Can gait patterns be explained by joint structure in people with and without radiographic knee osteoarthritis? Data from the IMI-APPROACH cohort.

OBJECTIVE: To determine the association between joint structure and gait in patients with knee osteoarthritis (OA). METHODS: IMI-APPROACH recruited 297 clinical knee OA patients. Gait data was collected (GaitSmart®) and OA-related joint measures determined from knee radiographs (KIDA) and MRIs (qMRI/MOAKS). Patients were divided into those with/without radiographic OA (ROA). Principal component analyses (PCA) were performed on gait parameters; linear regression models were used to evaluate whether image-based structural and demographic parameters were associated with gait principal components. RESULTS: Two hundred seventy-one patients (age median 68.0, BMI 27.0, 77% female) could be analyzed; 149 (55%) had ROA. PCA identified two components: upper leg (primarily walking speed, stride duration, hip range of motion [ROM], thigh ROM) and lower leg (calf ROM, knee ROM in swing and stance phases). Increased age, BMI, and radiographic subchondral bone density (sclerosis), decreased radiographic varus angle deviation, and female sex were statistically significantly associated with worse lower leg gait (i.e. reduced ROM) in patients without ROA (R2 = 0.24); in ROA patients, increased BMI, radiographic osteophytes, MRI meniscal extrusion and female sex showed significantly worse lower leg gait (R2 = 0.18). Higher BMI was significantly associated with reduced upper leg function for non-ROA patients (R2 = 0.05); ROA patients with male sex, higher BMI and less MRI synovitis showed significantly worse upper leg gait (R2 = 0.12). CONCLUSION: Structural OA pathology was significantly associated with gait in patients with clinical knee OA, though BMI may be more important. While associations were not strong, these results provide a significant association between OA symptoms (gait) and joint structure.

Defective chaperone-mediated autophagy is a hallmark of joint disease in patients with knee osteoarthritis.

OBJECTIVE: Defects in autophagy contribute to joint aging and Osteoarthritis (OA). Identifying specific autophagy types could be useful for developing novel treatments for OA. DESIGN: An autophagy-related gene array was performed in blood from non-OA and knee OA subjects from the Prospective Cohort of A Coruña (PROCOAC). The differential expression of candidate genes was confirmed in blood and knee cartilage and a regression analysis was performed adjusting for age and BMI. HSP90A, a chaperone mediated autophagy (CMA) marker was validated in human knee joint tissues, as well as, in mice with aging-related and surgically-induced OA. The consequences of HSP90AA1 deficiency were evaluated on OA pathogenesis. Finally, the contribution of CMA to homeostasis was studied by assessing the capacity to restore proteostasis upon ATG5-mediated macroautophagy deficiency and genetic HSP90AA1 overexpression. RESULTS: 16 autophagy-related genes were significantly down-regulated in blood from knee OA subjects. Validation studies showed that HSP90AA1 was down-regulated in blood and human OA cartilage and correlated with risk incidence of OA. Moreover, HSP90A was reduced in human OA joints tissues and with aging and OA in mice. HSP90AA1 knockdown was linked to defective macroautophagy, inflammation, oxidative stress, senescence and apoptosis. However, macroautophagy deficiency increased CMA, highlighting the CMA-macroautophagy crosstalk. Remarkably, CMA activation was sufficient to protect chondrocytes from damage. CONCLUSIONS: We show that HSP90A is a key chaperone for chondrocyte homeostasis, while defective CMA contributes to joint damage. We propose that CMA deficiency is a relevant disease mechanism and could represent a therapeutic target for OA.

Test-retest precision and longitudinal cartilage thickness loss in the IMI-APPROACH cohort.

OBJECTIVE: To investigate the test-retest precision and to report the longitudinal change in cartilage thickness, the percentage of knees with progression and the predictive value of the machine-learning-estimated structural progression score (s-score) for cartilage thickness loss in the IMI-APPROACH cohort - an exploratory, 5-center, 2-year prospective follow-up cohort. DESIGN: Quantitative cartilage morphology at baseline and at least one follow-up visit was available for 270 of the 297 IMI-APPROACH participants (78% females, age: 66.4 ± 7.1 years, body mass index (BMI): 28.1 ± 5.3 kg/m2, 55% with radiographic knee osteoarthritis (OA)) from 1.5T or 3T MRI. Test-retest precision (root mean square coefficient of variation) was assessed from 34 participants. To define progressor knees, smallest detectable change (SDC) thresholds were computed from 11 participants with longitudinal test-retest scans. Binary logistic regression was used to evaluate the odds of progression in femorotibial cartilage thickness (threshold: -211 µm) for the quartile with the highest vs the quartile with the lowest s-scores. RESULTS: The test-retest precision was 69 µm for the entire femorotibial joint. Over 24 months, mean cartilage thickness loss in the entire femorotibial joint reached -174 µm (95% CI: [-207, -141] µm, 32.7% with progression). The s-score was not associated with 24-month progression rates by MRI (OR: 1.30, 95% CI: [0.52, 3.28]). CONCLUSION: IMI-APPROACH successfully enrolled participants with substantial cartilage thickness loss, although the machine-learning-estimated s-score was not observed to be predictive of cartilage thickness loss. IMI-APPROACH data will be used in subsequent analyses to evaluate the impact of clinical, imaging, biomechanical and biochemical biomarkers on cartilage thickness loss and to refine the machine-learning-based s-score. GOV IDENTIFICATION: NCT03883568.

Evaluated electron scattering cross section dataset for gaseous benzene in the energy range 0.1-1000 eV.

In this study, a complete and self-consistent cross section dataset for electron transport simulations through gaseous benzene in the energy range 0.1-1000 eV has been critically compiled. Its reliability has been evaluated through a joint experimental and computational procedure. To accomplish this, the compiled dataset has been used as input for event-by-event Monte Carlo simulations of the magnetically confined electron transport through gaseous benzene, and the simulated transmitted intensity has been compared with the experimental one for different incident energies and benzene gas pressures.

The association of the lipid profile with knee and hand osteoarthritis severity: the IMI-APPROACH cohort.

OBJECTIVE: To investigate the association of the lipidomic profile with osteoarthritis (OA) severity, considering the outcomes radiographic knee and hand OA, pain and function. DESIGN: We used baseline data from the Applied Public-Private Research enabling OsteoArthritis Clinical Headway (APPROACH) cohort, comprising persons with knee OA fulfilling the clinical American College of Rheumatology classification criteria. Radiographic knee and hand OA severity was quantified with Kellgren-Lawrence sum scores. Knee and hand pain and function were assessed with validated questionnaires. We quantified fasted plasma higher order lipids and oxylipins with liquid chromatography with tandem mass spectrometry (LC-MS/MS)-based platforms. Using penalised linear regression, we assessed the variance in OA severity explained by lipidomics, with adjustment for clinical covariates (age, sex, body mass index (BMI) and lipid lowering medication), measurement batch and clinical centre. RESULTS: In 216 participants (mean age 66 years, mean BMI 27.3 kg/m2, 75% women) we quantified 603 higher order lipids (triacylglycerols, diacylglycerols, cholesteryl esters, ceramides, free fatty acids, sphingomyelins, phospholipids) and 28 oxylipins. Lipidomics explained 3% and 2% of the variance in radiographic knee and hand OA severity, respectively. Lipids were not associated with knee pain or function. Lipidomics accounted for 12% and 6% of variance in hand pain and function, respectively. The investigated OA severity outcomes were associated with the lipidomic fraction of bound and free arachidonic acid, bound palmitoleic acid, oleic acid, linoleic acid and docosapentaenoic acid. CONCLUSIONS: Within the APPROACH cohort lipidomics explained a minor portion of the variation in OA severity, which was most evident for the outcome hand pain. Our results suggest that eicosanoids may be involved in OA severity.

Velocity-based resistance training: do women need greater velocity loss to maximize adaptations?

PURPOSE: Men and women typically display different neuromuscular characteristics, force-velocity relationships, and differing strength deficit (upper vs. lower body). Thus, it is not clear how previous recommendations for training with velocity-loss resistance training based on data in men will apply to women. This study examined the inter-sex differences in neuromuscular adaptations using 20% and 40% velocity-loss protocols in back squat and bench press exercises. METHODS: The present study employed an 8-week intervention (2 × week) comparing 20% vs. 40% velocity-loss resistance training in the back squat and bench press exercises in young men and women (~ 26 years). Maximum strength (1-RM) and submaximal-load mean propulsive velocity (MPV) for low- and high-velocity lifts in squat and bench press, countermovement jump and vastus lateralis cross-sectional area were measured at pre-, mid-, and post-training. Surface EMG of quadriceps measured muscle activity during performance tests. RESULTS: All groups increased 1-RM strength in squat and bench press exercises, as well as MPV using submaximal loads and countermovement jump height (P < 0.05). No statistically significant between-group differences were observed, but higher magnitudes following 40% velocity loss in 1-RM (g = 0.60) and in low- (g = 1.42) and high-velocity (g = 0.98) lifts occurred in women. Training-induced improvements were accompanied by increases in surface EMG amplitude and vastus lateralis cross-sectional area. CONCLUSION: Similar increases in strength and power performance were observed in men and women over 8 weeks of velocity-based resistance training. However, some results suggest that strength and power gains favor using 40% rather than 20% velocity loss in women.

Identification of a distinct lipidomic profile in the osteoarthritic synovial membrane by mass spectrometry imaging.

OBJECTIVE: Synovial inflammation is one of the most characteristic events in different types of arthritis, including Osteoarthritis (OA). Emerging evidence also suggests the involvement of lipids in the regulation of inflammatory processes. The aim of this study was to elucidate the heterogeneity and spatial distribution of lipids in the OA synovial membrane and explore their putative involvement in inflammation. METHOD: The abundance and distribution of lipids were examined in human synovial membranes. To this end, histological cuts from this tissue were analysed by matrix-assisted laser desorption ionization - mass spectrometry imaging (MALDI-MSI). The lipidomic profile of OA synovium was characterized and compared with healthy and other forms of inflammatory arthropathies as Rheumatoid Arthritis (RA) and Psoriatic Arthritis (PsA) using principal component analysis and discriminant analysis methods. Lipid identification was undertaken by tandem MS analyses and database queries. RESULTS: Our results reveal differential and characteristic lipidomic profiles between OA and control samples. Specifically, we unveiled that OA synovium presents elevated levels of phosphatidylcholines, fatty acids and lysophosphatidic acids and lower levels of lysophosphatidylcholines compared to control tissues. The spatial distribution of particular glycerophospholipids was also correlated with hypertrophic, inflamed or vascularized synovial areas. Compared with other inflammatory arthritis, the OA tissue showed lower amounts of phosphatidylethanolamine-based plasmalogens. CONCLUSIONS: This study provides a novel insight into the lipid profiles of synovial membrane and differences in abundance between OA and control tissues. The lipidomic alterations improves understanding of the pathogenic mechanisms of OA and may be important for its diagnosis.

A clinical model including protein biomarkers predicts radiographic knee osteoarthritis: a prospective study using data from the Osteoarthritis Initiative.

OBJECTIVE: We aimed to provide a model to predict the prospective development of radiographic KOA (rKOA). METHOD: Baseline sera from 333 non-radiographic KOA subjects belonging to OA Initiative (OAI) who developed or not, rKOA during a follow-up period of 96 months were used in this study. The exploratory cohort included 200 subjects, whereas the replication cohort included 133. The levels of inter-alpha trypsin inhibitor heavy chain 1 (ITIH1), complement C3 (C3) and calcyclin (S100A6), identified in previous large proteomic analysis, were analyzed by using sandwich immunoassays on suspension bead arrays. The association of protein levels and clinical covariates with rKOA incidence was assessed by combining logistic regression analysis, Receiver Operating Characteristic (ROC) analysis, Integrated Discrimination Improvement (IDI) analysis and Kaplan-Meier curves. RESULTS: Levels of ITIH1, C3 and S100A6 were significantly associated with the prospective development of rKOA, showing an area under the curve (AUC) of 0.713 (0.624-0.802), 0.708 (0.618-0.799) and 0.654 (0.559-0.749), respectively to predict rKOA in the replication cohort. The inclusion of ITIH1 in the clinical model (age, gender, BMI, previous knee injury and WOMAC pain) improved the predictive capacity of the clinical covariates (AUC = 0.754 [0.670-0.838]) producing the model with the highest AUC (0.786 [0.705-0.867]) and the highest IDI index (9%). High levels of ITIH1 were also associated with an earlier onset of the disease. CONCLUSION: A clinical model including protein biomarkers that predicts incident rKOA has been developed. Among the tested biomarkers, ITIH1 showed potential to improve the capacity to predict rKOA incidence in clinical practice.

BROX haploinsufficiency in familial nonmedullary thyroid cancer.

BACKGROUND: The familial nonmedullary thyroid cancer (FNMTC) is suspected to be a Mendelian condition in up to 3-8% of thyroid cancers. The susceptibility chromosomal loci and genes of 95% of FNMTC cases remain to be characterized. The inheritance of FNMTC appears to be autosomal dominant with incomplete penetrance and variable expressivity. The finding of the causative gene of FNMTC and the identification of patients at risk that need genetic testing were our aim. METHODS: We analyzed by whole-exome sequencing patients and non-affected relatives of five families with at least two family members affected by papillary thyroid cancer, selecting for new or extremely rare variants with predicted pathogenic value. RESULTS: A family showed, in all three affected members, a new loss-of-function variant (frameshift deletion) in BROX gene at 1q41 that was absent from all internal and external databases. In a second family with three affected relatives, we found an additional new BROX variant. The smaller families presented no variants in BROX or in the other causative genes studied. CONCLUSIONS: BROX could be a new causative gene for FNMTC. Variants in BROX may result in the haploinsufficiency of a key gene involved in the morphogenesis of MVBs, in the endosomal sorting of cargo proteins, and in EGFR. Functional studies are needed to support this result. The thorough genomic analysis by NGS in all families with three or more affected members should become a routine approach to obtain a comprehensive genetic view and find confirmative second cases.

Mitochondrial biogenesis: a potential therapeutic target for osteoarthritis.

Mitochondrial dysfunction of human articular chondrocytes is considered a hallmark of cartilage degradation and OA pathogenesis. Due to the huge number of cellular processes in which mitochondria is implicated, even in the closed context of cellular respiration, the term mitochondrial function can refer to a variety of features which include fusion and fission, turnover (biogenesis and mitophagy), and plasticity. Mitochondrial biogenesis and mainly mitochondrial fusion and reduced mitophagy, contribute to the metabolic disorder and inflammation that occurs during OA. Reduced MFN2 and increased PARKIN expression represent potential therapeutic targets for the treatment of joint cartilage degradation during the OA process.

Electron scattering cross sections from nitrobenzene in the energy range 0.4-1000 eV: the role of dipole interactions in measurements and calculations.

Absolute total electron scattering cross sections (TCS) for nitrobenzene molecules with impact energies from 0.4 to 1000 eV have been measured by means of two different electron-transmission experimental arrangements. For the lower energies (0.4-250 eV) a magnetically confined electron beam system has been used, while for energies above 100 eV a linear beam transmission technique with high angular resolution allowed accurate measurements up to 1000 eV impact energy. In both cases random uncertainties were maintained below 5-8%. Systematic errors arising from the angular and energy resolution limits of each apparatus are analysed in detail and quantified with the help of our theoretical calculations. Differential elastic and integral elastic, excitation and ionisation as well as momentum transfer cross sections have been calculated, for the whole energy range considered here, by using an independent atom model in combination with the screening corrected additivity rule method including interference effects (IAM-SCARI). Due to the significant permanent dipole moment of nitrobenzene, additional differential and integral rotational excitation cross sections have been calculated in the framework of the Born approximation. If we ignore the rotational excitations, our calculated total cross section agrees well with our experimental results for impact energies above 15 eV. Additionally, they overlap at 10 eV with the low energy Schwinger Multichannel method with Pseudo Potentials (SMCPP) calculation available in the literature (L. S. Maioli and M. H. F. Bettega, J. Chem. Phys., 2017, 147, 164305). We find a broad feature in the experimental TCS at around 1.0 eV, which has been related to the formation of the NO2- anion and assigned to the π*(b1) resonance, according to previous mass spectra available in the literature. Other local maxima in the TCSs are found at 4.0 ± 0.2 and 5.0 ± 0.2 eV and are assigned to core excited resonances leading to the formation of the NO2- and O2- anions, respectively. Finally, for energies below 10 eV, differences found between the present measurements, the SMCPP calculation and our previous data for non-polar benzene have revealed the importance of accurately calculating the rotational excitation contribution to the TCS before comparing theoretical and experimental data. This comparison suggests that our dipole-Born calculation for nitrobenzene overestimates the magnitude of the rotational excitation cross sections below 10 eV.

A comparison of experimental and theoretical low energy positron scattering from furan.

This paper presents a joint experimental and theoretical study of positron scattering from furan. Experimental data were measured using the low energy positron beamline located at the Australian National University and cover an energy range from 1 eV to 30 eV. Cross sections were measured for total scattering, total elastic and inelastic scattering, positronium formation, and differential elastic scattering. Two theoretical approaches are presented: the Schwinger multichannel method and the independent atom method with screening corrected additivity rule. In addition, our data are compared to corresponding electron scattering results from the same target with a number of significant differences observed and discussed.

OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis.

OBJECTIVE: To update and expand upon prior Osteoarthritis Research Society International (OARSI) guidelines by developing patient-focused treatment recommendations for individuals with Knee, Hip, and Polyarticular osteoarthritis (OA) that are derived from expert consensus and based on objective review of high-quality meta-analytic data. METHODS: We sought evidence for 60 unique interventions. A systematic search of all relevant databases was conducted from inception through July 2018. After abstract and full-text screening by two independent reviewers, eligible studies were matched to PICO questions. Data were extracted and meta-analyses were conducted using RevMan software. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Evidence Profiles were compiled using the GRADEpro web application. Voting for Core Treatments took place first. Four subsequent voting sessions took place via anonymous online survey, during which Panel members were tasked with voting to produce recommendations for all joint locations and comorbidity classes. We designated non-Core treatments to Level 1A, 1B, 2, 3, 4A, 4B, or 5, based on the percentage of votes in favor, in addition to the strength of the recommendation. RESULTS: Core Treatments for Knee OA included arthritis education and structured land-based exercise programs with or without dietary weight management. Core Treatments for Hip and Polyarticular OA included arthritis education and structured land-based exercise programs. Topical non-steroidal anti-inflammatory drugs (NSAIDs) were strongly recommended for individuals with Knee OA (Level 1A). For individuals with gastrointestinal comorbidities, COX-2 inhibitors were Level 1B and NSAIDs with proton pump inhibitors Level 2. For individuals with cardiovascular comorbidities or frailty, use of any oral NSAID was not recommended. Intra-articular (IA) corticosteroids, IA hyaluronic acid, and aquatic exercise were Level 1B/Level 2 treatments for Knee OA, dependent upon comorbidity status, but were not recommended for individuals with Hip or Polyarticular OA. The use of Acetaminophen/Paracetamol (APAP) was conditionally not recommended (Level 4A and 4B), and the use of oral and transdermal opioids was strongly not recommended (Level 5). A treatment algorithm was constructed in order to guide clinical decision-making for a variety of patient profiles, using recommended treatments as input for each decision node. CONCLUSION: These guidelines offer comprehensive and patient-centered treatment profiles for individuals with Knee, Hip, and Polyarticular OA. The treatment algorithm will facilitate individualized treatment decisions regarding the management of OA.

Experimental and theoretical analysis for total electron scattering cross sections of benzene.

Measurements of the total electron scattering cross sections (TCSs) from benzene, in the impact energy range of 1-1000 eV, are presented here by combining two different experimental systems. The first utilizes a magnetically confined electron transmission beam for the lower energies (1-300 eV), while the second utilizes a linear transmission beam apparatus for the higher energies (100-1000 eV). These cross sections have also been calculated by means of two different theoretical methods, the Schwinger Multichannel with Pseudo Potential (SMCPP) procedure, employing two different approaches to account for the polarization of the target for impact energies between 0.1 and 15 eV, and the Independent Atom Model with the Screening Corrected Additivity Rule including Interference effect (IAM-SCAR+I) paradigm to cover the 10-10 000 eV impact energy range. The present results are compared with available theoretical and experimental data, with the level of accord being good in some cases and less satisfactory in others, and some predicted resonances have been identified. In particular, we found a π* shape resonance at 1.4 eV and another feature in the energy region 4.6-4.9 eV interpreted as a π* resonance (2B2g symmetry), which is a mixture of shape and a core excited resonance, as well as a Feshbach resonance at 5.87 eV associated with the 3s (a1g) Rydberg state. A Born-type formula to extrapolate TCS values for energies above 10 000 eV is also given. This study provides a complete set of TCS data, with uncertainty limits within 10%, ready to be used for modeling electron transport applications.

Electron scattering from 1-butanol at intermediate impact energies: Total cross sections.

We report experimental measurements of the absolute total cross sections (TCSs) for electron scattering from 1-butanol at impact energies in the range 80-400 eV. Those measurements were conducted by considering the attenuation of a collimated electron beam, at a given energy, through a gas cell containing 1-butanol, at a given pressure, and through application of the Beer-Lambert law to derive the required TCS. We also report theoretical results using the Independent-Atom Model with Screening Corrected Additivity Rule and Interference approach. Those results include the TCS, the elastic integral cross section (ICS), the ionization total ICS, and the sum over all excitation process ICSs with agreement at the TCS level between our measured and calculated results being encouraging.

Usefulness of Mesenchymal Cell Lines for Bone and Cartilage Regeneration Research.

The unavailability of sufficient numbers of human primary cells is a major roadblock for in vitro repair of bone and/or cartilage, and for performing disease modelling experiments. Immortalized mesenchymal stromal cells (iMSCs) may be employed as a research tool for avoiding these problems. The purpose of this review was to revise the available literature on the characteristics of the iMSC lines, paying special attention to the maintenance of the phenotype of the primary cells from which they were derived, and whether they are effectively useful for in vitro disease modeling and cell therapy purposes. This review was performed by searching on Web of Science, Scopus, and PubMed databases from 1 January 2015 to 30 September 2019. The keywords used were ALL = (mesenchymal AND ("cell line" OR immortal*) AND (cartilage OR chondrogenesis OR bone OR osteogenesis) AND human). Only original research studies in which a human iMSC line was employed for osteogenesis or chondrogenesis experiments were included. After describing the success of the immortalization protocol, we focused on the iMSCs maintenance of the parental phenotype and multipotency. According to the literature revised, it seems that the maintenance of these characteristics is not guaranteed by immortalization, and that careful selection and validation of clones with particular characteristics is necessary for taking advantage of the full potential of iMSC to be employed in bone and cartilage-related research.

Incident hand OA is strongly associated with reduced peripheral blood leukocyte telomere length.

OBJECTIVE: To evaluate the relationship of telomere length to the prevalence and incidence of hand osteoarthritis in a longitudinal cohort. DESIGN: We conducted a cross-sectional and longitudinal analysis of data from a subset of participants in the Osteoarthritis Initiative (OAI) recruited between February 2004 and May 2006. 274 individuals were eligible for the study based on availability of both baseline and 48-month hand radiographs and peripheral blood leucocyte telomere length data. Mean telomere length of peripheral blood leukocytes (PBL)s from the DNA samples was determined using a validated quantitative polymerase chain reaction (PCR)-based assay, and hand radiographs were analyzed and graded using the Kellgren-Lawrence scale. RESULTS: In joint -level analyses, prevalent Interphalangeal Joint Osteoarthritis (IPJOA) was significantly associated with PBL telomere length in the baseline sample in unadjusted analyses (RR = 2.84; 95% CI:0.87-9.29) or in models adjusted for age, sex, and body mass index (aRR = 1.10; 95% CI: 0.96-1.27). The association in crude and adjusted analyses appeared slightly stronger with incident IPJOA, especially in the subset with normal hands at baseline (aRR = 1.62; 95% CI: 1.02-2.57). PBL telomere length was also associated with prevalent HOA at baseline (significant in unadjusted analysis: RR = 1.22; 95% CI 1.06-1.42), but not after adjusting for covariates: aRR = 1.12; 95% CI: 0.96-1.30). The magnitude of association was stronger for incident HOA, especially incident symptomatic HOA (aRR = 1.53; 95% CI: 1.09-2.15). CONCLUSIONS: In summary, the results of this exploratory analysis are confirmatory of previous work showing a cross-sectional relationship between telomere length and HOA and add to the field by demonstrating an even stronger association with incident IPJOA, both radiographic and symptomatic.

Mitochondrial DNA haplogroups associated with MRI-detected structural damage in early knee osteoarthritis.

OBJECTIVE: Magnetic resonance imaging (MRI)-detected structural features are associated with increased risk of radiographic osteoarthritis (ROA). Specific mitochondrial DNA (mtDNA) haplogroups have been associated with incident ROA. Our objective was to compare the presence of MRI-detected structural features across mtDNA haplogroups among knees that developed incident ROA. DESIGN: Knees from the Osteoarthritis Initiative (OAI) that developed incident ROA during 48 months follow-up were identified from Caucasian participants. mtDNA haplogroups were assigned based on a single base extension assay. MRIs were obtained annually between baseline and 4-year follow-up and scored using the MRI Osteoarthritis Knee Score (MOAKS). The association between mtDNA haplogroups and MRI-detected structural features was estimated using log-binomial regression. Participants who carried haplogroup H served as the reference group. RESULTS: The sample included 255 participants contributing 277 knees that developed ROA. Haplogroups included H (116, 45%), J (17, 7%), T (26, 10%), Uk (61, 24%), and the remaining less common haplogroups ("others") (35, 14%). Knees of participants with haplogroup J had significantly lower risk of medium/large bone marrow lesions (BMLs) in the medial compartment [3.2%, relative risks (RR) = 0.17; 95%CI: 0.05, 0.64; P = 0.009] compared to knees of participants who carried haplogroup H [16.3%], as did knees from participants within the "others" group [2.8%, RR = 0.20; 95%CI: 0.08, 0.55; P = 0.002], over the 4 year follow-up period. CONCLUSIONS: mtDNA haplogroup J was associated with lower risk of BMLs in the medial compartment among knees that developed ROA. Our results offer a potential hypothesis to explain the mechanism underlying the previously reported protective association between haplogroup J and ROA.