively, of KL3 knees. The subregions most likely to have any damage were central medial femur (80.5%), medial patella (69.8%) and central medial tibia (69.9).ConclusionsKL2 and KL3 knees vary greatly in cartilage morphology. Heterogeneity in the prevalence, severity and location of cartilage damage in in KL2 and 3 knees should be considered when planning disease modifying trials for knee OA.

ObjectiveThe patellofemoral joint is frequently affected by osteoarthritis (PFOA) and is incompletely imaged on radiographs (XR). Weight-Bearing CT (WBCT) could offer advantages for visualization. This study determined the sensitivity, specificity, and accuracy of axial WBCT and lateral XR for detection of PFOA features in comparison with cartilage damage on MRI.DesignA convenience sample of 60 right knees from the MOST cohort were analyzed. WBCT and XR were read for OARSI JSN score and MRI for MOAKS cartilage score by two experienced musculoskeletal radiologists blinded to participant. Using MOAKS scoring on MRI (referent standard), the sensitivity, specificity and accuracy of patellofemoral OARSI JSN scores based on WBCT and XR were compared.ResultsThe mean ± SD age and BMI for the participants included (66.7% women) were 67.6 ± 9.8 years and 30.0 ± 5.3 kg/m2 respectively. WBCT demonstrated significantly greater sensitivity (0.85-0.97 on WBCT vs 0.47-0.57 on XR) and accuracy (0.85-0.92 on WBCT vs 0.48-0.57 on XR) for all parameters except lateral full-thickness cartilage loss (McNemar's test p-values all

ObjectiveInflammation worsens joint destruction in osteoarthritis (OA) and aggravates pain. Saturated and n-6 fatty acids (FAs) increase, whereas n-3 FAs reduce inflammation. We examined whether FA levels affected the development of OA.DesignWe studied participants from the Multicenter Osteoarthritis study (MOST) at risk of developing knee OA. After baseline, repeated knee x-rays and MRIs were obtained and knee symptoms queried through 60 month follow-up. Using baseline fasting samples, serum FAs were analyzed with standard assays. After excluding participants with baseline OA, we defined two sets of cases: those developing radiographic OA and those developing symptomatic OA (knee pain and radiographic OA). Controls did not develop these outcomes. Additionally, we examined worsening of MRI cartilage loss and synovitis and of knee pain using WOMAC and evaluated the number of hand joints affected by nodules. In regression models, we tested the association of each OA outcome with levels of saturated, n-3 and n-6 FAs adjusting for age, sex, BMI, education, race, baseline pain and depressive symptoms.ResultsWe studied 260 cases with incident symptomatic and 259 with incident radiographic OA. Mean age was 61 years (61% women). We found no signficant nor suggestive associations of FA levels with incident OA (e.g., for incident symptomatic OA, OR per s.d. increase in n-3 FA 1.00 (0.85, 1.18) nor with any OA outcome in knee or hand.ConclusionDespite previously described effects on systemic inflammation, blood levels of FAs were not associated with risk of later knee OA or other OA outcomes.

ObjectiveJoint injury rapidly induces expression of primary response genes (PRGs), which activate a cascade of secondary genes that destroy joint tissues and initiate post-traumatic osteoarthritis (PTOA). Bromodomain-containing-protein-4 (Brd4) and cyclin-dependent-kinase-9 (CDK9) cooperatively control the rate-limiting step of PRG transactivation, including pro-inflammatory genes. This study investigated whether Brd4 and CDK9 inhibitors suppress inflammation and prevent PTOA development in vitro and in a mouse PTOA model.MethodsThe effects of Brd4 and CDK9 inhibitors (JQ1 and Flavopiridol) on PRG and associated secondary damage were rigorously tested in different settings. Short-term effects of inflammatory stimuli (IL-1β, IL-6, TNF) on human chondrocyte PRG expression were assessed by RT-PCR and microarray after 5-h. We quantified glycosaminoglycan release from IL-1β-treated bovine cartilage explants after 3-6 days, and osteoarthritic changes in mice after ACL-rupture using RT-PCR (2-24hrs), in vivo imaging of MMP activity (24hrs), AFM-nanoindentation (3-7days), and histology (3days-4wks).ResultsFlavopiridol and JQ1 inhibitors act synergistically, and a combination of both almost completely prevented the activation of most IL-1β-induced PRGs in vitro by microarray analysis, and prevented IL-1β-induced glycosaminoglycan release from cartilage explants. Mice given the drug combination showed reduced IL-1β and IL-6 expression, less in vivo MMP activity, and lower synovitis (1.5 vs 4.9) and OARSI scores (2.8 vs 6.0) than untreated mice with ACL-rupture.ConclusionsJQ1 and Flavopiridol work synergistically to reduce injury response after joint trauma, suggesting that targeting Brd4 and/or CDK9 could be a viable strategy for PTOA prevention and treatment of early OA.

ObjectiveTo determine if presence of calcium-containing crystals (CaC) is associated with increased knee joint degeneration over 4 years and assess if total number of CaCs deposited is a useful measure of disease burden.DesignSeventy subjects with CaCs in right knees at baseline were selected from the Osteoarthritis Initiative and matched to 70 subjects without evidence of CaCs. T1-weighted gradient-echo sequences were used to confirm presence of CaCs and count the numbers of distinct circumscribed CaCs. Morphological abnormalities were assessed at baseline and 4-year follow-up using the modified semi-quantitative Whole-Organ Magnetic Resonance Imaging Score (WORMS). Linear regression models were used to analyze the associations between presence of CaCs at baseline and changes in WORMS and to analyze the associations between numbers of circumscribed CaCs at baseline and changes in WORMS.ResultsPresence of CaCs was associated with increased cartilage degeneration in the patella (coefficient: 0.33; 95% confidence interval (CI): 0.04-0.63), the medial femur (coefficient: 0.51; 95% CI: 0.18-0.83), the lateral tibia (coefficient: 0.36; 95% CI: 0.01-0.71) as well as the medial and lateral meniscus (coefficient: 0.38; 95% CI: 0.00-0.75 and coefficient: 0.72; 95% CI: 0.12-1.32). Knees with higher numbers of CaCs had increased cartilage degeneration in the patella and medial femur (coefficient: 0.09; 95% CI: 0.05-0.14; P

ObjectiveWe aim to study to what extent conventional and deep-learning-based T2 relaxometry patterns are able to distinguish between knees with and without radiographic osteoarthritis (OA).MethodsT2 relaxation time maps were analyzed for 4,384 subjects from the baseline Osteoarthritis Initiative (OAI) Dataset. Voxel Based Relaxometry (VBR) was used for automatic quantification and voxel-based analysis of the differences in T2 between subjects with and without radiographic OA. A Densely Connected Convolutional Neural Network (DenseNet) was trained to diagnose OA from T2 data. For comparison, more classical feature extraction techniques and shallow classifiers were used to benchmark the performance of our algorithm's results. Deep and shallow models were evaluated with and without the inclusion of risk factors. Sensitivity and Specificity values and McNemar test were used to compare the performance of the different classifiers.ResultsThe best shallow model was obtained when the first ten Principal Components, demographics and pain score were included as features (AUC = 77.77%, Sensitivity = 67.01%, Specificity = 71.79%). In comparison, DenseNet trained on raw T2 data obtained AUC = 83.44%, Sensitivity = 76.99%, Specificity = 77.94%. McNemar test on two misclassified proportions form the shallow and deep model showed that the boost in performance was statistically significant (McNemar's chi-squared = 10.33, degree of freedom (DF) = 1, P-value = 0.0013).ConclusionIn this study, we presented a Magnetic Resonance Imaging (MRI)-based data-driven platform using T2 measurements to characterize radiographic OA. Our results showed that feature learning from T2 maps has potential in uncovering information that can potentially better diagnose OA than simple averages or linear patterns decomposition.

OBJECTIVE:A recent randomized clinical trial reported that repeated intra-articular corticosteroids (IACs) were associated with a greater cartilage loss. This study aimed to examine the relation of IACs to knee radiographic osteoarthritis (ROA) progression in a real-world setting. DESIGN:A cohort that initiated IACs and a comparison cohort without IACs from participants with mild to moderate knee ROA in the Osteoarthritis Initiative (OAI) were assembled (from 0-month to 48-month). Two measures of knee ROA progression were assessed during the follow-up period: (1) an increase in Kellgren and Lawrence (KL) grade by ≥1 grade or having a knee replacement (i.e., KL grade worsening); and (2) a decrease in joint space width (JSW) by ≥0.7 mm or having a knee replacement (i.e., JSW worsening). The associations of IACs initiation using a propensity-score matched cohort study and continuous IACs using marginal structural models with the risk of knee ROA progression were examined. RESULTS:Among 684 propensity-score matched participants at baseline (148 IACs initiators, 536 comparators), 65 knees (21.7/100 person-years) in the IACs initiation cohort and 90 knees (7.1/100 person-years) in the comparison cohort experienced KL worsening. The hazard ratios (HRs) of KL worsening from IACs initiation and continuous IACs were 3.02 (95% confidence interval [CI], 2.19-4.16) and 4.67 (95% CI, 2.92-7.47), respectively. The corresponding HRs of JSW worsening were 2.93 (95% CI, 2.13-4.02) and 3.26 (95% CI, 1.78-5.96), respectively. All HRs for continuous use of IACs were further away from the null. CONCLUSIONS:IACs, especially continuous IACs, may be associated with an increased risk of knee ROA progression.

Purpose(1) To identify bone-shape changes from baseline to 3-years after anterior cruciate ligament reconstruction (ACLR). (2) to assess association between changes in bone-shape from baseline to 6-months and changes in cartilage matrix and patient functions and symptoms from baseline to 3-years after ACLR.MethodsBilateral knees of 30 patients with unilateral ACL injuries were scanned at baseline, 6-months, 1-, 2-, and 3-years after ACLR. Bilateral knees of 13 controls were scanned at baseline, 1- and 3-years. Mean T1ρ and T2 values of each cartilage compartment were computed. Bone shape was quantified using statistical shape modeling (SSM) and 3D-MRI. Patient functions and symptoms were evaluated using Knee Injury and Osteoarthritis Outcome Score (KOOS).ResultsStatistically significant changes were observed in Femur 2 (medial femoral condyle [MF] shape), Femur 6 (intercondylar notch width), Tibia 1 (tibia plateau area), and Tibia 7 (medial tibia slope) over 3-years after ACLR. Statistically significant differences were observed between injured and control knees in several modes. Statistically significant correlations were found between changes in bone shape (ΔFemur 6, ΔFemur 8 [trochlea inclination and MF height], ΔTibia 1) from baseline to 6-months and that of cartilage T1ρ and T2 and KOOS from baseline to 3-years after ACLR.ConclusionBone shape remodeling occurs after ACLR, and early bone shape changes (within 6 months) correlated with cartilage matrix and patient outcomes at 3-years after ACLR. Bone shape can be a promising imaging biomarker that stratifies patients at high risk for post-traumatic osteoarthritis (PTOA).

PurposeTo 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.MethodsWe 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.ResultsCompared 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

ObjectiveIntradiscal biologic therapy is a promising strategy for managing intervertebral disc degeneration. However, these therapies require a rich nutrient supply, which may be limited by the transport properties of the cartilage endplate (CEP). This study investigated how fluctuations in CEP transport properties impact nutrient diffusion and disc cell survival and function.DesignHuman CEP tissues harvested from six fresh cadaveric lumbar spines (38-66 years old) were placed at the open sides of diffusion chambers. Bovine nucleus pulposus (NP) cells cultured inside the chambers were nourished exclusively by nutrients diffusing through the CEP tissues. After 72 h in culture, depth-dependent NP cell viability and gene expression were measured, and related to CEP transport properties and biochemical composition determined using fluorescence recovery after photobleaching and Fourier transform infrared (FTIR) spectroscopy.ResultsSolute diffusivity varied nearly 4-fold amongst the CEPs studied, and chambers with the least permeable CEPs appeared to have lower aggrecan, collagen-2, and matrix metalloproteinase-2 gene expression, as well as a significantly shorter viable distance from the CEP/nutrient interface. Increasing chamber cell density shortened the viable distance; however, this effect was lost for low-diffusivity CEPs, which suggests that these CEPs may not provide enough nutrient diffusion to satisfy cell demands. Solute diffusivity in the CEP was associated with biochemical composition: low-diffusivity CEPs had greater amounts of collagen and aggrecan, more mineral, and lower cross-link maturity.ConclusionsCEP transport properties dramatically affect NP cell survival/function. Degeneration-related CEP matrix changes could hinder the success of biologic therapies that require increased nutrient supply.

PurposeTo 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.MethodsFifty-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.ResultsFour 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 (+2.94 ms, 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 (+3.61 ms, p = 0.003).ConclusionThe 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.

ObjectiveThe purpose of this study was to assess the associations between serum/urine biomarkers for osteoarthritis and magnetic resonance (MR) imaging measures of cartilage composition and joint structure (cartilage, meniscus, and bone marrow), using MR imaging data from the Osteoarthritis Initiative (OAI).Design141 subjects with Kellgren Lawrence (KL) grades 0-3 in the right knee and with available serum/urine biomarker assays were selected from the OAI. Cartilage magnetic resonance imaging (MRI) T2 measurements were performed in the medial femur, lateral femur, medial tibia, lateral tibia, and patella compartments. Compartment-specific knee morphologic grading [whole-organ magnetic resonance imaging score (WORMS)] in the cartilage, meniscus, and bone marrow was also performed. We focused on associations of serum hyaluronan (sHA), serum cartilage oligomeric matrix protein (sCOMP), serum matrix metalloproteinase-3 (sMMP3), and Urine Carboxy-Terminal Telepeptides of Type II Collagen (uCtX-II)) with MRI parameters (T2, WORMS), assessed using partial correlations adjusted for age, gender, body mass index (BMI), KL grade in both knees, and diabetes status.ResultsHigher levels of sHA, sMMP3 and sCOMP were correlated (P

PURPOSE:3D Magnetic resonance imaging (MRI) scans are generally used for quantitative cartilage measurements in knee osteoarthritis. However, a great deal of MRI data is from 2D scans, often thought to be unsuitable for quantitative cartilage assessment. The goal of our study was to demonstrate that mLACS, a modified version of the Local Area Cartilage Segmentation (LACS) method, could be used to measure cartilage volume on 2D MRI images. METHODS:We studied 301 randomly selected subjects from the OA Biomarkers Consortium FNIH Study, a nested case-control study within the Osteoarthritis Initiative (OAI). The study comprised four subgroups based on radiographic and pain progression. We compared mLACS applied to 2D TSE scans to LACS on 3D DESS data. The Pearson's correlation coefficient was used to establish agreement between LACS and mLACS, standardized response means (SRMs) for responsiveness, and intra-class correlation coefficients (ICCs) to measure reader precision. Logistic regression in a case/control analysis was used to compare the clinical validity between the two methods. RESULTS:We found R2 = 0.76 for the correlation between LACS and mLACs. For LACS, the responsiveness was SRM = 0.49 compared to 0.39 for mLACS. The odds ratios (OR) for the primary case/control analyses were 1.62 for LACS and 1.78 for mLACS. The intra and inter reader reproducibility values for mLACS were ICC = 0.90 and 0.86, respectively. CONCLUSION:This study has demonstrated that a reproducible, responsive, and clinically valid quantitative measurement of cartilage volume can be made using 2D TSE scans with a modest loss of responsiveness compared to 3D scans.

OBJECTIVE:To determine the relationship of meniscal damage to magnetic resonance imaging (MRI) features of compartment-specific patellofemoral joint (PFJ) osteoarthritis (OA) at baseline and 2 years later. METHOD:Individuals from a prospective cohort of individuals aged 50-79 with or at risk of knee OA were included. At the 60-month and 84-month study visit, Whole-Organ MRI Score (WORMS) was used to assess meniscal tears and extrusions as well as cartilage damage and bone marrow lesions (BMLs) in the medial and lateral patella and trochlea. Worsening of structural features was defined as any increase in WORMS score from 60 to 84 months. Logistic regression was used to determine the cross-sectional and longitudinal relation of meniscus damage to features of compartment-specific PFJ OA. RESULTS:Relative to knees without lateral meniscal pathology at baseline, those with grades 3-4 lateral meniscal tear and extrusion had greater risk of worsening of cartilage damage in the lateral PFJ 2 years later (Risk ratio: 1.7 [95% CI: 1.1-2.7) and (1.7 [1.2-2.5]), respectively. Relative to those without medial meniscal pathology at baseline, those with grades 1-2 (0.6 [0.4-0.9]) and 3-4 (0.7 [0.5-1.0]) medial meniscal tears had lower risk of worsening of BMLs in the medial PFJ 2 years later. CONCLUSION:Meniscal tear and extrusion are associated with increased risk of medial and lateral PFJ OA and more severe meniscal pathology is associated with worsening of PFJ OA 2 years later. Lateral meniscal pathology appears to be more detrimental to the lateral PFJ.

OBJECTIVE:To investigate changes in bone metabolism by positron emission tomography (PET), as well as spatial relationships between bone metabolism and magnetic resonance imaging (MRI) quantitative markers of early cartilage degradation, in anterior cruciate ligament (ACL)-reconstructed knees. DESIGN:Both knees of 15 participants with unilateral reconstructed ACL tears and unaffected contralateral knees were scanned using a simultaneous 3.0T PET-MRI system following injection of 18F-sodium fluoride (18F-NaF). The maximum pixel standardized uptake value (SUVmax) in the subchondral bone and the average T2 relaxation time in cartilage were measured in each knee in eight knee compartments. We tested differences in SUVmax and cartilage T2 relaxation times between the ACL-injured knee and the contralateral control knee as well as spatial relationships between these bone and cartilage changes. RESULTS:Significantly increased subchondral bone 18F-NaF SUVmax and cartilage T2 times were observed in the ACL-reconstructed knees (median [inter-quartile-range (IQR)]: 5.0 [5.8], 36.8 [3.6] ms) compared to the contralateral knees (median [IQR]: 1.9 [1.4], 34.4 [3.8] ms). A spatial relationship between the two markers was also seen. Using the contralateral knee as a control, we observed a significant correlation of r = 0.59 between the difference in subchondral bone SUVmax (between injured and contralateral knees) and the adjacent cartilage T2 (between the two knees) [P

PurposeOsteoarthritis (OA) and diabetes mellitus (DM) share common risk factors with a potential underlying relationship between both diseases. The purpose of this study was to investigate the longitudinal effects of DM on cartilage deterioration over 24-months with MR-based T2 relaxation time measurements.MethodsFrom the Osteoarthritis Initiative (OAI) cohort 196 diabetics were matched in small sets for age, sex, BMI and Kellgren-Lawrence score with 196 non-diabetic controls. Knee cartilage semi-automatic segmentation was performed on 2D multi-slice multi-echo spin-echo sequences. Texture of cartilage T2 maps was obtained via grey level co-occurrence matrix analysis. Linear regression analysis was used to compare cross-sectional and changes in T2 and texture parameters between the groups.ResultsBoth study groups were similar in age (63.3 vs 63.0 years, P = 0.70), BMI (30.9 vs 31.2 kg/m2, P = 0.52), sex (female 53.6% vs 54.1%, P = 0.92) and KL score distribution (P = 0.97). In diabetics, except for the patella, all compartments showed a significantly higher increase in mean T2 values when compared to non-diabetic controls. Global T2 values increased almost twice as much; 1.77ms vs 0.98ms (0.79ms [CI: 0.39,1.19]) (P

ObjectiveTo evaluate the longitudinal changes in meniscal T1ρ/T2 signal post-reconstruction in patients with acute anterior cruciate ligament (ACL) injury and to investigate the association with T1ρ/T2 signal in articular knee cartilage.MethodIn this prospective study, knees of 37 patients with ACL-injury and reconstruction in addition to 13 healthy controls were scanned using magnetic resonance imaging (MRI) T1ρ/T2 mapping. Quantitative analysis of the meniscus was performed in the anterior/posterior horns of lateral/medial meniscus fourteen sub-compartments of cartilage spanning the medial/lateral area of the tibia and femoral condyles. Meniscus T1ρ/T2 signals were compared between injured, contralateral and control knees at baseline, 6-months, 1-year and 2-years using t-tests for cross-sectional comparisons and a mixed model for longitudinal comparisons. Pearson-partial correlations between meniscal and cartilage T1ρ/T2 were evaluated.ResultsThere was a significant decrease of T1ρ/T2 signal in the posterior horn of lateral meniscus (PHLAT) of injured knees during a 2-year period. In the posterior horn of medial meniscus (PHMED), T1ρ/T2 signal of injured knees was significantly elevated at all time points post-reconstruction compared to contralateral and control knees. Within injured knees, PHMED T1ρ/T2 signal showed significant positive correlations with medial tibia (MT) cartilage T1ρ/T2 signal at all time points.ConclusionA significant decrease in PHLAT T1ρ/T2 signal by 2-years suggests potential tissue recovery after ACL-injury. Elevated T1ρ/T2 signal in the PHMED of injured knees at 2-years correlating with knee cartilage T1ρ/T2 signal elevations suggests involvement of the PHMED in subacute cartilage degeneration after ACL-injury and reconstruction.

ObjectivesOsteoarthritis (OA) is a degenerative disease characterized by loss of cartilage and increased subchondral bone within synovial joints. Wnt signaling affects the pathogenesis of OA as this pathway modulates both the differentiation of osteoblasts and chondrocytes, and production of catabolic proteases. A novel small-molecule Wnt pathway inhibitor, SM04690, was evaluated in a series of in vitro and in vivo animal studies to determine its effects on chondrogenesis, cartilage protection and synovial-lined joint pathology.DesignA high-throughput screen was performed using a cell-based reporter assay for Wnt pathway activity to develop a small molecule designated SM04690. Its properties were evaluated in bone-marrow-derived human mesenchymal stem cells (hMSCs) to assess chondrocyte differentiation and effects on cartilage catabolism by immunocytochemistry and gene expression, and glycosaminoglycan breakdown. In vivo effects of SM04690 on Wnt signaling, cartilage regeneration and protection were measured using biochemical and histopathological techniques in a rodent acute cruciate ligament tear and partial medial meniscectomy (ACLT + pMMx) OA model.ResultsSM04690 induced hMSC differentiation into mature, functional chondrocytes and decreased cartilage catabolic marker levels compared to vehicle. A single SM04690 intra-articular (IA) injection was efficacious in a rodent OA model, with increased cartilage thickness, evidence for cartilage regeneration, and protection from cartilage catabolism observed, resulting in significantly improved Osteoarthritis Research Society International (OARSI) histology scores and biomarkers, compared to vehicle.ConclusionsSM04690 induced chondrogenesis and appeared to inhibit joint destruction in a rat OA model, and is a candidate for a potential disease modifying therapy for OA.

ObjectiveThe aim of this study was to determine the ability of undenatured native chicken type II collagen (UC-II) to prevent excessive articular cartilage deterioration in a rat model of osteoarthritis (OA).MethodsTwenty male rats were subjected to partial medial meniscectomy tear (PMMT) surgery to induce OA. Immediately after the surgery 10 rats received vehicle and another 10 rats oral daily dose of UC-II at 0.66 mg/kg for a period of 8 weeks. In addition 10 naïve rats were used as an intact control and another 10 rats received sham surgery. Study endpoints included a weight-bearing capacity of front and hind legs, serum biomarkers of bone and cartilage metabolism, analyses of subchondral and cancellous bone at the tibial epiphysis and metaphysis, and cartilage pathology at the medial tibial plateau using histological methods.ResultsPMMT surgery produced moderate OA at the medial tibial plateau. Specifically, the deterioration of articular cartilage negatively impacted the weight bearing capacity of the operated limb. Immediate treatment with the UC-II preserved the weight-bearing capacity of the injured leg, preserved integrity of the cancellous bone at tibial metaphysis and limited the excessive osteophyte formation and deterioration of articular cartilage.ConclusionStudy results demonstrate that a clinically relevant daily dose of UC-II when applied immediately after injury can improve the mechanical function of the injured knee and prevent excessive deterioration of articular cartilage.

Objective: This study aims to establish an accurate and robust imaging biomarker for pre-clinical osteoarthritis (OA) research, focusing on early detection of cartilage surface degeneration., Method: Using 50 male Wistar rats, this study aims to observe Collagenase-induced OA (CIOA) progression through microcomputed x-ray tomography (µCT), histopathological analysis, and gait analysis. A novel parameter, Cartilage Roughness Score (CRS), was developed for assessing cartilage structural damage from µCT data and was compared with histological OARSI Cartilage Degeneration Score (OARSI CDS). Additionally, as CRS maps the full surface, it was used to simulate the level of uncertainty in histological sampling., Results: CRS and OARSI CDS have a linear relationship. CRS for healthy cartilage is 2.75 (95% CI: 1.14-4.36), and with every 1 unit increase in OARSI, CRS is expected to increase by 0.64 (95% CI: 0.35-0.92). Cartilage degeneration due to CIOA was evident in both histopathological scoring and CRS. However, only CRS was sensitive enough to show consistent damage progression from day 10 to day 60. Furthermore, our simulation for histological sampling suggested that up to 16 coronal slices with 200 µm spacing would be needed to accurately represent the full extent of cartilage surface degeneration in a slice-wise manner. Gait analysis showed changes solely at eight days post-collagenase injection, normalizing by day 60., Conclusion: The CRS analysis method emerges as a robust tool for cartilage surface damage assessment. This study demonstrates the potential of automatic 3D analysis over the traditional 2D histological approach when evaluating cartilage surface damage., Competing Interests: Conflict of interest Authors report no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Sufficient evidence within the past two decades have shown that osteoarthritis (OA) has a sex-specific component. However, efforts to reveal the biological causes of this disparity have emerged more gradually. In this narrative review, we discuss anatomical differences within the knee, incidence of injuries in youth sports, and metabolic factors that present early in life (childhood and early adulthood) that can contribute to a higher risk of OA in females., Design: We compiled clinical data from multiple tissues within the knee joint-since OA is a whole joint disorder-aiming to reveal relevant factors behind the sex differences from different perspectives., Results: The data gathered in this review indicate that sex differences in articular cartilage, meniscus, and anterior cruciate ligament are detected as early as childhood and are not only explained by sex hormones. Aiming to unveil the biological causes of the uneven sex-specific risks for knee OA, we review the current knowledge of sex differences mostly in young, but also including old populations, from the perspective of (i) human anatomy in both healthy and pathological conditions, (ii) physical activity and response to injury, and (iii) metabolic signatures., Conclusions: We propose that to close the gap in health disparities, and specifically regarding OA, we should address sex-specific anatomic, biologic, and metabolic factors at early stages in life, as a way to prevent the higher severity and incidence of OA in women later in life., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Osteoarthritis is a common and complex joint disorder that shows higher prevalence and greater disease severity in women. Here, we investigate genome-wide methylation profiles of primary chondrocytes from osteoarthritis patients., Design: We compare genome-wide methylation profiles of macroscopically intact (low-grade) and degraded (high-grade) osteoarthritis cartilage samples matched from osteoarthritis patients undergoing knee replacement surgery. We perform an epigenome-wide association study for cartilage degeneration across 170 patients and separately in 96 women and 74 men., Results: We reveal widespread epigenetic differences with enrichments of nervous system and apoptosis-related processes. We further identify substantial similarities between sexes, but also sex-specific markers and pathways., Conclusions: Together, we provide the largest genome-wide methylation profiles of primary cartilage to date with enhanced and sex-specific insights into epigenetic processes underlying osteoarthritis progression., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Understanding gender-specific differences in patterns of cartilage loss can improve our knowledge of the pathogenesis of knee osteoarthritis (KOA) development and progression and may inform clinical trials of treatments for KOA. The goal of our observational study was to examine gender differences in patterns of cartilage loss in the central weight-bearing regions of the femur., Methods: We measured cartilage volume change in the indexed knee of 700 subjects with Kellgren-Lawrence 1, 2, or 3 from the Osteoarthritis Initiative for four follow-up periods (baseline [BL] to 24 mo, BL to 48 mo, BL to 72 mo, and BL to 96 mo) using the local area cartilage segmentation (LACS) method. Briefly, the LACS method uses robust coordinate systems fixed to anatomical landmarks to measure patterns of change in cartilage volume in sub-regions using responsiveness heat maps., Results: We observed a statistically significant gender difference in cartilage change in the medial femur (MF), lateral femur (LF), and medial tibia. The heat maps showed loss was primarily in the posterior central weight-bearing portion of the LF and more general in the LT and MF. Similar patterns were observed for each of the four follow-up periods., Conclusions: The LACS method was capable of illustrating gender-specific differences in patterns of cartilage loss that may offer insight into the variation of gender differences in the natural history of KOA and may be useful in evaluating the benefit of interventions for KOA., (Copyright © 2024 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: AMP-activated protein kinase (AMPK) dysregulation is implicated in osteoarthritis (OA), but the mechanisms underlying this dysregulation remain unclear. We investigated the role of cereblon, a substrate-recognition protein within the E3-ligase ubiquitin complex, in AMPK dysregulation and OA pathogenesis., Methods: Cereblon expression was examined in human (n=5) and mouse (n=10) OA cartilage. The role of cereblon was investigated through its adenoviral overexpression (n=10) or knockout (KO, n=15) in destabilization of the medial meniscus (DMM)-operated mice. The therapeutic potentials of the chemical cereblon degrader, TD-165, and the AMPK activator, metformin, were assessed through intra-articular (IA) injection to mice (n=15)., Results: Immunostaining revealed that cereblon is upregulated in human and mouse OA cartilage. In DMM model mice, cartilage destruction was exacerbated by overexpression of cereblon in mouse joint tissues (OARSI grade; 1.11 [95% CI: 0.50 to 2.75]), but inhibited in global (-2.50 [95% CI: -3.00 to -1.17]) and chondrocyte-specific (-2.17 [95% CI: -3.14 to -1.06]) cereblon KO mice. The inhibitory effects were more pronounced in mice fed a high-fat diet compared to a regular diet. The degradation of cereblon through IA injection of TD-165 inhibited OA cartilage destruction (-2.47 [95% CI: -3.22 to -1.56]). Mechanistically, cereblon exerts its catabolic effects by negatively modulating AMPK activity within chondrocytes. Consistently, activation of AMPK by IA injection of metformin inhibited posttraumatic OA cartilage destruction (-1.20 ([95% CI: -1.89 to -0.45])., Conclusions: The cereblon-AMPK axis acts as a catabolic regulator of OA pathogenesis and seems to be a promising therapeutic target in animal models of OA., (Copyright © 2024. Published by Elsevier Ltd.)

Objective: Based on our recent study, which showed that cartilage fatigue failure in reciprocating sliding contact results from cyclical compressive forces, not from cyclical frictional forces, we hypothesize that a major functional role for synovial fluid (SF) is to reduce the rate of articular cartilage fatigue failure from cyclical compressive loading., Design: The rate of cartilage fatigue failure due to repetitive compressive loading was measured by sliding a glass lens against an immature bovine cartilage tibial plateau strip immersed in mature bovine SF, phosphate-buffered saline (PBS), or SF/PBS dilutions (50% SF and 25% SF; n=8 for all four bath conditions). After 24 hours of reciprocating sliding (5,400 cycles), samples were visually assessed and if damage was observed, the test was terminated; otherwise, testing was continued for 72 hours (16,200 cycles), with solution refreshed daily., Results: All eight samples in the PBS group exhibited physical damage after 24 hours, with an average final surface roughness of R q =0.210±0.067 mm. The SF group showed no damage after 24 hours; however, two of eight samples became damaged after 72 hours, producing a significantly lower average surface roughness than the PBS group (R q =0.059±0.030 mm; p<10 -4 ). For the remaining groups, at 72 hours one of eight samples damaged in the 50% SF group, and five of eight samples damaged in the 25% SF group., Conclusions: The results strongly support our hypothesis, showing that decreased amounts of SF in the testing bath produces increased rates of fatigue failure in cartilage that was subjected to reciprocating sliding contact., (Copyright © 2024. Published by Elsevier Ltd.)

Objective: Traumatic meniscal injuries can cause acute pain, hemarthrosis (bleeding into the joint), joint immobility, and post-traumatic osteoarthritis (PTOA). However, the exact mechanism(s) by which PTOA develops following meniscal injuries is unknown. Since meniscus tears commonly coincide with hemarthrosis, investigating the direct effects of blood and its constituents on meniscus tissue is warranted. The goal of this study was to determine the direct effects of blood and blood components on meniscus tissue catabolism., Methods: Porcine meniscus explants or primary meniscus cells were exposed to whole blood or various fractions of blood for 3 days to simulate blood exposure following injury. Explants were then washed and cultured for an additional 3 days prior to collection for biochemical analyses., Results: Whole blood increased matrix metalloproteinase (MMP) activity. Fractionation experiments revealed blood-derived red blood cells did not affect meniscus catabolism. Conversely, viable mononuclear leukocytes induced MMP activity, nitric oxide (NO) production, and loss of tissue sulfated glycosaminoglycan (sGAG) content, suggesting that these cells are mediating meniscus catabolism., Conclusions: These findings highlight the potential challenges of meniscus healing in the presence of hemarthrosis and the need for further research to elucidate the in vivo effects of blood and blood-derived mononuclear leukocytes due to both hemarthrosis and blood-derived therapeutics., (Copyright © 2024 Osteoarthritis Research Society International. All rights reserved.)

ObjectiveTo assess the associations of atrophic tibiofemoral osteoarthritis (OA) with progression of radiographic joint space narrowing (JSN) and magnetic resonance imaging (MRI)-defined progression of cartilage damage.DesignParticipants of the Multicenter Osteoarthritis (MOST) Study with available radiographic and MRI assessments at baseline and 30 months were included. The atrophic OA phenotype was defined as Osteoarthritis Research Society International (OARSI) grades 1 or 2 for JSN and grade 0 for osteophytes. Based on MRI, atrophic OA was defined as tibiofemoral (TF) cartilage damage grades ≥3 in at least 2 of 10 subregions with absent or tiny osteophytes in all TF subregions. Progression of JSN and cartilage loss on MRI, was defined as (1) no, (2) slow, and (3) fast progression. Co-variance and logistic regression with generalized estimated equations were performed to assess the association of atrophic knee OA with any progression, compared to non-atrophic OA knees.ResultsA total of 476 knees from 432 participants were included. There were 50 (10.5%) knees with atrophic OA using the radiographic definition, and 16 (3.4%) knees with atrophic OA using MRI definition. Non-atrophic OA knees more commonly exhibited fast progression of JSN and cartilage damage. Logistic regression showed that the atrophic phenotype of knee OA was associated with a decreased likelihood of progression of JSN and cartilage loss.ConclusionIn this sample, the atrophic phenotype of knee OA was associated with a decreased likelihood of progression of JSN and cartilage loss compared to the non-atrophic knee OA phenotype.

PurposeTo determine the relation of superolateral Hoffa's fat pad (SHFP) hyperintensity to cartilage damage and bone marrow lesions (BMLs) in the patellofemoral joint (PFJ) and tibiofemoral joint (TFJ).MethodsWe used data from the 60 and 84-month study visits from the Multicenter Osteoarthritis (MOST) study. SHFP hyperintensity and Hoffa-synovitis were graded from 0 to 3. Cartilage damage and BMLs were scored in the PFJ and TFJ. Structural damage was defined as: any cartilage damage, full-thickness cartilage damage and any BML. Worsening structural damage was defined as any increase in cartilage and BML scores. Logistic regression was used to determine the relation of SHFP hyperintensity and Hoffa-synovitis (>0) to structural damage, adjusting for age, sex and body mass index (BMI).Results1,094 knees were included in the study. Compared to knees without SHFP hyperintensity, those with SHFP hyperintensity had 1.2 (95% Confidence Interval (CI), 1.1-1.4), 1.7 (1.3-2.3) and 1.6 (1.3-1.9) times the prevalence of any cartilage damage, full-thickness cartilage damage, and BMLs in the lateral PFJ respectively, and 1.1 (1.0-1.2), 1.3 (1.0-1.8), and 1.2 (1.0-1.4) times the prevalence of any cartilage damage, full-thickness cartilage damage, and BMLs in the medial PFJ. SHFP hyperintensity was associated with worsening BMLs in the medial PFJ (RR: 1.4 (1.0-1.9)). In general, there was no relation between SHFP hyperintensity and TFJ outcomes. Hoffa-synovitis was associated both cross-sectionally and longitudinally with structural damage, regardless of definition, in all compartments.ConclusionSHFP hyperintensity may be a local marker of PFJ structural damage.

ObjectiveLarge studies of knee osteoarthritis (KOA) require well-characterized efficient methods to assess progression. We previously developed the local-area cartilage segmentation (LACS) software method, to measure cartilage volume on magnetic resonance imaging (MRI) scans. The present study further validates this method in a larger patient cohort and assesses predictive validity in a case-control study.MethodThe OA Biomarkers Consortium FNIH Project, a case-control study of KOA progression nested within the Osteoarthritis Initiative (OAI), includes 600 subjects in four subgroups based on radiographic and pain progression. Our software tool measured change in medial femoral cartilage volume in a central weight-bearing region. Different sized regions of cartilage were assessed to explore their sensitivity to change. The readings were performed on MRI scans at the baseline and 24-month visits. We used standardized response means (SRMs) for responsiveness and logistic regression for predictive validity.ResultsCartilage volume change was associated strongly with radiographic progression (odds ratios (OR) = 4.66; 95% confidence intervals (CI) = 2.85-7.62). OR were significant but of lesser magnitude for the combined radiographic and pain progression outcome (OR = 1.70; 95% CI = 1.40-2.07). For the full 600 subjects, theSRM was -0.51 for the largest segmented area. Smaller areas of cartilage segmentation were also able to predict the case-control status. The average reader time for the largest area was less than 20 min per scan. Smaller areas could be assessed with less reader time.ConclusionWe demonstrated that the LACS method is fast, responsive, and associated with radiographic and pain progression, and is appropriate for existing and future large studies of KOA.

ObjectiveAmong high risk individuals, whether knee lesions in tissues involved in osteoarthritis (OA) can improve prediction of knee OA is unclear. We hypothesized that models predicting (1) incident osteophytes and (2) incident osteophytes and joint space narrowing can be improved by including symptoms or function, and further improved by lesion status.DesignIn Osteoarthritis Initiative (OAI) participants with normal knee X-rays, we assessed cartilage damage, bone marrow lesions (BMLs), and menisci. Cox proportional hazards models were used to develop risk prediction models for risk of each outcome. Nested models (increasingly larger baseline covariable sets) were compared using likelihood ratio tests and Schwarz Bayesian Information Criterion (SBC). Model discrimination used receiver operating characteristic (ROC) curves and area under the curve (AUC).ResultsIn 841 participants [age 59.6, body mass index (BMI) 26.7, 55.9% women] over up to 7 years follow-up, each larger set improved prediction (+hand OA, injury, surgery, activities; +symptoms/function). Prediction was further improved by including cartilage damage both compartments, BMLs both compartments, meniscal tear, meniscal extrusion, sum of lesion types, number of subregions with cartilage damage, number of subregions with BMLs, and (concurrently) subregion number with cartilage damage, subregion number with BMLs, and meniscal tear. AUCs were ≥0.80 for both outcomes for number of subregions with cartilage damage and the combined model.ConclusionsAmong persons at higher risk for knee OA with normal X-rays, MRI tissue lesions improved prediction of mild as well as moderate disease. These findings support that disease onset is likely occurring during the "high-risk" period and encourage a reorientation of approach.

ObjectiveTo determine the association of varus thrust during walking to incident and worsening medial tibiofemoral cartilage damage and bone marrow lesions (BMLs) over 2 years in older adults with or at risk for osteoarthritis (OA).MethodSubjects from the Multicenter Osteoarthritis Study (MOST) were studied. Varus thrust was visually assessed from high-speed videos of forward walking trials. Baseline and two-year MRIs were acquired from one knee per subject and read for cartilage loss and BMLs. Logistic regression with generalized estimating equations was used to estimate the odds of incident and worsening cartilage loss and BMLs, adjusting for age, sex, race, body mass index (BMI), and clinic site. The analysis was repeated stratified by varus, neutral, and valgus alignment.Results1007 participants contributed one knee each. Varus thrust was observed in 29.9% of knees. Knees with thrust had 2.17 [95% CI: 1.51, 3.11] times the odds of incident medial BML, 2.51 [1.85, 3.40] times the odds of worsening medial BML, and 1.85 [1.35, 2.55] times the odds of worsening medial cartilage loss. When stratified by alignment, varus knees also had significantly increased odds of these outcomes.ConclusionVarus thrust observed during walking is associated with increased odds of incident and worsening medial BMLs and worsening medial cartilage loss. Increased odds of these outcomes persist in varus-aligned knees.

ObjectiveCCN family protein 2/connective tissue growth factor (CCN2/CTGF) promotes cartilage regeneration in experimental osteoarthritis (OA) models. However, CCN2 production is very low in articular cartilage. The aim of this study was to investigate whether or not CCN2 was promoted by cultured chondrocytes treated with low-intensity pulsed ultrasound (LIPUS) and to clarify its mechanism.MethodsHuman chondrocytic cell line (HCS)-2/8, rat primary epiphyseal and articular cartilage cells, and Ccn2-deficient chondrocytes that impaired chondrocyte differentiation, were treated with LIPUS for 20 min at 3.0 MHz frequency and 60 mW/cm2 power. Expressions of chondrocyte differentiation marker mRNAs were examined by real-time PCR (RT-PCR) analysis from HCS-2/8 cells and Ccn2-deficient chondrocytes at 30 min and 1 h after LIPUS treatment, respectively. CCN2 production was examined by Western blotting after 5 h of LIPUS treatment. Moreover, Ca2+ influx was measured by using a Fluo-4 probe.ResultsThe gene expression of chondrocyte differentiation markers and CCN2 production were increased in cultured chondrocytes treated with LIPUS. In addition, Ca2+ influx and phosphorylation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK)1/2 were increased by LIPUS treatment, and the stability of TRPV4 and BKca channel mRNAs was decreased by siRNA against CCN2. Consistent with those findings, the LIPUS-induced the gene expressions of type II collagen (COL2a1) and Aggrecan (ACAN) observed in wild-type cells were not observed in the Ccn2-deficient chondrocytes.ConclusionThese data indicate that chondrocyte differentiation represented by CCN2 production was mediated via MAPK pathways activated by LIPUS-stimulated Ca2+ influx, which in turn was supported by the induced CCN2 molecules in articular chondrocytes.

ObjectiveThe aim of this study was to assess cross-sectional and longitudinal effects of meniscal lesions on adjacent cartilage T1ρ and T2 relaxation times, patient-reported outcomes and gait biomechanics.DesignThirty patients with no cartilage morphological defects reported by Whole Organ MRI Score (WORMS) magnetic resonance imaging (MRI) grading and no radiographic osteoarthritis (OA) (Kellgren--Lawrence (KL) ≤ 1) were selected, 15 with posterior meniscus horn lesions and 15 matched controls without meniscal lesions. All were imaged on a 3T MR scanner for three consecutive years, except those who dropped from the study. Sagittal and frontal plane kinematic gait data were acquired at baseline. The Knee Injury and Osteoarthritis Outcome Score (KOOS) survey was taken each time. All images were automatically segmented and registered to an atlas for voxel-by-voxel cross-sectional and longitudinal analyses.ResultsRelaxation time comparisons between groups showed elevated T1ρ of the lateral tibia (LP) and elevated T2 of the medial tibia (MT) and LT at 1 and 2 years in the lesion group. Longitudinal comparisons within each group revealed greater relaxation time elevations over one and 2 years in the group with lesions. KOOS Quality of Life (QOL) was significantly different between the groups at all time points (P

ObjectiveIsolated lateral compartment tibiofemoral radiographic osteoarthritis (IL-ROA) is an understudied form of knee osteoarthritis (OA). The objective of the present study was to characterize Magnetic Resonance Imaging (MRI) abnormalities and MR-T2 relaxation time measurements associated with IL-ROA and with isolated medial compartment ROA (IM-ROA) compared with knees without OA.Method200 case subjects with IL-ROA (Kellgren/Lawrence (K/L) grade≥2 and joint space narrowing (JSN) > 0 in the lateral compartment but JSN = 0 in the medial compartment) were randomly selected from the Osteoarthritis Initiative baseline visit. 200 cases with IM-ROA and 200 controls were frequency matched to the IL-ROA cases. Cases and controls were analyzed for odds of having a subregion with >10% cartilage area affected, with ≥25% bone marrow lesions (BML), with meniscal tear or maceration, and for association with cartilage T2 values.ResultsIL-ROA was more strongly associated with ipsilateral MRI knee pathologies than IM-ROA (IL-ROA: OR = 135.2 for size of cartilage lesion, 95% CI 42.7-427.4; OR = 145.4 for large size BML, 95% CI 41.5-509.5; OR = 176 for meniscal tears, 95% CI 59.8-517.7; IM-ROA: OR = 28.4 for size of cartilage lesion, 95% CI 14.7-54.7; OR = 38.1 for size of BML, 95% CI 12.7-114; OR = 37.0 for meniscal tears, 95% CI 12-113.6). Cartilage T2 values were higher in both tibial and medial femoral compartments in IL-ROA, but in IM-ROA were only significantly different from controls in the medial femur.ConclusionIL-ROA knees show a greater prevalence and severity of MRI lesions and higher cartilage T2 values than IM-ROA knees compared with controls.

ObjectiveTo determine in a 48-month longitudinal study the association of thigh muscle cross-sectional area (CSA) and strength on progression of morphologic knee cartilage degeneration using 3T magnetic resonance imaging (MRI).DesignSeventy Osteoarthritis Initiative (OAI) subjects aged 50-60 years, with no radiographic evidence of osteoarthritis (OA) and constant muscle strength over 48 months as measured by isometric knee extension testing were included. Baseline right thigh muscle CSAs were assessed on axial T1-weighted magnetic resonance (MR) images, and extensor to flexor CSA ratios were calculated. Degenerative knee abnormalities at baseline and 48-months were graded on right knee 3T MRIs using a modified whole organ MRI score (WORMS). Statistical analysis employed Student's t-tests and multivariable regression models adjusted for age, body mass index and gender.ResultsExtension strength was significantly and positively correlated with baseline thigh muscle CSA (r = 0.65, P

ObjectiveThis study aimed to investigate the associations between patellofemoral cartilage T1ρ and T2 relaxation times and knee flexion moment (KFM) and KFM impulse during gait.MethodKnee magnetic resonance (MR) images were obtained from 99 subjects with and without patellofemoral joint (PFJ) osteoarthritis (OA), using fast spin-echo, T1ρ and T2 relaxation time sequences. Patellar and trochlear cartilage relaxation times were computed for the whole cartilage, and superficial and deep layers (laminar analysis). Subjects also underwent three-dimensional (3D) gait analysis. Peak KFM and KFM impulse were calculated during the stance phase. Linear regressions were used to examine whether cartilage relaxation times were associated with knee kinetics during walking while adjusting age, sex, body mass index (BMI) and walking speed.ResultsHigher peak KFM and KFM impulse were significantly related to higher T1ρ and T2 relaxation times of the trochlear and patellar cartilage, with standardized regression coefficients ranging from 0.21 to 0.28. Laminar analysis showed that overall the superficial layer of patellofemoral cartilage showed stronger associations with knee kinetics. Subgroup analysis revealed that in subjects with PFJ OA, every standard deviation change in knee kinetics was related to greater increases in PFJ cartilage T1ρ and T2 (standardized coefficients: 0.29 to 0.41). Conversely, in subjects without OA, weaker relationships were observed between knee kinetics and PFJ cartilage T1ρ and T2.ConclusionsOur findings suggest that increased peak KFM and KFM impulse were related to worse cartilage health at the PFJ. This association is more prominent in superficial layer cartilage and cartilage with morphological lesions.

ObjectiveTo evaluate whether baseline T1ρ and T2 relaxation times of hip cartilage are associated with magnetic resonance imaging (MRI) based progression of hip osteoarthritis (OA) at 18 months.Methods3T MRI studies of the hip were obtained at baseline and 18-month follow-up for 54 subjects without evidence of severe OA at baseline [Kellgren-Lawrence (KL) score of 0-3]. 2D fast spin-echo sequences were used for semi-quantitative morphological scoring of cartilage lesions and a combined T1ρ/T2 sequence was used to quantitatively assess cartilage composition. Progression of hip OA was defined based on incident or progression of morphological semi-quantitative grade at 18 months. Baseline T1ρ and T2 relaxation times were compared between progressors and non-progressors using one-way analysis of variance and Mann-Whitney U tests and used to predict progression with binary logistic regression after adjusting for age, gender, body mass index, and KL score. Additionally, a novel voxel-based relaxometry technique was used to compare the spatial distribution of baseline T1ρ and T2 between progressors and non-progressors.ResultsSignificantly higher baseline T1ρ and T2 values were observed in hip OA progressors compared to non-progressors, particularly in the posterosuperior and anterior aspects of the femoral cartilage. Logistic regression showed that higher baseline T1ρ or T2 values in the femoral cartilage were significantly associated with progression of femoral cartilage lesions at 18 months.ConclusionT1ρ and T2 relaxation parameters are associated with morphological cartilage degeneration at 18 months and may serve as potential imaging biomarkers for progression of cartilage lesions in hip OA.

ObjectivesTo investigate the change in cartilage T2 values and structural degeneration in knee joints over 72 months in women of African American (AA) vs Caucasian American (CA) ethnicity.MethodsKnee 3T magnetic resonance imaging (MRIs) from baseline, 24, 48 and 72 months visits of 100 AA and 100 CA women from the Osteoarthritis Initiative (OAI) were assessed for cartilage T2 values and whole-organ magnetic resonance imaging (WORMS) score. Subjects were pair-matched by age, body mass index (BMI), Kellgren-Lawrence (KL) score, clinical site and subcohort within the OAI. We compared the rate of change in whole knee cartilage T2 values and WORMS cartilage, bone marrow edema pattern (BMEP) and meniscus scores between the two ethnic groups using mixed random effects models.ResultsAt 24 and 48 months 60 subjects and at 72 months 45 subjects per group were available for analysis resulting in 38 complete pairs with data of all time points. Compared to CA, cartilage T2 values in AA increased at a significantly faster rate at baseline (AA: 0.45 ms/y, CA: 0.35 ms/y, P = 0.029) and averaged over 6 years (AA: 0.36 ms/y, CA: 0.27 ms/y, P = 0.039) with changes in both groups reaching a plateau by 48 months. Cartilage, meniscus and BMEP scores tended to increase in both groups during follow up, but rates of change did not differ by ethnicity.ConclusionCartilage T2 values increased faster over 72 months in AA than CA, however changes in WORMS cartilage, meniscus and BMEP scores did not differ. T2 values may be able to distinguish ethnicity-related differences of cartilage degeneration at an early stage before differences in structural joint degeneration appear.

ObjectiveTo investigate compositional cartilage changes measured with 3T MRI-based T2 values over 48 months in overweight and obese individuals with different degrees of weight loss (WL) and to study whether WL slows knee cartilage degeneration and symptom worsening.DesignWe studied participants from the Osteoarthritis Initiative with risk factors or radiographic evidence of mild to moderate knee osteoarthritis with a baseline BMI ≥25 kg/m(2). We selected subjects who over 48 months lost a, moderate (BMI change, 5-10%WL, n = 180) or large amount of weight (≥10%WL, n = 78) and frequency-matched these to individuals with stable weight (10%WL group compared to the stable weight group (both comparisons, P = 0.04).ConclusionsWL over 48 months is associated with slowed knee cartilage degeneration and improved knee symptoms.

ObjectivesTo investigate changes in cartilage damage and bone marrow lesions (BMLs) on MRI in the patellofemoral and tibiofemoral joints (TFJs) over 7 years.MethodsThe Multicenter Osteoarthritis (MOST) Study is a cohort study of persons aged 50-79 years at baseline with or at high risk for knee osteoarthritis (OA). Knees were eligible for the current study if they had knee MRI (1.0T) assessed for cartilage damage and BMLs at the baseline and 84-month visits. Knees were categorized as having MRI-detected structural damage (cartilage and BMLs) isolated to the patellofemoral joint (PFJ), isolated to the TFJ, mixed or no damage at baseline and 84-months. We determined the changes in PFJ and TFJ structural damage over 7 years and used logistic regression to assess the relation of baseline compartment distribution to incident isolated PFJ, isolated TFJ and mixed damage.ResultsAmong 339 knees that had full-thickness cartilage loss isolated to the PFJ or TFJ at baseline, only 68 (20.1%) developed full-thickness cartilage loss in the other compartment while 271 (79.9%) continued to only have the initial compartment affected. Compared to knees without full-thickness cartilage damage (n = 582), those with isolated TFJ and PFJ full-thickness cartilage damage had 2.7 (1.5, 4.9) and 5.8 (3.6, 9.6) times the odds of incident mixed full-thickness cartilage damage, respectively. Similar results were seen when using other definitions of MRI-defined structural damage.ConclusionsMost knees with structural damage at baseline do not develop it in the other compartment. Knees that develop mixed structural damage are more likely to start with it isolated to the PFJ.

ObjectiveTo determine if cartilage T1ρ and T2 relaxation time measures after ACL injury and prior to reconstruction (baseline) are associated with patient-reported outcomes at baseline, 6-months, and 1-year after surgery.DesignFifty-four ACL-injured participants were scanned in both knees at baseline using 3T MR T1ρ and T2 mapping. Participants also completed Knee-injury and Osteoarthritis Outcome Score (KOOS) and Marx activity level questionnaires at baseline, 6-months, and 1-year after reconstruction. The difference between cartilage T1ρ or T2 of the injured and contralateral knee (side-to-side difference, SSD) was calculated to account for physiological variations among patients. Linear regression models were built to evaluate the association between the baseline SSD T1ρ or T2 and KOOS or Marx at all time points.ResultsHigher baseline SSD T1ρ posterolateral tibia (pLT) was associated with worse KOOS in all subscales except symptoms at baseline, worse KOOS pain at 6-months, and worse KOOS in all subscales except sports function at 1-year. Higher baseline SSD T2 femoral trochlea (TrF) was associated with worse KOOS activities of daily living (ADL) at 1-year. Higher baseline SSD T1ρ pLT was associated with lower Marx activity level at 1-year. More severe cartilage lesions, as assessed by Whole-Organ MRI Scoring (WORMS), was significantly associated with worse KOOS pain at 6-months and 1-year.ConclusionT1ρ and T2 of cartilage after ACL injury were associated with KOOS after injury and both KOOS and Marx after reconstruction. Such associations may help clinicians stratify outcomes post-injury, and thus, improve patient management.

ObjectiveExercise is vital for maintaining cartilage integrity in healthy joints. Here we examined the exercise-driven transcriptional regulation of genes in healthy rat articular cartilage to dissect the metabolic pathways responsible for the potential benefits of exercise.MethodsTranscriptome-wide gene expression in the articular cartilage of healthy Sprague-Dawley female rats exercised daily (low intensity treadmill walking) for 2, 5, or 15 days was compared to that of non-exercised rats, using Affymetrix GeneChip arrays. Database for Annotation, Visualization and Integrated Discovery (DAVID) was used for Gene Ontology (GO)-term enrichment and Functional Annotation analysis of differentially expressed genes (DEGs). Kyoto Encyclopedia of Genes and Genome (KEGG) pathway mapper was used to identify the metabolic pathways regulated by exercise.ResultsMicroarray analysis revealed that exercise-induced 644 DEGs in healthy articular cartilage. The DAVID bioinformatics tool demonstrated high prevalence of functional annotation clusters with greater enrichment scores and GO-terms associated with extracellular matrix (ECM) biosynthesis/remodeling and inflammation/immune response. The KEGG database revealed that exercise regulates 147 metabolic pathways representing molecular interaction networks for Metabolism, Genetic Information Processing, Environmental Information Processing, Cellular Processes, Organismal Systems, and Diseases. These pathways collectively supported the complex regulation of the beneficial effects of exercise on the cartilage.ConclusionsOverall, the findings highlight that exercise is a robust transcriptional regulator of a wide array of metabolic pathways in healthy cartilage. The major actions of exercise involve ECM biosynthesis/cartilage strengthening and attenuation of inflammatory pathways to provide prophylaxis against onset of arthritic diseases in healthy cartilage.

ObjectivesTo determine T2* relaxation in articular cartilage using ultrashort echo time (UTE) imaging and bi-component analysis, with an emphasis on the deep radial and calcified cartilage.MethodsTen patellar samples were imaged using two-dimensional (2D) UTE and Car-Purcell-Meiboom-Gill (CPMG) sequences. UTE images were fitted with a bi-component model to calculate T2* and relative fractions. CPMG images were fitted with a single-component model to calculate T2. The high signal line above the subchondral bone was regarded as the deep radial and calcified cartilage. Depth and orientation dependence of T2*, fraction and T2 were analyzed with histopathology and polarized light microscopy (PLM), confirming normal regions of articular cartilage. An interleaved multi-echo UTE acquisition scheme was proposed for in vivo applications (n = 5).ResultsThe short T2* values remained relatively constant across the cartilage depth while the long T2* values and long T2* fractions tended to increase from subchondral bone to the superficial cartilage. Long T2*s and T2s showed significant magic angle effect for all layers of cartilage from the medial to lateral facets, while the short T2* values and T2* fractions are insensitive to the magic angle effect. The deep radial and calcified cartilage showed a mean short T2* of 0.80 ± 0.05 ms and short T2* fraction of 39.93 ± 3.05% in vitro, and a mean short T2* of 0.93 ± 0.58 ms and short T2* fraction of 35.03 ± 4.09% in vivo.ConclusionUTE bi-component analysis can characterize the short and long T2* values and fractions across the cartilage depth, including the deep radial and calcified cartilage. The short T2* values and T2* fractions are magic angle insensitive.

ObjectiveTo evaluate the longitudinal reproducibility and variations of cartilage T1ρ and T2 measurements using different coils, MR systems and sites.MethodsSingle-Site study: Phantom data were collected monthly for up to 29 months on four GE 3T MR systems. Data from phantoms and human subjects were collected on two MR systems using the same model of coil; and were collected on one MR system using two models of coils. Multi-site study: Three participating sites used the same model of MR systems and coils, and identical imaging protocols. Phantom data were collected monthly. Human subjects were scanned and rescanned on the same day at each site. Two traveling human subjects were scanned at all three sites.ResultsSingle-Site Study: The phantom longitudinal RMS-CVs ranged from 1.8% to 2.7% for T1ρ and 1.8-2.8% for T2. Significant differences were found in T1ρ and T2 values using different MR systems and coils. Multi-Site Study: The phantom longitudinal RMS-CVs ranged from 1.3% to 2.6% for T1ρ and 1.2-2.7% for T2. Across three sites (n = 16), the in vivo scan-rescan RMS-CV was 3.1% and 4.0% for T1ρ and T2, respectively. Phantom T1ρ and T2 values were significantly different between three sites but highly correlated (R > 0.99). No significant difference was found in T1ρ and T2 values of traveling controls, with cross-site RMS-CV as 4.9% and 4.4% for T1ρ and T2, respectively.ConclusionWith careful quality control and cross-calibration, quantitative MRI can be readily applied in multi-site studies and clinical trials for evaluating cartilage degeneration.

ObjectivesTo provide a comprehensive simultaneous relation of various semiquantitative knee OA MRI features as well as the presence of baseline radiographic osteoarthritis (OA) to quantitative longitudinal cartilage loss.MethodsWe studied Multicenter OA Study (MOST) participants from a longitudinal observational study that included quantitative MRI measurement of cartilage thickness. These subjects also had Whole Organ MRI Score (WORMS) scoring of cartilage damage, bone marrow lesions (BMLs), meniscal pathology, and synovitis, as well as baseline radiographic evaluation for Kellgren and Lawrence (KL) grading. Knee compartments were classified as progressors when exceeding thresholds of measurement variability in normal knees. All potential risk factors of cartilage loss were dichotomized into "present" (score ≥2 for cartilage, ≥1 for others) or "absent". Differences in baseline scores of ipsi-compartmental risk factors were compared between progressor and non-progressor knees by multivariable logistic regression, adjusting for age, sex, body mass index, alignment axis (degrees) and baseline KL grade. Odds ratios (OR) and 95% CIs were calculated for medial femorotibial compartment (MFTC) and lateral femorotibial compartment (LFTC) cartilage loss. Cartilage loss across both compartments was studied using Generalized Estimating Equations.Results196 knees of 196 participants were included (age 59.8 ± 6.3 years [mean ± SD], BMI 29.5 ± 4.6, 62% women). For combined analyses of MFTC and LFTC, baseline factors related to cartilage loss were radiographic OA (KL grade ≥2: aOR 4.8 [2.4-9.5], cartilage damage (aOR 2.3 [1.2-4.4])), meniscal damage (aOR 3.9 [2.1-7.4]) and extrusion (aOR 2.9 [1.6-5.3]), all in the ipsilateral compartment, but not BMLs or synovitis.ConclusionBaseline radiographic OA and semiquantitatively (SQ) assessed MRI-detected cartilage damage, meniscal damage and extrusion, but not BMLs or synovitis is related to quantitatively measured ipsi-compartmental cartilage thinning over 30 months.

Objective: To explore associations between hip muscle strength and cartilage defects (presence and severity) on magnetic resonance imaging (MRI) in young adults with hip/groin pain participating in sub-elite football., Design: Sub-elite football players with hip/groin pain (>6 months) completed assessments of isometric hip strength and functional task performance. Hip cartilage defects were assessed using the Scoring Hip Osteoarthritis with MRI tool. This exploratory, cross-sectional study used logistic and negative binomial models to assess the relationships between hip muscle strength or functional task performance and hip cartilage defects, controlling for body mass index, age, testing site and cam morphology, incorporating sex-specific interaction terms., Results: One hundred and eighty-two (37 women) sub-elite (soccer or Australian football) players with hip/groin pain (age 26 ± 7 years) were included. Greater hip extension strength was associated with higher cartilage total score (adjusted incidence rate ratio [aIRR] 1.01, 95%CI: 1.0 to 1.02, p = 0.013) and superolateral cartilage score (adjusted odds ratio (aOR) 1.03, 95% confidence interval (CI): 1.01 to 1.06, p < 0.01). In female sub-elite football players, greater hip external rotation strength was associated with lateral cartilage defects (aOR 1.61, 95%CI: 1.05 to 2.48, p = 0.03) and higher cartilage total score (aIRR 1.25, 95%CI: 1.01 to 1.66, p = 0.042). A one-repetition increase in one-leg rise performance was related to lower odds of superomedial cartilage defects (aOR 0.96, 95%CI: 0.94 to 0.99, p < 0.01)., Conclusions: Overall, there were few associations between peak isometric hip muscle strength and overall hip cartilage defects. It is possible that other factors may have relevance in sub-elite football players. Additional studies are needed to support or refute our findings that higher one leg rise performance was associated with reduced superomedial cartilage defect severity and greater hip extension strength was related to higher cartilage defect severity scores., Competing Interests: Competing interests The authors declare they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)