IL-6 Reduces Spheroid Sizes of Osteophytic Cells Derived from Osteoarthritis Knee Joint via Induction of Apoptosis.

Osteophytes in osteoarthritis (OA) joints contribute to restriction of joint movement, joint pain, and OA progression, but little is known about osteophyte regulators. Examination of gene expression related to cartilage extracellular matrix, endochondral ossification, and growth factor signaling in articular cartilage and osteophytes obtained from OA knee joints showed that several genes such as COL1A1, VCAN, BGLAP, BMP8B, RUNX2, and SOST were overexpressed in osteophytes compared with articular cartilage. Ratios of mesenchymal stem/progenitor cells, which were characterized by co-expression of CD105 and CD166, were significantly higher in osteophytic cells than articular cells. A three-dimensional culture method for cartilage and osteophyte cells was developed by modification of cultures of self-assembled spheroid cell organoids (spheroids). These spheroids cultured in the media for mesenchymal stem cells containing transforming growth factor-ß3 showed characteristic morphologies and gene expression profiles of articular cartilage and osteophytes, respectively. The effects of IL-1ß, tumor necrosis factor-α, and IL-6 on the spheroids of articular and osteophytic cells were studied. To the best of our knowledge, they provide the first evidence that IL-6 suppresses the spheroid size of osteophytic cells by inducing apoptosis and reducing extracellular matrix molecules. These data show that IL-6 is the suppressor of osteophyte growth and suggest that IL-6 expression and/or activity are implicated in the regulation of osteophyte formation in pathologic joints.

OA susceptibility in mice is partially mediated by the gut microbiome, is transferrable via microbiome transplantation and is associated with immunophenotype changes.

OBJECTIVES: The Murphy Roths Large (MRL)/MpJ 'superhealer' mouse strain is protected from post-traumatic osteoarthritis (OA), although no studies have evaluated the microbiome in the context of this protection. This study characterised microbiome differences between MRL and wild-type mice, evaluated microbiome transplantation and OA and investigated microbiome-associated immunophenotypes. METHODS: Cecal material from mixed sex C57BL6/J (B6) or female MRL/MpJ (MRL) was transplanted into B6 and MRL mice, then OA was induced by disruption of the medial meniscus surgery (DMM). In other experiments, transplantation was performed after DMM and transplantation was performed into germ-free mice. Transplanted mice were bred through F2. OARSI, synovitis and osteophyte scores were determined blindly 8 weeks after DMM. 16S microbiome sequencing was performed and metagenomic function was imputed. Immunophenotypes were determined using mass cytometry. RESULTS: MRL-into-B6 transplant prior to DMM showed reduced OA histopathology (OARSI score 70% lower transplant vs B6 control), synovitis (60% reduction) and osteophyte scores (30% reduction) 8 weeks after DMM. When performed 48 hours after DMM, MRL-into-B6 transplant improved OA outcomes but not when performed 1-2 weeks after DMM. Protection was seen in F1 (60% reduction) and F2 progeny (30% reduction). Several cecal microbiome clades were correlated with either better (eg, Lactobacillus, R=-0.32, p=0.02) or worse (eg, Rikenellaceae, R=0.43, p=0.001) OA outcomes. Baseline immunophenotypes associated with MRL-into-B6 transplants and MRL included reduced double-negative T cells and increased CD25+CD4+ T cells. CONCLUSION: The gut microbiome is responsible in part for OA protection in MRL mice and is transferrable by microbiome transplantation. Transplantation induces resting systemic immunophenotyping changes that correlate with OA protection.

Finite Element Modeling of Chondrolabral Lesions in Pincer-Type Femoroacetabular Impingement.

BACKGROUND: The prevalence of chondrolabral lesions due to femoroacetabular impingement (FAI) is 93% in cadaveric material. As a biomechanically determined factor, it can lead to hip destruction and early osteoarthritis in pincer-type impingement. The aim of this work was to study the biomechanism and stress-strain behavior of chondrolabral lesions in pincer-type impingement during daily activity-associated movements. MATERIAL AND METHODS: The SolidWorks package was used to build a 3D pelvis model with and without pincer-type impingement in the femoroacetabular (FA) region. Finite element analysis (FEA) in ANSYS was performed to determine von Mises stress, strain and total deformations for the models during 90 hip flexion and 15 internal rotation during daily activities. RESULTS: Maximum stress-strain values increased 2-3.4 times in the bone along the anterior upper acetabular rim, femoral neck and acetabular labrum in the area of the pincer osteophyte compared to the non-pincer condition in the FA model. CONCLUSIONS: 1. The increase in stress-strain in the contact area at the pincer osteophyte and femoral neck can be a factor of cam-type osteophyte formation and progression of acetabular rim ossification. 2. Daily activity can lead to an increase in maximum stress, as a factor of chondral delamination and destruction of the acetabular labrum. 3. Early surgery is needed to avoid progression of osteoarthritis in pincer-type impingement.

Assessment of bony changes in temporomandibular joint in patients using cone beam computed tomography - a cross sectional study.

BACKGROUND AND AIM: The aim of this study is to evaluate the changes in the temporomandibular joint (TMJ) in patients with temporomandibular disorder (TMD) and the relationship between age, sex, and types of TMJ change using Cone Beam Computed Tomography (CBCT). METHODS AND MATERIAL: CBCT records of 200 patients (123 women and 67 men) were retrieved and assessed. Right and left TMJs were evaluated separately, resulting in a total of 400 TMJs. The images were analyzed using On demand 3D Application The radiographic findings were classified as erosion, proliferative changes mainly, including flattening and osteophytes of the condyle, sclerosis, Ely cyst, hypoplasia and hyperplasia of the condyles, ankylosis, and joint cavity. Data analysis was performed using descriptive statistics, paired T-tests, and repeated measure ANOVA (Analysis of Variance) in SPSS Software. RESULTS: The most prevalent types of condylar bony changes observed was osteophyte (63.5%) followed by flattening of the articular surface (42%), erosion (40%), ankylosis (10%) and sclerosis (10%). 7.5% of joints showed hyperplastic condyles but only 2% showed hypoplasia. The least prevalent change observed was Ely Cyst (1%). Osteophyte was the most prevalent change observed in all age groups and both sexes except for men aged 31 ~ 50, where flattening was more frequent. A statistically significant difference was found between sex and prevalence of erosion in the age group of 10 ~ 30 (P = 0.001); as well as between sex and condylar hyperplasia in the same age group. CONCLUSION: Based on the findings of this research, the prevalence of bony changes of TMJ from highest to lowest is as follows: osteophyte, flattening of the articular surface, erosion, ankylosis, sclerosis, hyperplastic condyles, hypoplastic condyles and Ely Cyst. CBCT is an accurate 3 dimensional imaging modality for assessment of TMJ bony structures.

Disease-modifying interactions between chronic kidney disease and osteoarthritis: a new comorbid mouse model.

OBJECTIVE: The prevalence of comorbid chronic kidney disease (CKD) and osteoarthritis (OA) is increasing globally. While sharing common risk factors, the mechanism and consequences of concurrent CKD-OA are unclear. The aims of the study were to develop a preclinical comorbid model, and to investigate the disease-modifying interactions. METHODS: Seventy (70) male 8-10 week-old C57BL/6 mice were subjected to 5/6 nephrectomy (5/6Nx)±destabilisation of medial meniscus (DMM) or sham surgery. OA pathology and CKD were assessed 12 weeks postinduction by blinded histology scoring, micro-CT, immunohistochemistry for osteoclast and matrix metalloproteinase (MMP)-13 activity, and serum analysis of bone metabolic markers. RESULTS: The 5/6Nx model recapitulated characteristic features of CKD, with renal fibrosis and deranged serum alkaline phosphatase, calcium and phosphate. There was no histological evidence of cartilage pathology induced by 5/6Nx alone, however, synovial MMP-13 expression and subchondral bone osteoclastic activity were increased (p<0.05), with accompanying reductions (p<0.05) in subchondral trabecular bone, bone volume and mineral density. DMM significantly (p<0.05) increased tibiofemoral cartilage damage, subchondral bone sclerosis, marginal osteophytes and synovitis, in association with increased cartilage and synovial MMP-13. DMM alone induced (p<0.05) renal fibrosis, proteinuria and increased (p<0.05) 5/6Nx-induced serum urea. However, DMM in 5/6Nx-mice resulted in significantly reduced (p<0.05) cartilage pathology and marginal osteophyte development, in association with reduced subchondral bone volume and density, and inhibition of 5/6Nx-induced subchondral bone osteoclast activation. CONCLUSION: This study assessed a world-first preclinical comorbid CKD-OA model. Our findings demonstrate significant bidirectional disease-modifying interaction between CKD and OA.

Sacroiliac joint MRI for diagnosis of ax-SpA: algorithm to improve the specificity of the current ASAS MRI criteria.

OBJECTIVE: To compare sacroiliac joint (SIJ) lesions on MRI in women with versus without axial spondyloarthritis (ax-SpA) and establish an algorithm to determine whether such lesions are due to ax-SpA. METHODS: This retrospective comparative study assessed bone marrow edema (BME), sclerosis, erosions, osteophytes, and ankylosis at the SIJ in two groups of women, one with and another without ax-SpA. Sensitivity and specificity were calculated for combinations/characteristics of lesions, using rheumatologists' assessment with assessment of spondyloarthritis international society (ASAS) criteria as the gold standard for diagnosis of ax-SpA. RESULTS: Compared to women without ax-SpA, women with ax-SpA had more BME (61% vs 17%, p < 0.001), sclerosis (40% vs 22%, p < 0.001), erosions (35% vs 5%, p < 0.001), and ankylosis (2% vs 0%, p = 0.007), but less osteophytes (5% vs 33%, p < 0.001). The ASAS MRI criteria yielded 59% sensitivity and 88% specificity, while a new algorithm achieved 56% sensitivity and 95% specificity using the following criteria: no osteophytes at the SIJ and either (i) BME at the SIJ with at least one dimension ≥ 8 mm or (ii) at least one erosion at the SIJ. CONCLUSIONS: We recommend the following pragmatic algorithm for MRI diagnosis of ax-SpA in women: no osteophytes at the SIJ and either (i) BME at the SIJ with at least one dimension ≥ 8 mm or (ii) at least one erosion at the SIJ. The false positive rate when using the new algorithm (3.3%) is less than half than when using the ASAS MRI criteria (7.7%); thus, its application in clinical practice could reduce overdiagnosis and prevent overtreatment of ax-SpA. CLINICAL RELEVANCE STATEMENT: The developed algorithm has a false-positive rate that is less than half than when using the ASAS MRI criteria (3.3% vs 7.7%), thus its application in clinical practice could reduce overdiagnosis and prevent overtreatment of axial spondyloarthritis. KEY POINTS: • Compared to women without axial spondyloarthritis (ax-SpA), women with ax-SpA had a significantly higher prevalence of bone marrow edema (BME), sclerosis, erosions, and ankylosis, but a significantly lower prevalence of osteophytes. • A new algorithm for positive ax-SpA based on sacroiliac joint MRI was developed: no osteophytes at the sacroiliac joint (SIJ) and either (i) BME at the SIJ with at least one dimension ≥ 8 mm or (ii) at least one erosion at the SIJ. • We recommend this new algorithm for diagnosis of ax-SpA in women, as it has a significantly better specificity than the assessment of spondyloarthritis international society (ASAS) MRI criteria and less than half the false positive rate; thus, its application in clinical practice could reduce overdiagnosis and prevent overtreatment of ax-SpA.

Tibial Retro-Malleolar Groove Morphology in Patients With Posterior Tibialis Tendon Dysfunction.

The posterior tibial tendon is a gliding tendon which courses around the medial malleolus and fails in posterior tibialis tendon dysfunction (PTTD) leading to a flat foot deformity. Distal tibial bone spurs have been identified as a secondary sign of PTTD although they have not been quantified in detail. The aim of this study was to assess the association of tendon dysfunction with the bony morphology of the tibial retro-malleolar groove. We performed a retrospective review of the clinical presentation, plain radiographs, and 103 magnetic resonance imaging (MRI) scans in 82 consecutive patients with PTTD compared with a non-PTTD group. We carried out a quantitative and qualitative assessment of the presence of plain radiographic bone spurs, stage of PTTD and MRI imaging of the morphology of the tibial bony malleolar groove. Plain radiographic bone spurs, as a secondary sign of PTTD, were present in 21.3% of ankle radiographs. MRI bone spurs were identified in 26/41 (63.4%) for all high-grade partial and complete tears and 7/41 (17.1%) for isolated complete tears compared with only 3.9% of the non-PTTD group. There was a significant association between the presence of bone spurs on MRI imaging and high-grade partial and complete tibialis posterior tears (p < .001; odds ratio of 4.98). Eleven of 103 (10.7%) of spurs were large and in 4/103 (3.9%) were substantial enough to create a tunnel-like hypertrophic groove not previously reported. There is variation in the bony structure of the malleolar groove in PTTD not observed in the non-PTTD group. Further investigation over time may elucidate whether the groove morphology may lead to mechanical attrition of the tibialis posterior tendon and contribute to failure of healing and progressive tendon degeneration.

Relationship between the morphology of osteophytes and cartilage lesions in anterior ankle impingement in athletes: a cross-sectional study.

BACKGROUND: The present study aimed to describe the frequency and severity of tram-track lesions in anterior ankle impingement in athletes and to evaluate the association between osteophyte morphology and severity of tram-track lesions, the distinctive cartilage lesions associated with tibial osteophytes in anterior ankle impingement syndrome. METHODS: We evaluated 34 athletes who underwent arthroscopic osteophyte resection for anterior ankle impingement between January 2017 and March 2021. RESULTS: We found tram-track lesions in 26 athletes (76.5%). Arthroscopic findings revealed the distribution of the International Cartilage Repair Society grades of tram-track lesions (grade 0, eight; grade 1, seven; grade 2, ten; grade 3, nine; grade 4, zero). These findings indicate that athletes with anterior ankle impingement syndrome may have more severe cartilage lesions than non-athletes. There was a positive correlation between the International Cartilage Repair Society grade and osteophyte size (r = 0.393, p = 0.021). We divided athletes into two groups according to the presence or absence of osteophyte protrusion into the joint space. Osteophyte protrusion was present in 14 athletes (41.2%). All athletes in the protrusion-type group had tram-track lesions; seven (50%) had International Cartilage Repair Society grade 3. The protrusion-type group's International Cartilage Repair Society grade was significantly higher than that of the non-protrusion-type group (p = 0.008). The osteophyte sizes in the two groups were not significantly different (p = 0.341). CONCLUSIONS: Based on these findings, osteophyte protrusion should be assessed when an indication of arthroscopic treatment for anterior ankle impingement syndrome is considered, particularly in athletes.

MRI Does Not Improve Inter- or Intrarater Reliability for Hip Arthritis Grading Systems.

BACKGROUND: Magnetic resonance imaging (MRI) scans and radiographs are often utilized in assessing for preoperative osteoarthritis in patients undergoing hip preservation surgery. PURPOSE: To determine if MRI scans improve inter- or intrarater reliabilities over radiographs for findings of hip arthritis. STUDY DESIGN: Cohort study (Diagnosis); Level of evidence, 3. METHODS: Anteroposterior and cross-table lateral radiographs as well as a representative coronal and sagittal T2-weighted MRI scan were reviewed for 50 patients by 7 experienced subspecialty hip preservation surgeons, with a minimum experience of 10 years. Radiographs and MRI scans were assessed for joint space narrowing, subchondral cysts, osteophytes, subchondral sclerosis, Likert osteoarthritis grade (none, mild, moderate, or severe), and Tönnis grade. MRI scans were also evaluated for bony edema, heterogeneous articular cartilage, and chondral defects. Inter- and intrarater reliabilities were calculated utilizing the Fleiss method with a 95% CI. RESULTS: The scans of 50 patients (28 female and 22 male) with a mean age of 42.8 years (SD, 14.2 years; range, 19-70 years) were reviewed. Radiographs revealed fair agreement for joint space narrowing (κ = 0.25 [95% CI, 0.21-0.30]), osteophytes (κ = 0.26 [95% CI, 0.14-0.40]), Likert osteoarthritis grading (κ = 0.33 [95% CI, 0.28-0.37]) and Tönnis grade (κ = 0.30 [95% CI, 0.26-0.34). Radiographs revealed moderate agreement for subchondral cysts (κ = 0.53 [95% CI, 0.35-0.69]). MRI scans demonstrated poor to fair agreement for joint space narrowing (κ = 0.15 [95% CI, 0.09-0.21]), subchondral sclerosis (κ = 0.27 [0.19-0.34]), heterogeneous articular cartilage (κ = 0.07 [95% CI, 0.00-0.14]), Likert osteoarthritis grade (κ = 0.19 [95% CI, 0.15-0.24]), and Tönnis grade (κ = 0.20 [95% CI, 0.15-0.24]). MRI scans demonstrated substantial agreement for subchondral cysts (κ = 0.73 [95% CI, 0.63-0.83]). Intrarater reliabilities were statistically improved compared with interrater reliabilities, but no differences were found between radiographs and MRI scans for joint space narrowing, subchondral cysts, osteophytes, osteoarthritis grade, or Tönnis grade. CONCLUSION: Radiographs and MRI scans had substantial limitations and inconsistency between raters in evaluating common markers of hip osteoarthritis. MRI scans demonstrated strong reliability in evaluating for subchondral cysts but did not improve the interobserver variability of grading hip arthritis.

Axial Compressive Loading Attenuates Early Osteoarthritis by Reducing Subchondral Bone Remodeling.

BACKGROUND: Mechanical loading and alendronate (ALN) can be used as noninvasive physical therapy methods for osteoarthritis (OA). However, the timing and efficacy for treatments are unknown. PURPOSE: To determine whether the timing of mechanical loading and ALN influences the pathobiological changes of OA. STUDY DESIGN: Controlled laboratory study. METHODS: Mice with OA induced by anterior cruciate ligament transection were subjected to early (1-3 weeks) or late (5-7 weeks) axial compressive dynamic load or intraperitoneal injection of ALN. Changes in gait were analyzed using gait analysis system, pathobiological changes in subchondral bone, cartilage, osteophyte, and synovitis were assessed using micro-computed tomography, tartrate-resistant acid phosphatase staining, pathologic section staining, and immunohistochemistry at 1, 2, 4, and 8 weeks. RESULTS: At 1, 2, and 4 weeks, the OA limb had lower mean footprint pressure intensity, lower bone volume per tissue volume (BV/TV) in the subchondral bone, and more osteoclasts. At 4 weeks, the early loading, ALN, and load + ALN treatments induced less cartilage destruction, with a corresponding reduction in Osteoarthritis Research Society International score and increased hyaline cartilage thickness. The treatments also resulted in fewer osteoclasts and higher BV/TV and bone mineral density of subchondral bone and suppressed inflammation and interleukin 1ß- and tumor necrosis factor α-positive cells in synovium. At 8 weeks, early loading or load + ALN improved the mean footprint pressure intensity and knee flexion. At 8 weeks, early load + ALN had a synergistic effect on protecting hyaline cartilage and proteoglycans. Footprint pressure intensity and cartilage destruction were worse in late loading limbs, and no differences in BV/TV, bone mineral density, osteophyte formation, and synovium inflammation were found between the late load, ALN, and load + ALN groups and the anterior cruciate ligament transection group. CONCLUSION: Dynamic axial mechanical loading or ALN in the early stages of knee trauma protected against OA by suppressing subchondral bone remodeling. However, late loading promoted cartilage degeneration in advanced OA, indicating that reduced loading should be performed in the late stages of OA to avoid the acceleration of OA. CLINICAL RELEVANCE: Early low-level functional exercise or antiosteoporotic drugs could clearly slow or prevent the progression of early OA. For patients with mild to severe OA, loading reduction via brace protection or maintenance of joint stability via early ligament reconstruction surgery may ameliorate OA exacerbation.

Metabolic syndrome and the progression of knee osteoarthritis on MRI.

OBJECTIVE: Metabolic osteoarthritis (OA) is one of the proposed clinical phenotypes defined by the existence of metabolic syndrome (MetS). This study aimed to (1) investigate whether MetS and its components are associated with progression of knee OA magnetic resonance imaging (MRI) features, and (2) to evaluate the interaction of MetS with menopause and progression of MRI features. METHOD: 682 women from the Rotterdam Study who participated in a sub-study with knee MRI data available and 5-year follow-up were included. Tibiofemoral (TF) and patellofemoral (PF) OA features were assessed with the MRI Osteoarthritis Knee Score. MetS was quantified by the MetS severity Z-score. Generalized estimating equations were used to evaluate associations between MetS and menopausal transition and progression of MRI features. RESULTS: MetS severity at baseline was associated with progression of osteophytes in all compartments, bone marrow lesions (BMLs) in the PF compartment, and cartilage defects in the medial TF compartment. Waist circumference was associated with progression of osteophytes in all compartments and cartilage defects in the medial TF compartment. High-density lipoprotein (HDL)-cholesterol levels were associated with progression of osteophytes in the medial and lateral TF compartment and glucose levels with osteophytes in the PF and medial TF compartment. No interactions were found between MetS with menopausal transition and MRI features. CONCLUSION: Women with higher MetS severity at baseline showed progression of osteophytes, BMLs, and cartilage defects, indicating more structural knee OA progression after 5 years. Further studies are required to understand whether targeting MetS components may prevent the progression of structural knee OA in women.

The combined effects of treadmill exercise and steroid administration on anterior cruciate ligament reconstruction-induced joint contracture and muscle atrophy in rats.

Rehabilitation protocols to treat joint contracture and muscle atrophy following anterior cruciate ligament (ACL) reconstruction have not been established. In this study, we examined the combined effects of exercise therapy and steroid administration on joint contracture and muscle atrophy following ACL reconstruction. Rats received ACL transection and reconstructive surgery in one knee. After surgery, they were divided into four groups: no intervention, treadmill exercise (started from day three post-surgery, 12 m/min, 60 min/d, 6 d/week), treatment with the steroidal drug dexamethasone (250 µg/kg on days 0-5, 7, and 9 post-surgery), and dexamethasone treatment plus treadmill exercise. Age-matched untreated rats were used as controls. At day 10 or 30 post-surgery, we assessed ACL-reconstruction-induced joint contracture, joint capsule fibrosis, osteophyte formation, and muscle atrophy of the rectus femoris and gastrocnemius. Treadmill exercise after ACL reconstruction improved several indicators of muscle atrophy in both muscles, but it did not have positive effects on joint contracture. Dexamethasone treatment after ACL reconstruction improved joint contracture and joint capsule fibrosis at both timepoints and partially attenuated osteophyte formation at day 10 post-surgery, but delayed recovery from atrophy of the rectus femoris at day 30 post-surgery. The two treatments combined improved both joint contracture and atrophy of the rectus femoris and gastrocnemius. Exercise therapy combined with steroid administration may therefore be a novel therapeutic strategy for joint contracture and muscle atrophy following ACL reconstruction.

Potential surrogate outcomes in individuals at high risk for incident knee osteoarthritis.

OBJECTIVE: To study potential surrogate outcomes for osteoarthritis (OA) incidence by evaluating the association of short-term changes in clinical and imaging biomarkers with long-term clinical knee OA incidence. DESIGN: Middle-aged women with overweight/obesity, but free of knee symptoms were recruited through their general practitioners. At baseline, after 2.5 years, and after 6.5 years, questionnaires, physical examination, radiographs, and Magnetic resonance imaging (MRI) scans were obtained. The percentage of knees with a minimal clinically important difference for knee pain severity, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain/stiffness/function, and joint space narrowing, and of those with progression/regression of medial knee alignment, chronic knee pain, radiographic osteophytes, and cartilage defects, bone marrow lesions, osteophytes, and effusion/synovitis on MRI were determined. For each of these potential surrogate outcomes with ≥10% improvement or progression in the population over 2.5 years, the association with incident clinical knee OA, defined using the combined ACR-criteria, after 6.5 years was determined. RESULTS: Most pre-defined potential surrogate outcomes showed ≥10% change in the population over 2.5 years, but only worsening of TF cartilage defects, worsening of TF osteophytes on MRI, and an increase in pain severity were significantly associated with greater clinical knee OA incidence after 6.5 years. These potential surrogate outcomes had high specificity and negative predictive value (89-91%) and low sensitivity and positive predictive value (20-28%) CONCLUSIONS: Worsening of TF cartilage defects and TF osteophytes on MRI, and increased pain severity could be seen as surrogate outcomes for long-term OA incidence. However, higher positive predictive values seem warranted for the applicability of these factors in future preventive trials.

Development of a Magnetic Resonance Imaging-Based Definition of Knee Osteoarthritis: Data From the Multicenter Osteoarthritis Study.

OBJECTIVE: Although magnetic resonance imaging (MRI) is the imaging modality of choice for research, there is no widely accepted MRI definition of knee osteoarthritis (OA). We undertook this study to test the performance of different MRI definitions of OA. METHODS: We studied Multicenter Osteoarthritis Study participants with knee symptoms using posteroanterior and lateral knee radiographs and MRIs. Radiographic OA was defined as Kellgren/Lawrence grade ≥2 in the tibiofemoral (TF) and/or patellofemoral (PF) joint. Symptomatic OA was defined using a validated questionnaire. MRI findings of cartilage damage, osteophytes, bone marrow lesions (BMLs), and synovitis were scored using the Whole-Organ MRI Score system. We compared definitions using combinations of MRI features to the validation criteria of prevalent radiographic OA and symptomatic OA. All combinations included cartilage damage score ≥2 (0-6 scale) and osteophyte score ≥2 (0-6 scale); addition of BMLs and synovitis score was also tested. We also evaluated a Delphi panel definition that defined OA differently for the PF and TF joints. For each definition, we calculated sensitivity, specificity, and the area under the curve (AUC). RESULTS: We included 1,185 knees from 1,185 participants (mean age 66 years, 62% female, 89% White). Among the 1,185 knees, 482 knees had radiographic OA, and 524 knees had symptomatic OA. The MRI definitions with a cartilage score ≥2 and osteophyte score ≥2 and definitions which added BMLs or synovitis score ≥1 had the highest sensitivities (95.2% and 94.5%, respectively) for prevalent radiographic OA (AUCs 0.67 and 0.69, respectively), and also had the highest sensitivities for symptomatic OA. The Delphi panel definition had similar performance but was more complex to apply. CONCLUSION: An MRI OA definition requiring cartilage damage and a small osteophyte with or without BMLs or synovitis had the best performance and was simplest for identifying radiographic OA and symptomatic OA.

Risk estimation of degenerative joint disease in temporomandibular disorder patients with different types of sagittal and coronal disc displacements: MRI and CBCT analysis.

BACKGROUND: Degenerative joint disease (DJD) can be associated with disc displacement (DD) in temporomandibular disorder (TMD) patients. However, the relationship between different types of DDs and DJD remains unclear. OBJECTIVES: To investigate the odds ratios of different types of sagittal and coronal DDs confirmed by magnetic resonance imaging (MRI) and DJD confirmed by cone-beam computed tomography (CBCT) in TMD patients. METHODS: Radiographic data from 69 males and 232 females were collected for analysis. CBCT was used to diagnose DJD, with criteria including erosion, osteophytes, generalised sclerosis and cysts in the joint. Eight types of DDs were evaluated by sagittal and coronal MRIs: NA, no abnormality; SW, sideways; ADDR, anterior with reduction; ADDR+SW; ADDNR, anterior without reduction; ADDNR + SW; single SW; PDD, posterior; PDD + SW. The odds ratios of DJD in joints with different types of DDs were determined after joint correlation, age and gender adjustment. RESULTS: Compared with NA, the odds ratio of DJD in ADDR was 2.397 (95% CI [confidence interval]: 1.070-5.368), ADDR + SW was 4.808 (95% CI: 1.709-3.528), ADDNR was 29.982 (95% CI: 15.512-57.950) and ADDNR + SW was 25.974 (95% CI: 12.743-52.945). Erosion was significantly increased in ADDR, ADDR + SW, ADDNR and ADDNR + SW; osteophytes were significantly increased in ADDR + SW, ADDNR and ADDNR + SW; and generalised sclerosis and cysts were significantly increased in ADDNR and ADDNR + SW. There were no significant associations between single SW, PDD, PDD + SW and the DJD. CONCLUSIONS: ADDR, ADDR+SW, ADDNR and ADDNR+SW were associated with DJD. ADDNR had a significantly higher prevalence of DJD than ADDR. There were no significant relationships between single SW, PDD, PDD + SW and the DJD.

Association between statins and progression of osteoarthritis features on magnetic resonance imaging in a predominantly pre-radiographic cohort: the Vancouver Longitudinal Study of Early Knee Osteoarthritis (VALSEKO): a cohort study.

BACKGROUND: To evaluate the effect of statin use on osteoarthritis (OA) incidence/progression using magnetic resonance imaging (MRI) in a population-based cohort with predominantly pre-radiographic knee OA. METHODS: A cohort aged 40-79 years with knee pain was recruited using random population sampling and followed for 7 years. Baseline exclusions were inflammatory arthritis, recent knee surgery/injury, and inability to undergo MRI. At baseline, current statin use was ascertained. Baseline and follow-up MRIs were read semi-quantitatively for cartilage damage (grade 0-4, 0/1 collapsed, 6 regions), osteophytes (grade 0-3, 8 regions), bone marrow lesions (BML) (grade 0-3, 6 regions) and effusion (grade 0-3). The primary outcome was cartilage damage incidence/progression, while secondary outcomes were incidence/progression of osteophytes, BML, and effusion, each defined as an increase by ≥1 grade at any region. To ensure population representative samples, sample weights were used. Logistic regression was used to assess the association of statin use at baseline with incidence/progression of MRI outcomes. Analyses were adjusted for sex, age, BMI, and multiple comorbidities requiring statin therapy. RESULTS: Of 255 participants evaluated at baseline, 122 completed the 7-year follow-up. Statin use was not significantly associated with progression of cartilage damage (OR 0.82; 95% CI 0.17, 4.06), osteophytes (OR 3.48; 95% CI 0.40, 30.31), BML (OR 0.61; 95% CI 0.12, 3.02), or effusion (OR 2.38; 95% CI 0.42, 13.63), after adjusting for confounders. CONCLUSION: In this population-based cohort of predominantly pre-radiographic knee OA, statins did not affect MRI incidence/progression of cartilage damage, BML, osteophytes or effusion. Therefore, statin use does not appear to affect people with pre-radiographic stages of knee OA.

Osteophytes mediate the associations between cartilage morphology and changes in knee symptoms in patients with knee osteoarthritis.

AIMS: To investigate whether the associations between cartilage defects and cartilage volumes with changes in knee symptoms were mediated by osteophytes. METHODS: Data from the Vitamin D Effects on Osteoarthritis (VIDEO) study were analyzed as a cohort. The Western Ontario and McMaster Universities Osteoarthritis Index was used to assess knee symptoms at baseline and follow-up. Osteophytes, cartilage defects, and cartilage volumes were measured using magnetic resonance imaging at baseline. Associations between cartilage morphology and changes in knee symptoms were assessed using linear regression models, and mediation analysis was used to test whether these associations were mediated by osteophytes. RESULTS: A total of 334 participants (aged 50 to 79 years) with symptomatic knee osteoarthritis were included in the analysis. Cartilage defects were significantly associated with change in total knee pain, change in weight-bearing pain, and change in non-weight-bearing pain after adjustment for age, sex, body mass index, and intervention. Cartilage volume was significantly associated with change in weight-bearing pain and change in physical dysfunction after adjustment. Lateral tibiofemoral and patellar osteophyte mediated the associations of cartilage defects with change in total knee pain (49-55%) and change in weight-bearing pain (61-62%) and the association of cartilage volume with change in weight-bearing pain (27-30%) and dysfunction (24-25%). Both cartilage defects and cartilage volume had no direct effects on change in knee symptoms. CONCLUSIONS: The significant associations between cartilage morphology and changes in knee symptoms were indirect and were partly mediated by osteophytes.

Salinomycin alleviates osteoarthritis progression via inhibiting Wnt/ß-catenin signaling.

Osteoarthritis (OA) is the most prevalent degenerative whole-joint disease characterized by cartilage degeneration, synovial hyperplasia, osteophyte formation, and subchondral bone sclerosis. Currently there are no disease-modifying treatments available for OA because its etiology and pathogenesis are largely unknown. Here we report that a natural carboxylic polyether ionophore that is used as an anti-tumor drug, salinomycin (SAL), may be a promising therapeutic drug for OA in the future. We found that SAL showed no cytotoxicity on mouse chondrocytes and displayed a protective effect against interleukin-1ß (IL-1ß), in cultured mouse chondrocytes and cartilage explants. Treatment with low SAL concentrations directly upregulated the anabolism factors collagen II and aggrecan, while it inhibited the catabolic factors matrix metalloproteinase-13 (MMP13) and metalloproteinase with thrombospondin motifs-5 (ADAMTS5) to protect against extracellular matrix (ECM) degradation, and also suppressed inflammatory responses in mouse chondrocytes. Furthermore, SAL reduced the severity of OA-associated changes and delayed cartilage destruction, subchondral bone sclerosis, and osteophyte formation in a destabilized medial meniscus (DMM) surgery-induced mouse OA model. Mechanistically, a low SAL concentration induced anabolism and inhibited catabolism in chondrocytes via inhibiting Lrp6 phosphorylation and Wnt/ß-catenin signaling. Our results suggested that SAL may serve as a potential disease-modifying therapeutic against OA pathogenesis.

High bone mass and cam morphology are independently related to hip osteoarthritis: findings from the High Bone Mass cohort.

BACKGROUND: High bone mass (HBM, BMD Z-score ≥ + 3.2) and cam morphology (bulging of lateral femoral head) are associated with greater odds of prevalent radiographic hip osteoarthritis (rHOA). As cam morphology is itself a manifestation of increased bone deposition around the femoral head, it is conceivable that cam morphology may mediate the relationship between HBM and rHOA. We therefore aimed to determine if individuals with HBM have increased odds of prevalent cam morphology. In addition, we investigated whether the relationship between cam and prevalent and incident osteoarthritis was preserved in a HBM population. METHODS: In the HBM study, a UK based cohort of adults with unexplained HBM and their relatives and spouses (controls), we determined the presence of cam morphology using semi-automatic methods of alpha angle derivation from pelvic radiographs. Associations between HBM status and presence of cam morphology, and between cam morphology and presence of rHOA (or its subphenotypes: osteophytes, joint space narrowing, cysts, and subchondral sclerosis) were determined using multivariable logistic regression, adjusting for age, sex, height, weight, and adolescent physical activity levels. The association between cam at baseline and incidence of rHOA after an average of 8 years was determined. Generalised estimating equations accounted for individual-level clustering. RESULTS: The study included 352 individuals, of whom 235 (66.7%) were female and 234 (66.5%) had HBM. Included individuals contributed 694 hips, of which 143 had a cam deformity (20.6%). There was no evidence of an association between HBM and cam morphology (OR = 0.97 [95% CI: 0.63-1.51], p = 0.90) but a strong relationship was observed between cam morphology and rHOA (OR = 3.96 [2.63-5.98], p = 5.46 × 10-11) and rHOA subphenotypes joint space narrowing (OR = 3.70 [2.48-5.54], p = 1.76 × 10-10), subchondral sclerosis (OR = 3.28 [1.60-6.60], p = 9.57 × 10-4) and osteophytes (OR = 3.01 [1.87-4.87], p = 6.37 × 10-6). Cam morphology was not associated with incident osteoarthritis (OR = 0.76 [0.16-3.49], p = 0.72). CONCLUSIONS: The relationship between cam morphology and rHOA seen in other studies is preserved in a HBM population. This study suggests that the risk of OA conferred by high BMD and by cam morphology are mediated via distinct pathways.

Subchondral Drilling Independent of Drill Hole Number Improves Articular Cartilage Repair and Reduces Subchondral Bone Alterations Compared With Debridement in Adult Sheep.

BACKGROUND: Subchondral drilling is an established marrow stimulation technique for small cartilage defects, but whether drilling is required at all and if the drill hole density affects repair remains unclear. HYPOTHESES: Osteochondral repair is improved when the subchondral bone is perforated by a higher number of drill holes per unit area, and drilling is superior to defect debridement alone. STUDY DESIGN: Controlled laboratory study. METHODS: Rectangular full-thickness chondral defects (4 × 8 mm) were created in the trochlea of adult sheep (N = 16), debrided down to the subchondral bone plate without further treatment as controls (no treatment; n = 7) or treated with either 2 or 6 (n = 7 each) subchondral drill holes (diameter, 1.0 mm; depth, 10.0 mm). Osteochondral repair was assessed at 6 months postoperatively by standardized (semi-)quantitative macroscopic, histological, immunohistochemical, biochemical, and micro-computed tomography analyses. RESULTS: Compared with defect debridement alone, histological overall cartilaginous repair tissue quality (P = .025) and the macroscopic aspect of the adjacent cartilage (P≤ .032) were improved after both drilling densities. Only drilling with 6 holes increased type 2 collagen content in the repair tissue compared with controls (P = .038). After debridement, bone mineral density was significantly decreased in the subchondral bone plate (P≤ .015) and the subarticular spongiosa (P≤ .041) compared with both drilling groups. Debridement also significantly increased intralesional osteophyte sectional area compared with drilling (P≤ .034). No other differences in osteochondral repair existed between subchondral drilling with 6 or 2 drill holes. CONCLUSION: Subchondral drilling independent of drill hole density significantly improves structural cartilage repair compared with sole defect debridement of full-thickness cartilage defects in sheep after 6 months. Subchondral drilling also leads to a better reconstitution of the subchondral bone compartment below the defects. Simultaneously, drilling reduced the formation of intralesional osteophytes caused by osseous overgrowth compared with debridement. CLINICAL RELEVANCE: These results have important clinical implications, as they support subchondral drilling independent of drill hole number but discourage debridement alone for the treatment of small cartilage defects. Clinical studies are warranted to further quantify the effects of subchondral drilling in similar settings.