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In this histologically controlled in vitro study, we evaluated the validity of plain radiography for the assessment of lateral knee joint cartilage degeneration (25 specimens). We examined the correlation between histological grade and radiography findings along with patient demographics. Our study indicated that the Mankin score had a significant inverse correlation with middle joint space width (JSW ; r=-0.19,P=0.02), but not with inner and outer JSW (inner : r=-0.11,P=0.10, outer : r=-0.14,P=0.06) under a non-weight bearing condition. The Mankin score had a significant inverse correlation with middle and outer JSW (middle : r=-0.17,P=0.04, outer : r=-0.14,P=0.04), but not with inner JSW (inner : r=-0.15,P=0.06) under valgus stress. There was no significant correlation between the Mankin score and osteophyte thickness (r=0.004,P=0.76). We also examined the correlation with patient demographics. We found that only the preoperative femorotibial angle had a significant inverse correlation with the Mankin score. These results indicate that JSW, but not osteophyte thickness, is reliable for evaluating lateral femoral cartilage degeneration.

Osteoarthritis (OA) is a debilitating, degenerative joint disease characterized by progressive destruction of articular cartilage. Given the poor repair capacity of articular cartilage and the associated local destructive immune/inflammatory responses involving all joint structures, OA frequently ends up as a "whole joint failure" requiring prosthetic replacement. Current pharmacological efforts, belatedly started, mainly aim at symptomatic pain relief, underscoring the need for novel therapeutic schemes designed to modify the course of the disease. Mesenchymal stem cell (MSC)-based therapy has gained significant interest, sparking the design of multiple trials proving safety while providing promising preliminary efficacy results. MSCs possess 'medicinal signaling cell' properties related to their immunomodulatory and anti-inflammatory effects, which induce the establishment of a pro-regenerative microenvironment at the injured tissue. Those trophic effects are paralleled by the long-established chondroprogenitor capacity that can be harnessed to ex vivo fabricate engineered constructs to repair damaged articular cartilage. The present review focuses on these two aspects of the use of MSCs for articular cartilage damage, namely, cell therapy and tissue engineering, providing information on their use criteria, advancements, challenges and strategies to overcome them., (Copyright © 2019 International Society for Cell and Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Traumatic joint injury is known to cause cartilage deterioration and osteoarthritis. In order to study the mechanical mechanism of damage evolution on articular cartilage, taking the fresh porcine articular cartilage as the experimental samples, the creep experiments of the intact cartilages and the cartilages with different depth defect were carried out by using the noncontact digital image correlation technology. And then, the creep constitutive equations of cartilages were established. The results showed that the creep curves of different layers changed exponentially and were not coincident for the cartilage sample. The defect affected the strain values of the creep curves. The creep behavior of cartilage was dependent on defect depth. The deeper the defect was, the larger the strain value was. The built three-parameter viscoelastic constitutive equation had a good correlation with the experimental results and could predict the creep performance of the articular cartilage. The creep values of the microdefective cartilage in the damaged early stage were different from the diseased articular cartilage. These findings pointed out that defect could accelerate the damage of cartilage. It was helpful to study the mechanical mechanism of damage evolution., Competing Interests: The authors declared that they have no conflicts of interest to this work., (Copyright © 2019 Huchen Gong et al.)

Introduction: Given the expansion of commercial and recreational space exploration, orthopaedic surgeons will need to understand the implications of microgravity on cartilaginous damage and to anticipate the resulting pathology from accelerated chondrolysis. The purpose of this systematic review is to evaluate the effects of space and microgravity on hip and knee articular cartilage, including its impact on joint mobility and functional status., Materials and Methods: A review of the current literature was performed utilizing the terms "joints," "joint mobility," "articular cartilage," "knee," "hip," "space," "microgravity," and "osteoarthritis" in PubMed and Google Scholar from 1990 to 2018, yielding a total of 1,400 citations following the removal of 500 duplicates. Following screening by eligibility criteria, five reports were included., Results: Dysregulation of osteogenesis and weakened structural integrity of hip and knee cartilage were demonstrated secondary to microgravity. Adequate cartilage repair requires Earth-like conditions as signified by a statistically significant increase in serum cartilage oligomeric matrix protein concentrations in astronauts. Reduced loading led to the degradation of knee ligaments and menisci which may pose a risk for subluxation or dislocation. Murine studies demonstrated decreased articular cartilage thickness in the medial femoral condyle and patella as assessed by ultrasound. Additionally, glycosaminoglycan levels in unloaded rats were lower than weight-bearing rats, with a concomitant increase in matrix metalloproteinase-13 protein, degrading collagen. Return to weight-bearing demonstrated partial recovery of cartilaginous degeneration., Conclusions: Space and associated microgravity conditions adversely impact articular cartilage as demonstrated in murine and human studies. The pathogenetic process occurs due to the mechanically responsive nature of cartilage, with an increase in cartilage metabolism in microgravity. There remains a marked paucity of literature regarding the gravitational force necessary for adequate cartilage survival and the impact of space-related radiation on cartilage repair. Additionally, further studies should assess pharmacologic interventions, such as recombinant human fibroblast growth factor to stimulate cartilaginous growth.

Objective: To investigate whether and how a sedentary lifestyle contributes to knee osteoarthritis (OA) incidence and severity., Design: An experiment was conducted using Hartley guinea pigs, an established idiopathic knee OA model. To simulate a sedentary lifestyle, growing animals (n = 18) were housed for 22 weeks in small cages that restricted their mobility, while another group of animals (n = 17) received daily treadmill exercise to simulate moderate physical activity. After the experiment, histological assessments, biochemical assays, and mechanical testing were conducted to compare tibial articular cartilage structure, strength, and degree of OA degeneration between sedentary and physically active animals. Groups were also compared based on body weight and composition, as well as gut microbial community composition assessed using fecal 16S rRNA gene sequencing., Results: Prevalence of knee OA was similar between sedentary and physically active animals, but severity of the disease (cartilage lesion depth) was substantially greater in the sedentary group (P = 0.02). In addition, during the experiment, sedentary animals developed cartilage with lower aggrecan quantity (P = 0.03) and accumulated more body weight (P = 0.005) and visceral adiposity (P = 0.007). Groups did not differ greatly, however, in terms of cartilage thickness, collagen quantity, or stiffness, nor in terms of muscle weight, subcutaneous adiposity, or gut microbial community composition., Conclusions: Our findings indicate that a sedentary lifestyle promotes the development of knee OA, particularly by enhancing disease severity rather than risk of onset, and this potentially occurs through multiple pathways including by engendering growth of functionally deficient joint tissues and the accumulation of excess body weight and adiposity., (Copyright © 2019 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: To investigate changes in response to sequential pressure-controlled loading and unloading in human articular cartilage of variable histological degeneration using serial T1ρ mapping., Method: We obtained 42 cartilage samples of variable degeneration from the medial femoral condyles of 42 patients undergoing total knee replacement. Samples were placed in a standardized artificial knee joint within an MRI-compatible whole knee-joint compressive loading device and imaged before (δ 0 ), during (δ ld1 , δ ld2 , δ ld3 , δ ld4 , δ ld5 ) and after (δ rl1 , δ rl2 , δ rl3 , δ rl4 , δ rl5 ) pressure-controlled loading to 0.663 ± 0.021 kN (94% body weight) using serial T1ρ mapping (spin-lock multigradient echo sequence; 3.0T MRI system [Achieva, Philips]). Reference assessment included histology (Mankin scoring) and conventional biomechanics (Tangent stiffness). We dichotomized sample into intact (n = 21) and degenerative (n = 21) based on histology and analyzed data using Mann Whitney, Kruskal Wallis, one-way ANOVA tests and Spearman's correlation, respectively., Results: At δ 0 , we found no significant differences between intact and degenerative samples, while the response-to-loading patterns were distinctly different. In intact samples, T1ρ increases were consistent and non-significant, while in degenerative samples, T1ρ increases were significantly higher (P = 0.004, δ0 vs δld1, δ0 vs δld3), yet undulating and variable. With unloading, T1ρ increases subsided, yet were persistently elevated beyond δ0., Conclusion: Cartilage mechanosensitivity is related to histological degeneration and assessable by serial T1ρ mapping. Unloaded, T1ρ characteristics are not significantly different in intact vs degenerative cartilage, while load bearing is organized in intact cartilage and disorganized in degenerative cartilage., (Copyright © 2019 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Introduction: Updated three column fixation of tibial plateau fractures (TPFs) arouse the importance of posterior column articular reduction. Complex TPFs with posterolateral (PL) articular injury is difficult to manage. We presented a strategy of combined positions and approaches to treat these injuries. Surgical technique was described and outcome of these were reported., Materials and Methods: From 2014 Jan to 2016 Dec, there were 132 patients of TPFs treated in our institute. Preoperative evaluation included plain films and 2D/3D CT scan to evaluate the involvement of articular surface and associated columns. Inclusion criteria were three column TPFs with PL corner injury. We put patients in prone position first with reverse L incision to manage PL articular impaction and posteromedial (PM) fractures. Then we repositioned the patients in supine to treat anterolateral fixation. Postoperative radiographic analysis, physical examination findings, and patient reported outcome scores from the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire were recorded., Results: Patient demographic information was retrospectively reviewed with a mean follow-up time of 34.4 months (range 24-48 months). The average time to union was 5.2 months (range 4-8months). 13/16 (81%) of patients had satisfactory articular reduction by plain films (less than 2 mm articular step off). All patients demonstrated healed without secondary displacement or infection. All patients demonstrated satisfactory coronal (medial proximal tibia angle 84.68 degrees) and sagittal alignment (posterior proximal tibia angle 84.75 degrees). Condylar width averaged 3.93 mm. 3/16 (19%) of cases required posterolateral columnar plating in addition to posteromedial columnar plating. The knee range of motion averaged 115 degrees (ranged from 0 degrees of extension to140 degrees flexion). The average KOOS score was 83/100 (range 76-90). 3 patients in the series developed a surgical site superficial infection and resolved after debridement and oral antibiotics use. No patient eventually received total knee arthroplasty at the last follow up., Conclusions: Our strategy provides an effective method to treat three column tibial plateau fractures with PL articular injury., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Treating joint diseases remains a significant clinical challenge. Conventional in vitro cultures and animal models have been helpful, but suffer from limited predictive power for the human response. Advanced models are therefore required to mimic the complex biological interactions within the human joint. However, the intricate structure of the joint microenvironment and the complex nature of joint diseases have challenged the development of in vitro models that can faithfully mimic the in vivo physiological and pathological environments. In this review, we discuss the current in vitro models of the joint and the progress achieved in the development of novel and potentially more predictive models, and highlight the application of new technologies to accurately emulate the articular joint., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Macro-cracks on the surface of articular cartilage are one of the hallmarks of early osteoarthritis and joint damage initiation. Macro-cracks negatively affect cartilage mechanobiology and load bearing capacity. The aim of this study was to quantify the changes in transient and steady-state force response of healthy cartilage in the presence of macro-cracks when compressed. Ten macro-cracks were created on the surface of intact articular cartilage. The force-time responses of intact cartilage and cartilage with macro-cracks (n = 22) were compared for multiple nominal axial compressive strain levels and strain rates. Experiments were simulated using a fiber-reinforced biphasic finite element model to gain insight into the possible mechanisms contributing to changes in the mechanical response of articular cartilage when introducing macro-cracks. We found a significant reduction in the transient and steady-state load bearing capacity of cartilage samples following the introduction of macro-cracks. Two mechanisms were identified as potential causes of this reduction: (1) an increase in permeability and associated decrease in fluid pressure, and (2) damage of the structural integrity of the solid matrix. The first cause was predicted by the finite element model, while the second cause was not.

Background: The variation in articular cartilage thickness (ACT) in healthy knees is difficult to quantify and therefore poorly documented. Our aims are to (1) define how machine learning (ML) algorithms can automate the segmentation and measurement of ACT on magnetic resonance imaging (MRI) (2) use ML to provide reference data on ACT in healthy knees, and (3) identify whether demographic variables impact these results., Methods: Patients recruited into the Osteoarthritis Initiative with a radiographic Kellgren-Lawrence grade of 0 or 1 with 3D double-echo steady-state MRIs were included and their gender, age, and body mass index were collected. Using a validated ML algorithm, 2 orthogonal points on each femoral condyle were identified (distal and posterior) and ACT was measured on each MRI. Site-specific ACT was compared using paired t-tests, and multivariate regression was used to investigate the risk-adjusted effect of each demographic variable on ACT., Results: A total of 3910 MRI were included. The average femoral ACT was 2.34 mm (standard deviation, 0.71; 95% confidence interval, 0.95-3.73). In multivariate analysis, distal-medial (-0.17 mm) and distal-lateral cartilage (-0.32 mm) were found to be thinner than posterior-lateral cartilage, while posterior-medial cartilage was found to be thicker (0.21 mm). In addition, female sex was found to negatively impact cartilage thickness (OR, -0.36; all values: P < .001)., Conclusion: ML was effectively used to automate the segmentation and measurement of cartilage thickness on a large number of MRIs of healthy knees to provide normative data on the variation in ACT in this population. We further report patient variables that can influence ACT. Further validation will determine whether this technique represents a powerful new tool for tracking the impact of medical intervention on the progression of articular cartilage degeneration., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To investigate the potential of quantitative susceptibility mapping (QSM) and T2* relaxation time mapping to determine mechanical and structural properties of articular cartilage via univariate and multivariate analysis., Methods: Samples were obtained from a cartilage repair study, in which surgically induced full-thickness chondral defects in the stifle joints of seven Shetland ponies caused post-traumatic osteoarthritis (14 samples). Control samples were collected from non-operated joints of three animals (6 samples). Magnetic resonance imaging (MRI) was performed at 9.4 T, using a 3-D multi-echo gradient echo sequence. Biomechanical testing, digital densitometry (DD) and polarized light microscopy (PLM) were utilized as reference methods. To compare MRI parameters with reference parameters (equilibrium and dynamic moduli, proteoglycan content, collagen fiber angle and -anisotropy), depth-wise profiles of MRI parameters were acquired at the biomechanical testing locations. Partial least squares regression (PLSR) and Spearman's rank correlation were utilized in data analysis., Results: PLSR indicated a moderate-to-strong correlation (ρ = 0.49-0.66) and a moderate correlation (ρ = 0.41-0.55) between the reference values and T2* relaxation time and QSM profiles, respectively (excluding superficial-only results). PLSR correlations were noticeably higher than direct correlations between bulk MRI and reference parameters. 3-D parametric surface maps revealed spatial variations in the MRI parameters between experimental and control groups., Conclusion: Quantitative parameters from 3-D multi-echo gradient echo MRI can be utilized to predict the properties of articular cartilage. With PLSR, especially the T2* relaxation time profile appeared to correlate with the properties of cartilage. Furthermore, the results suggest that degeneration affects the QSM-contrast in the cartilage. However, this change in contrast is not easy to quantify., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Knee varus alignment may increase loading in the medial tibiofemoral compartment, which can increase strain on the articular cartilage. Knee valgus unloader braces seek to reduce loading through the medial femoral compartment, but their effects on cartilage characteristics during dynamic tasks have not been evaluated., Objective: To determine the effects of a knee valgus unloader brace on medial femoral articular cartilage deformation following a single 5000-step walking protocol in individuals with varus-knee alignment., Methods: Twenty-four healthy individuals (63% female, BMI = 22 ± 3 kg/m 2 , age = 21 ± 3 years) completed two testing sessions (braced and unbraced) separated by one week. During both sessions, femoral cartilage ultrasound images were acquired prior to and following a 5000-step treadmill walking protocol at self-selected speed. Percent change scores in medial cartilage cross-sectional area (MCCA) were calculated and used as the primary outcome, and compared between the braced and unbraced conditions., Results: There was no difference in percent change of MCCA between conditions (braced = -2.77%, unbraced = -3.15%, p = 0.699). Individuals whose cartilage deformed more than a previously established minimal detectable change (MDC ≥ 1.58 mm 2 ) deformed less during the braced condition (braced = -2.94%, unbraced = -6.34%, p = 0.028), compared to individuals who did not deform greater than the MDC (n = 15, braced = -2.67%, unbraced = -1.23%, p = 0.210)., Conclusions: There was no significant difference in MCCA percent change between the braced and unbraced conditions across the entire cohort; yet a valgus unloader braces may serve as a potential intervention strategy for reducing articular cartilage deformation in certain varus-aligned individuals who normally undergo measurable deformation during walking., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: Develop a framework to quantify the size, location and severity of femoral and acetabular-sided cartilage and labral damage observed in patients undergoing hip arthroscopy, and generate a database of individual defect parameters to facilitate future research and treatment efforts., Methods: The size, location, and severity of cartilage and labral damage were prospectively collected using a custom, standardized post-operative template for 100 consecutive patients with femoroacetabular impingement syndrome. Chondrolabral junction damage, isolated intrasubstance labral damage, isolated acetabular cartilage damage and femoral cartilage damage were quantified and recorded using a combination of Beck and ICRS criteria. Radiographic measurements including alpha angle, head-neck offset, lateral centre edge angle and acetabular index were calculated and compared to the aforementioned chondral data using a multivariable logistic regression model and adjusted odd's ratio. Reliability among measurements were assessed using the kappa statistic and intraclass coefficients were used to evaluate continuous variables., Results: Damage to the acetabular cartilage originating at the chondrolabral junction was the most common finding in 97 hips (97%) and was usually accompanied by labral damage in 65 hips (65%). The width (p = 0.003) and clock-face length (p = 0.016) of the damaged region both increased alpha angle on anteroposterior films. 10% of hips had femoral cartilage damage while only 2 (2%) of hips had isolated defects to either the acetabular cartilage or labrum. The adjusted odds of severe cartilage (p = 0.022) and labral damage (p = 0.046) increased with radiographic cam deformity but was not related to radiographic measures of acetabular coverage., Conclusions: Damage at the chondrolabral junction was very common in this hip arthroscopy cohort, while isolated defects to the acetabular cartilage or labrum were rare. These data demonstrate that the severity of cam morphology, quantified through radiographic measurements, is a primary predictor of location and severity of chondral and labral damage and focal chondral defects may represent a unique subset of patients that deserve further study., Level of Evidence: IV.

Objective: To investigate the impact of knee joint loading exercise on articular cartilage in people at risk of, or with established, knee osteoarthritis (OA) by conducting a systematic review of randomised controlled trials (RCTs)., Design: We followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines., Data Sources: We performed a literature search with no restriction on publication year or language in MEDLINE, EMBASE, CINAHL, the Cochrane Central Register of Controlled Trials and Web of Science up to September 2017., Eligibility Criteria: RCTs investigating the impact of exercise on MRI-assessed articular cartilage in people over 18 years of age., Results: We included nine trials, including a total of 14 comparisons of cartilage morphometry, morphology and composition outcomes, of which two included participants at increased risk of knee OA and 12 included participants with knee OA. In participants at increased risk, one study comparison reported no effect on cartilage defects and one had positive effects on glycosaminoglycans (GAG). In participants with OA, six study comparisons reported no effect on cartilage thickness, volume or defects; one reported a negative effect and one no effect on GAG; two reported a positive effect and two no effect on collagen., Conclusions: Knee joint loading exercise seems to not be harmful for articular cartilage in people at increased risk of, or with, knee OA. However, the quality of evidence was low, including some interventions studying activities considered outside the therapeutic loading spectrum to promote cartilage health., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2019. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: An ideal disease modifying osteoarthritis drug (DMOAD) has chondroprotective, anti-inflammatory, and analgesic effects. This study describes the production and characterization of a canine IL4-10 fusion protein (IL4-10 FP) and evaluates its in vivo DMOAD activity in a canine model of osteoarthritis (OA)., Design: The canine Groove model was used as an in vivo model of degenerative knee OA. Six weeks after OA induction dogs were intra-articularly injected weekly, for ten weeks, with either IL4-10 FP or phosphate buffered saline (PBS). In addition to the use of human IL4-10 FP, canine IL4-10 FP was developed and characterized in vitro, and tested in vivo. Force plate analysis (FPA) was performed to analyze joint loading as a proxy measure for pain. After ten weeks dogs were euthanized and cartilage and synovial tissue samples were analyzed by histochemistry (OARSI scores) and biochemistry (cartilage proteoglycan turnover)., Results: Repetitive intra-articular injections with human IL4-10 FP led to antibody formation, that blocked its functional activity. Therefore, a canine IL4-10 FP was developed, which completely inhibited LPS-induced TNFα production by canine blood cells, and increased proteoglycan synthesis of canine cartilage in vitro (p = 0.043). In vivo, canine IL4-10 FP restored the, by OA impaired, joint loading (p = 0.002) and increased cartilage proteoglycan content (p = 0.029)., Conclusions: This first study on the potential DMOAD activity upon prolonged repeated treatment with IL4-10 FP demonstrates that a species-specific variant has anti-inflammatory and chondroprotective effects in vitro and chondroprotective and analgesic effects in vivo. These data warrant further research on the DMOAD potential of the IL4-10 FP., Competing Interests: FL and CEH are inventors on the patent WO2013070076 owned by UMC Utrecht Holdings. This does not alter our adherence to PLOS ONE policies on sharing data and materials. JP, NE, and CEH are shareholders of Synerkine Pharma BV, a spin-off of the UMC Utrecht licensing the patents on the IL4-10 fusion protein.

Objective: To compare the long-term disease state, in terms of activity and damage, of children with juvenile idiopathic arthritis (JIA) who had their disease onset in methotrexate (MTX) or biologic eras., Methods: Patients were included in MTX or biologic era cohort depending on whether their disease presentation occurred before or after January 2000. All patients had disease duration ≥ 5 years and underwent a prospective cross-sectional assessment, which included measurement of disease activity and damage. Inactive disease (ID) and low disease activity (LDA) states were defined according to Wallace, JADAS10, and cJADAS10 criteria. Articular and extraarticular damage was assessed with the Juvenile Arthritis Damage Index (JADI)., Results: MTX and biologic era cohorts included 239 and 269 patients, respectively. Patients were divided in the "functional phenotypes" of oligoarthritis and polyarthritis. At cross-sectional visit, patients in the biologic era cohort with either oligoarthritis or polyarthritis had consistently higher frequencies of ID and LDA by all criteria. The measurement of disease damage at cross-sectional visit revealed that the frequency of impairment of > 1 JADI-Articular items was higher in MTX than in biologic era cohort (17.6% versus 11% in oligoarthritis and 52.6% versus 21.8% in polyarthritis). Likewise, frequency of involvement of > 1 JADI-Extraarticular items was higher in the MTX than in the biologic era cohort (26.5% versus 16.2% in oligoarthritis and 31.4% versus 13.5% in polyarthritis)., Conclusion: Our study provides evidence of the remarkable outcome improvement obtained with the recent therapeutic advance in JIA.

Objective: Knee osteoarthritis (KOA) is a heterogeneous condition representing a variety of potentially distinct phenotypes. The purpose of this study was to apply innovative machine learning approaches to KOA phenotyping in order to define progression phenotypes that are potentially more responsive to interventions., Design: We used publicly available data from the Foundation for the National Institutes of Health (FNIH) osteoarthritis (OA) Biomarkers Consortium, where radiographic (medial joint space narrowing of ≥0.7 mm), and pain progression (increase of ≥9 Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC] points) were defined at 48 months, as four mutually exclusive outcome groups (none, both, pain only, radiographic only), along with an extensive set of covariates. We applied distance weighted discrimination (DWD), direction-projection-permutation (DiProPerm) testing, and clustering methods to focus on the contrast (z-scores) between those progressing by both criteria ("progressors") and those progressing by neither ("non-progressors")., Results: Using all observations (597 individuals, 59% women, mean age 62 years and BMI 31 kg/m 2 ) and all 73 baseline variables available in the dataset, there was a clear separation among progressors and non-progressors (z = 10.1). Higher z-scores were seen for the magnetic resonance imaging (MRI)-based variables than for demographic/clinical variables or biochemical markers. Baseline variables with the greatest contribution to non-progression at 48 months included WOMAC pain, lateral meniscal extrusion, and serum N-terminal pro-peptide of collagen IIA (PIIANP), while those contributing to progression included bone marrow lesions, osteophytes, medial meniscal extrusion, and urine C-terminal crosslinked telopeptide type II collagen (CTX-II)., Conclusions: Using methods that provide a way to assess numerous variables of different types and scalings simultaneously in relation to an outcome of interest enabled a data-driven approach that identified key variables associated with a progression phenotype., (Copyright © 2019 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: The aim of the study was to examine how mechanical unloading affects articular cartilage degeneration in the patellofemoral (PF) and tibiofemoral (TF) joints of a monosodium iodoacetate (MIA)-induced rat model of osteoarthritis (OA)., Design: The study involved 60 male rats. OA was induced by intra-articular injecting MIA into both knee joints. All animals were equally divided into two groups: sedentary (SE) and hindlimb unloading (HU) groups. Histopathological changes in the articular cartilage of the PF and TF joints were evaluated using the Osteoarthritis Research Society International (OARSI) score and modified Mankin score at 2 and 4 weeks after MIA injection., Results: In the SE and HU groups, representative histopathological changes in OA were detected in the PF and TF joints. The OARSI and modified Mankin scores for the PF and TF joints tended to increase over time after the injection of 0.2 mg or 1.0 mg of MIA in the SE and HU groups. Both the scores for the HU group were significantly lower than those for the SE group [OARSI score: P < 0.0001 (1.0-mg injection at 4 weeks); modified Mankin score: P = 0.0116 (0.2-mg injection at 4 weeks); P = 0.0004 and < 0.0001 (1.0-mg injection at 2 and 4 weeks, respectively)]., Conclusion: This study revealed new histological evidence that indicates that unloading condition suppresses articular cartilage degeneration and is beneficial in many areas of basal and clinical research involving OA., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: We evaluated changes in bone tracer uptake (BTU) in open wedge high tibial osteotomy (OWHTO) and determined if BTU correlates with clinical symptoms, postoperative alignment, or cartilage regeneration after OWHTO., Materials and Methods: Seventy-five knees in 64 patients who underwent OWHTO for medial compartment osteoarthritis were enrolled in this retrospective study. All cases were assessed preoperatively and at plate removal using bone scintigraphy. Visual analog scale (VAS), Japanese Orthopedic Association (JOA) score, Oxford Knee Score (OKS), Knee Injury and Osteoarthritis Outcome Score (KOOS), and the weight-bearing line ratio (WBLR) were assessed preoperatively and at plate removal. In addition, cartilage regeneration was evaluated at plate removal. We assessed changes in BTU for the medial and lateral compartment after OWHTO and the correlations between BTU of the medial compartment and all other parameters were analyzed., Results: Postoperatively, all outcome measures significantly improved: mean VAS 61.4 ± 18.3 to 9.5 ± 8.2, mean JOA score 65.1 ± 11.5 to 94.7 ± 6.0, mean OKS 29.4 ± 8.1 to 42.3 ± 4.1, mean KOOS 57.0 ± 14.3 to 83.7 ± 9.6, mean WBLR 22.8 ± 10.9 to 70.0 ± 9.4. Cartilage regeneration was observed in 53 knees (70.7%). BTU of the medial compartment significantly decreased after OWTHO, whereas no increased postoperative BTU was found in the lateral compartment. Postoperative BTU of the medial compartment significantly correlated with VAS, KOOS, and WBLR. No statistically significant associations were found between BTU and cartilage regeneration., Conclusions: OWHTO significantly decreased BTU of the medial compartment, which correlated with knee pain and postoperative mechanical alignment. Unloading effects of OWHTO led to pain relief after surgery, regardless of cartilage regeneration., (Copyright © 2018 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: Although discomfort during walking is a common complaint in individuals with knee osteoarthritis (OA), how an acute bout of walking affects femoral cartilage remains unclear. Current literature has suggested that frontal plane knee malalignment (ie, varus and valgus) is associated with the initiation and/or progression of knee OA. However, the association between knee alignment and femoral cartilage deformation after an acute bout of loading has not yet been investigated. This study was aimed to compare the acute effects of walking on femoral cartilage deformation between older adults with and without knee OA. We also examined the association between frontal plane knee alignment and loading-induced femoral cartilage deformation., Methods: Ten persons without OA (Kellgren Lawrence grading = 0 or 1; 5 females and 5 males; 55.0 [1.8] years of age; 78.8 [14.1] kg; 1.8 [0.2] m) and 9 persons with OA (Kellgren Lawrence grading ≥2; 4 females and 5 males; 55.6 [4.5] years of age; 97.4 [15.0] kg; 1.7 [0.1] m) participated. Each participant underwent magnetic resonance imaging before and immediately after 30 minutes of fast walking at 3 to 4 miles per hour. To obtain cartilage deformation postwalking, the medial and lateral femoral cartilage of the weight-bearing areas was segmented on participants' magnetic resonance imaging. Cartilage thickness was quantified by computing the average perpendicular distance between opposing voxels defining the edges of the femoral cartilage. Cartilage deformation of the medial and lateral femurs was defined as the percent changes in cartilage thickness after walking. Frontal plane knee alignment was obtained by measuring the angle between the long axes of femur and tibia. Independent t tests were used to compare cartilage deformation between the 2 groups. Pearson correlation coefficients were used to assess the association between cartilage deformation and knee alignment., Results and Discussion: There was no significant difference in cartilage deformation between the OA and control groups in lateral (P = .69) or medial (P = .87) femur. A significant correlation was found between lateral femoral cartilage deformation and increased knee valgus alignment (r = 0.497; P = .03). No difference was found between medial femoral cartilage deformation and frontal plane knee alignment (r = 273; P = .26)., Conclusions: This is the first study comparing the acute effects of walking on femoral cartilage deformation between older adults with and without knee OA. Although there was not a difference in walking-induced femoral cartilage deformation between the OA and control groups, knee valgus was related to lateral femoral cartilage deformation after walking. Our findings suggested that walking exercises may be used safely in older adults without knee malalignment.

Objective: In ovine hips chondrolabral damage as seen in cam-type femoroacetabular impingement (FAI) can be induced via an intertrochanteric varus osteotomy. However, it is yet to proven whether the observed cartilage damage is caused by a dynamic cam type impingement. Thus we asked, (1) whether actual cartilage damage observed after FAI induction in ovine hips occurs at the predicted, computed zone of FAI; (2) whether the extent of cartilage damage increases with ambulation time in this animal model?, Design: In this experimental, controlled, comparative study 20 sheep underwent unilateral FAI induction through an intertrochanteric varus osteotomy. Preoperatively sheep underwent computed tomography to generate three-dimensional models of the osseous pelvis and femur. The models were used to predict impingement zones before and after simulated varus osteotomy using range of motion (ROM) analysis. Sheep were sacrificed after 14-40 weeks of ambulation. At sacrifice cartilage was inspected and (1) location of actual damage and computed impingement zones were compared; (2) Cartilage damage was compared between short- and long ambulation groups., Results: (1) The average location and the extent of peripheral and central cartilage lesions did not differ with the computed impingement zones (all P > 0.05). (2) Grades of central, posterior cartilage damage were more severe in the long-compared to the short ambulation group (2.2 ± 1.8 vs 0.4 ± 0.5; P = 0.030)., Conclusions: In this experimental ovine FAI model the surgical induction of an osseous impingement conflict between the femur and acetabulum causes cartilage damage at the zone of simulated FAI., (Copyright © 2019 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Mechanical stress plays a key role in regulating cartilage degradation in osteoarthritis (OA). The aim of this study was to evaluate the effects and mechanisms of mechanical stress on articular cartilage. A total of 80 male Sprague-Dawley rats were randomly divided into eight groups (n = 10 for each group): control group (CG), OA group (OAG), and CG or OAG subjected to low-, moderate-, or high-intensity treadmill exercise (CL, CM, CH, OAL, OAM, and OAH, respectively). Chondrocytes were obtained from the knee joints of rats; they were cultured on Bioflex 6-well culture plates and subjected to different durations of cyclic tensile strain (CTS) with or without exposure to interleukin-1β (IL-1β). The results of the histological score, immunohistochemistry, enzyme-linked immunosorbent assay, and western-blot analyses indicated that there were no differences between CM and CG, but OAM showed therapeutic effects compared with OAG. However, CH and OAH experienced more cartilage damage than CG and OAG, respectively. CTS had no therapeutic effects on collagen II of normal chondrocytes, which is consistent with findings after treadmill exercise. However, CTS for 4 hr could alleviate the chondrocyte damage induced by IL-1β by activating AMP-activated protein kinase (AMPK) phosphorylation and suppressing nuclear translocation of nuclear factor (NF)-κB p65. Our findings indicate that mechanical stress had no therapeutic effects on normal articular cartilage and chondrocytes; mechanical stress only caused damage with excessive stimulation. Still, moderate biomechanical stress could reduce sensitization to the inflammatory response of articular cartilage and chondrocytes through the AMPK/NF-κB signaling pathway., (© 2018 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.)

Objectives: Osteoarthritis (OA) is a disease of the whole joint characterized by cartilage loss and subchondral bone remodeling. The role of microcracks in cartilage integrity and subchondral bone homeostasis is not fully understood. The main goal of this work was to evaluate microcrack density in both calcified cartilage and subchondral bone plate in relation to cartilage damage in humans and to better define the association of microcracks and osteocyte density in subchondral bone., Methods: We investigated 18 bone cores from cadaveric human knees that were stained with En-Bloc Basic Fuchsin. We quantified microcrack density, osteocyte density, cartilage surfaces and cartilage damage. The presence of microcracks was confirmed for each bone core by scanning electron microscopy. Finally, trabecular subchondral bone parameters were measured by micro-CT., Results: Microcracks were detected in both calcified cartilage and subchondral bone plate. The density of microcracks in both calcified cartilage (CC) and subchondral bone plate (SBP) was negatively correlated with cartilage damage (r = -0.45, p < 0.05). The presence of microcracks in SBP was associated with a lower histological OA score. Osteocytes formed a dendrite network that abruptly stopped at the border of calcified cartilage. Osteocyte density in subchondral bone plate was increased in the presence of microcracks in calcified cartilage., Conclusions: Subchondral bone plate microcracks might be required for maintaining cartilage homeostasis. Microcracks in calcified cartilage may trigger osteocyte density in subchondral bone plate with subsequent regulation of subchondral bone remodeling to prevent cartilage damage., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The extended life expectancy and the raise of accidental trauma call for an increase of osteoarticular surgical procedures. Arthroplasty, the main clinical option to treat osteoarticular lesions, has limitations and drawbacks. In this manuscript, we test the preclinical safety of the innovative implant ARTiCAR for the treatment of osteoarticular lesions. Thanks to the combination of two advanced therapy medicinal products, a polymeric nanofibrous bone wound dressing and bone marrow-derived mesenchymal stem cells, the ARTiCAR promotes both subchondral bone and cartilage regeneration. In this work, the ARTiCAR shows 1) the feasibility in treating osteochondral defects in a large animal model, 2) the possibility to monitor non-invasively the healing process and 3) the overall safety in two animal models under GLP preclinical standards. Our data indicate the preclinical safety of ARTiCAR according to the international regulatory guidelines; the ARTiCAR could therefore undergo phase I clinical trial.

Objective: During osteoarthritis (OA), chondrocytes seem to change their spatial arrangement from single to double strings, small and big clusters. Since the pericellular matrix (PCM) appears to degrade alongside this reorganisation, it has been suggested that spatial patterns act as an image-based biomarker for OA. The aim of this study was to establish the functional relevance of spatial organisation in articular cartilage., Method: Cartilage samples were selected according to their predominant spatial cellular pattern. Young's modulus of their PCM was measured by atomic force microscopy (AFM) (∼500 measurements/pattern). The distribution of two major PCM components (collagen type VI and perlecan) was analysed by immunohistochemistry (8 patients) and protein content quantified by enzyme-linked immunosorbent assay (ELISA) (58 patients)., Results: PCM stiffness significantly decreased with the development from single to double strings (p = 0.030), from double strings to small clusters (p = 0.015), and from small clusters to big clusters (p < 0.001). At the same time, the initially compact collagen type VI and perlecan staining progressively weakened and was less focalised. The earliest point with a significant reduction in protein content as shown by ELISA was the transition from single strings to small clusters for collagen type VI (p = 0.016) and from double strings to small clusters for perlecan (p = 0.008), with the lowest amounts for both proteins seen in big clusters., Conclusions: This study demonstrates the functional relevance of spatial chondrocyte organisation as an image-based biomarker. At the transition from single to double strings PCM stiffness decreases, followed by protein degradation from double strings to small clusters., (Copyright © 2019 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Background: Individuals with a cam deformity and a decreased (varus) femoral neck-shaft angle may be predisposed to symptomatic femoroacetabular impingement (FAI). However, it is unclear what combined effects the cam deformity and neck angle have on acetabular cartilage and subchondral bone stresses during an impinging squat motion. We therefore used finite element analysis to examine the combined effects of cam morphology and femoral neck-shaft angle on acetabular cartilage and subchondral bone stresses during squatting, examining the differences in stress characteristics between symptomatic and asymptomatic individuals with cam deformities and individuals without cam deformities and no hip pain., Questions/purposes: Using finite element analysis in this population, we asked: (1) What are the differences in acetabular cartilage stresses? (2) What are the differences in subchondral bone stresses? (3) What are the effects of high and low femoral neck-shaft angles on these stresses?, Methods: Six male participants were included to represent three groups (symptomatic cam, asymptomatic cam, control without cam deformity) with two participants per group, one with the highest femoral neck-shaft angle and one with the lowest (that is, most valgus and most varus neck angles, respectively). Each participant's finite element hip models were reconstructed from imaging data and assigned subject-specific bone material properties. Hip contact forces during squatting were determined and applied to the finite element models to examine maximum shear stresses in the acetabular cartilage and subchondral bone., Results: Both groups with cam deformities experienced higher subchondral bone stresses than cartilage stresses. Both groups with cam deformities also had higher subchondral bone stresses (symptomatic with high and low femoral neck-shaft angle = 14.1 and 15.8 MPa, respectively; asymptomatic with high and low femoral neck-shaft angle = 10.9 and 13.0 MPa, respectively) compared with the control subjects (high and low femoral neck-shaft angle = 6.4 and 6.5 MPa, respectively). The symptomatic and asymptomatic participants with low femoral neck-shaft angles had the highest cartilage and subchondral bone stresses in their respective subgroups. The asymptomatic participant with low femoral neck-shaft angle (123°) demonstrated anterolateral subchondral bone stresses (13.0 MPa), similar to the symptomatic group. The control group also showed no differences between cartilage and subchondral bone stresses., Conclusions: The resultant subchondral bone stresses modeled here coincide with findings that acetabular subchondral bone is denser in hips with cam lesions. Future laboratory studies will expand the parametric finite element analyses, varying these anatomic and subchondral bone stiffness parameters to better understand the contributions to the pathomechanism of FAI., Clinical Relevance: Individuals with a cam deformity and more varus neck orientation may experience elevated subchondral bone stresses, which may increase the risks of early clinical signs and degenerative processes associated with FAI, whereas individuals with cam morphology and normal-to-higher femoral neck-shaft angles may be at lesser risk of disease progression that would potentially require surgical intervention.

Background & Objectives: Articular cartilage defects in the knee have a very poor capacity for repair due to avascularity. Autologous chondrocyte transplantation (ACT) is an established treatment for articular cartilage defects. Animal studies have shown promising results with allogenic chondrocyte transplantation since articular cartilage is non-immunogenic. In addition to being economical, allogenic transplantation has less morbidity compared to ACT. This study was undertaken to compare ACT with allogenic chondrocyte transplantation in the treatment of experimentally created articular cartilage defects in rabbit knee joints., Methods: Cartilage was harvested from the left knee joints of six New Zealand white rabbits (R1-R6). The harvested chondrocytes were cultured to confluence and transplanted onto a 3.5 mm chondral defect in the right knees of 12 rabbits [autologous in 6 rabbits (R1-R6) and allogenic in 6 rabbits (R7-R12)]. After 12 wk, the rabbits were euthanized and histological evaluation of the right knee joints were done with hematoxylin and eosin and safranin O staining. Quality of the repair tissue was assessed by the modified Wakitani histological grading scale., Results: Both autologous and allogenic chondrocyte transplantation resulted in the regeneration of hyaline/mixed hyaline cartilage. The total histological scores between the two groups showed no significant difference., Interpretation & Conclusions: Allogenic chondrocyte transplantation seems to be as effective as ACT in cartilage regeneration, with the added advantages of increased cell availability and reduced morbidity of a single surgery., Competing Interests: None

Objective: The composition and structure of articular cartilage evolves during the development and progression of osteoarthritis (OA) resulting in changing mechanical responses. We aimed to assess the evolution of the intrinsic, large-strain mechanics of human articular cartilage-governed by collagen and proteoglycan and their interactions-during the progression of OA., Design: We completed quasi-static, large-strain shear tests on 64 specimens from ten donors undergoing total knee arthroplasty (TKA), and quantified the corresponding state of OA (OARSI grade), structural integrity (PLM score), and composition (glycosaminoglycan and collagen content)., Results: We observed nonlinear stress-strain relationships with distinct hystereses for all magnitudes of applied strain where stiffnesses, nonlinearities, and hystereses all reduced as OA advanced. We found a reduction in energy dissipation density up to 80% in severely degenerated (OARSI grade 4, OA-4) vs normal (OA-1) cartilage, and more importantly, we found that even cartilage with a normal appearance in structure and composition (OA-1) dissipated 50% less energy than healthy (control) load-bearing cartilage (HL 0 ). Changes in stresses and stiffnesses were in general less pronounced and did not allow us to distinguish between healthy load-bearing controls and very early-stage OA (OA-1), or to distinguish consistently among different levels of degeneration, i.e., OARSI grades., Conclusions: Our results suggest that reductions in energy dissipation density can be detected by bulk-tissue testing, and that these reductions precede visible signs of degeneration. We highlight the potential of energy dissipation, as opposed to stress- or stiffness-based measures, as a marker to diagnose early-stage OA., (Copyright © 2019 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Chondral lesions provide a potential risk factor for development of osteoarthritis. Despite the variety of in vitro studies on lesion degeneration, in vivo studies that evaluate relation between lesion characteristics and the risk for the possible progression of OA are lacking. Here, we aimed to characterize different lesions and quantify biomechanical responses experienced by surrounding cartilage tissue. We generated computational knee joint models with nine chondral injuries based on clinical in vivo arthrographic computed tomography images. Finite element models with fibril-reinforced poro(visco)elastic cartilage and menisci were constructed to simulate physiological loading. Systematically, the lesions experienced increased peak values of maximum principal strain, maximum shear strain, and minimum principal strain in the surrounding chondral tissue (p < 0.01) compared with intact tissue. Depth, volume, and area of the lesion correlated with the maximum shear strain (p < 0.05, Spearman rank correlation coefficient ρ = 0.733-0.917). Depth and volume of the lesion correlated also with the maximum principal strain (p < 0.05, ρ = 0.767, and ρ = 0.717, respectively). However, the lesion area had non-significant correlation with this strain parameter (p = 0.06, ρ = 0.65). Potentially, the introduced approach could be developed for clinical evaluation of biomechanical risks of a chondral lesion and planning an intervention. Statement of Clinical Relevance: In this study, we computationally characterized different in vivo chondral lesions and evaluated their risk of cartilage degeneration. This information is vital in decision-making for intervention in order to prevent post-traumatic osteoarthritis. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res., (© 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

To assess human articular cartilage tissue functionality by serial multiparametric quantitative MRI (qMRI) mapping as a function of histological degeneration. Forty-nine cartilage samples obtained during total knee replacement surgeries were placed in a standardized artificial knee joint within an MRI-compatible compressive loading device and imaged in situ and at three loading positions, i.e. unloaded, at 2.5 mm displacement (20% body weight [BW]) and at 5 mm displacement (110% BW). Using a clinical 3.0 T MRI system (Achieva, Philips), serial T1, T1ρ, T2 and T2* maps were generated for each sample and loading position. Histology (Mankin scoring) and biomechanics (Young's modulus) served as references. Samples were dichotomized as intact (int, n = 27) or early degenerative (deg, n = 22) based on histology and analyzed using repeated-measures ANOVA and unpaired Student's t-tests after log-transformation. For T1ρ, T2 and T2*, significant loading-induced differences were found in deg (in contrast to int) samples, while for T1 significant decreases in all zones were observed, irrespective of degeneration. In conclusion, cartilage functionality may be visualized using serial qMRI parameter mapping and the response-to-loading patterns are associated with histological degeneration. Hence, loading-induced changes in qMRI parameter maps provide promising surrogate parameters of tissue functionality and status in health and disease.

Osteoarthritis (OA) is the most common cause of disability in ageing societies, with no effective therapies available to date. Two preclinical models are widely used to validate novel OA interventions (MCL-MM and DMM). Our aim is to discern disease dynamics in these models to provide a clear timeline in which various pathological changes occur. OA was surgically induced in mice by destabilisation of the medial meniscus. Analysis of OA progression revealed that the intensity and duration of chondrocyte loss and cartilage lesion formation were significantly different in MCL-MM vs DMM. Firstly, apoptosis was seen prior to week two and was narrowly restricted to the weight bearing area. Four weeks post injury the magnitude of apoptosis led to a 40-60% reduction of chondrocytes in the non-calcified zone. Secondly, the progression of cell loss preceded the structural changes of the cartilage spatio-temporally. Lastly, while proteoglycan loss was similar in both models, collagen type II degradation only occurred more prominently in MCL-MM. Dynamics of chondrocyte loss and lesion formation in preclinical models has important implications for validating new therapeutic strategies. Our work could be helpful in assessing the feasibility and expected response of the DMM- and the MCL-MM models to chondrocyte mediated therapies., Competing Interests: All authors declare that they have no competing financial interests.

The aim of this study was to assess the effect of low-intensity pulsed ultrasound (LIPUS) application on rat temporomandibular joints (TMJs) with early-stage of osteoarthritis-like conditions induced by mechanical overloading. Fifteen-week-old male Wistar rats were divided into two experimental groups and a control group (n = 10 each). Both TMJs of all rats in one experimental group were subjected to mechanical overloading for 5 d, and those in the other experimental group were exposed to LIPUS for 20 min/d after overloading. Condyles were assessed using micro-computed tomography, histology and histomorphometry. LIPUS treatment attenuated cartilage degeneration, decreased the number of osteoclastic cells and restored the expression of aggrecan after an initial decrease induced by mechanical overloading. These results indicate that LIPUS may have a protective effect on the early progression of TMJ osteoarthritis., (Copyright © 2018 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Objective: To determine biomechanical effects of knee cartilage defect perimeter morphology based on cartilage strain and opposing subchondral bone contact., Design: Articular cartilage defects were created in 5 bovine femoral condyles: group 1, 45° inner bevel with 8-mm rim; group 2, vertical with 8-mm rim; and group 3, 45° outer bevel with 8-mm base. Samples were placed into a custom-machined micro-computed tomography tube and subjected to 800 N of axial loading. DICOM data were used to calculate cartilage thickness 4 and 6 mm from the center, distance between tibial cartilage surface and femoral subchondral bone, and contact width between tibial cartilage and subchondral bone. Strain 4 mm from the center and both absolute and change in distance (mm) to subchondral bone were compared between groups 1 and 2 using paired t tests. Strain at 6 mm and distance changed, loaded distance, and contact width (mm) were compared between groups using the Friedman test with post hoc analysis using Wilcoxon signed rank test., Results: No significant differences in rim strain were noted between groups 1 and 2 at 4 mm ( P = 0.10) and between groups 1, 2, and 3 at 6 mm ( P = 0.247) from the defect center. The loaded distance was significantly different between groups 1 and 3 ( P = 0.013). No significant change in distance to the subchondral bone was found between groups ( P = 0.156). The difference in subchondral bone contact area approached but did not reach significance ( P = 0.074)., Conclusion: When debriding focal articular cartilage defects, establishment of an inner bevel decreases tissue deformation and contact with opposing subchondral bone.

Purpose: Aberrant walking biomechanics after anterior cruciate ligament reconstruction (ACLR) are hypothesized to be associated with deleterious changes in knee cartilage. T1ρ magnetic resonance imaging (MRI) is sensitive to decreased proteoglycan density of cartilage. Our purpose was to determine associations between T1ρ MRI interlimb ratios (ILR) and walking biomechanics 6 months after ACLR., Methods: Walking biomechanics (peak vertical ground reaction force (vGRF), vGRF loading rate, knee extension moment, knee abduction moment) were extracted from the first 50% of stance phase in 29 individuals with unilateral ACLR. T1ρ MRI ILR (ACLR limb/uninjured limb) was calculated for regions of interest in both medial and lateral femoral (LFC) and medial and lateral tibial condyles. Separate, stepwise linear regressions were used to determine associations between biomechanical outcomes and T1ρ MRI ILR after accounting for walking speed and meniscal/chondral injury (P ≤ 0.05)., Results: Lesser peak vGRF in the ACLR limb was associated with greater T1ρ MRI ILR for the LFC (posterior ΔR = 0.14, P = 0.05; central ΔR = 0.15, P = 0.05) and medial femoral condyle (central ΔR = 0.24, P = 0.01). Lesser peak vGRF loading rate in the ACLR limb (ΔR = 0.21, P = 0.02) and the uninjured limb (ΔR = 0.27, P = 0.01) was associated with greater T1ρ MRI ILR for the anterior LFC. Lesser knee abduction moment for the injured limb was associated with greater T1ρ MRI ILR for the anterior LFC (ΔR = 0.16, P = 0.04) as well as the posterior medial tibial condyle (ΔR = 0.13, P = 0.04)., Conclusion: Associations between outcomes related to lesser mechanical loading during walking and greater T1ρ MRI ILR were found 6 months after ACLR. Although preliminary, our results suggest that underloading of the ACLR limb at 6 months after ACLR may be associated with lesser proteoglycan density in the ACLR limb compared with the uninjured limb.

Objective: Hyaline cartilage degenerative pathologies induce morphologic and biomechanical changes resulting in cartilage tissue damage. In pursuit of therapeutic options, electrical and mechanical stimulation have been proposed for improving tissue engineering approaches for cartilage repair. The purpose of this review was to highlight the effect of electrical stimulation and mechanical stimuli in chondrocyte behavior., Design: Different information sources and the MEDLINE database were systematically revised to summarize the different contributions for the past 40 years., Results: It has been shown that electric stimulation may increase cell proliferation and stimulate the synthesis of molecules associated with the extracellular matrix of the articular cartilage, such as collagen type II, aggrecan and glycosaminoglycans, while mechanical loads trigger anabolic and catabolic responses in chondrocytes., Conclusion: The biophysical stimuli can increase cell proliferation and stimulate molecules associated with hyaline cartilage extracellular matrix maintenance.

The paper shows that osteoporosis (OA) changes the SF content and the lipid profile substantially. To estimate the implication of the lipid environment in case the articular cartilage (AC) changes, we measured friction coefficient normal samples, with early and late stages of (OA). During joint inflammation and osteoarthritis, enzymatically activated β 2 -Glycoprotein I is transformed into antibody conformation. Our hypothesis about cartilage degradation of PL bilayers by antibodies (β 2 -Glycoprotein I) is considering antiphospholipid syndrome (APS), which was not discussed in the literature before. Deactivated PL molecule has no ability to form bilayers, lamellar phases, and liposomes. The phospholipid content in synovial fluid (SF) during joint inflammation, osteoarthritis, and rheumatoid arthritis is significantly higher (2-3 times) above the normal concentration of PL, and has a poor boundary-lubricating ability is deactivated., (Copyright © 2018. Published by Elsevier B.V.)

The study aims to analyze the association between the bone and cartilage/periarticular components of the radiographic joint damage and disability over the course of disease, in a cohort of rheumatoid arthritis (RA) patients from a day-to-day clinical practice. The secondary aim is to study the role of demographic and disease-related variables in this association. We performed a retrospective longitudinal study including 736 RA patients. Disability was assessed with the health assessment questionnaire (HAQ), and radiographic joint damage of hands and wrists with the Sharp van-der-Heijde score (total (SHS), erosion (ES), and narrowing/(sub)luxation (NSLS) components]. Generalized estimating equations models, adjusted by disease activity, demographic and disease-related variables, were used to test the relationship between SHS and medium-term (median value of the HAQs performed in the following year after each radiograph) and long-term (set of HAQ measures performed during follow-up, at least 1 year apart from the first x-ray) disability. Interaction terms between the SHS and demographic and disease-related variables were introduced in the models. To account for multiple testing, Bonferroni correction was applied. NSLS was independently associated with medium-term disability, even after Bonferroni correction. We observed significant and positive interactions between NSLS and age at x-ray, and with the ES. SHS showed no association with long-term disability. The cartilage/soft tissue component of the radiographic joint damage seems to exert a much more important role in medium-term disability than the erosive component. This association could be modulated by the age at the x-ray and by the magnitude of the erosive damage.

In our previous study, chondrocyte apoptosis in femoral head necrosis (FHN)-affected broilers was found to be associated with the endoplasmic reticulum stress (ERS) signaling pathway. In the present study, we further explored the role of ERS-induced chondrocyte apoptosis in FHN-affected broilers and the parallel test was carried out with articular chondrocytes cultivated in vitro. The broilers and chondrocytes were treated with methylprednisolone (MP). The main pathological changes in FHN-affected broilers included the proximal femoral head separated from its articular cartilage and growth plate lesions. MP-treated chondrocytes demonstrated morphology changes, cell viability reduction, secretory capacity dysfunction, and apoptosis. The mRNA expressions of pro-apoptotic genes controlled by ERS signaling pathway were up-regulated both in vivo and in vitro experiments. It showed that MP induced FHN in broilers, activated apoptosis-related genes on ERS signaling pathway, and affected the survival and apoptosis of chondrocytes, and bone growth., (© 2018 Poultry Science Association Inc.)

In dysplastic infant hips undergoing abduction harness treatment, cartilage contact pressure is believed to have a role in therapeutic cartilage remodeling and also in the complication of femoral head avascular necrosis. To improve our understanding of the role of contact pressure in the remodeling and the complication, we modeled cartilage contact pressure in cartilaginous infant hips undergoing Pavlik harness treatment. In subject-specific finite element modeling, we simulated contact pressure of normal and dysplastic hips in Pavlik harness at 90° flexion and gravity-induced abduction angles of 40°, 60° and 80°. We demonstrated that morphologies of acetabulum and femoral head both affected contact pressure distributions. The simulations showed that in Pavlik harness, contact pressure was mainly distributed along anterior and posterior acetabulum, leaving the acetabular roof only lightly loaded (normal hip) or unloaded (dysplastic hip). From a mechanobiological perspective, these conditions may contribute to therapeutic remodeling of the joint in Pavlik harness. Furthermore, contact pressure increased with the angle of abduction, until at the extreme abduction angle (80°), the lateral femoral head also contacted the posterior acetabular edge. Contact pressure in this area could contribute to femoral head avascular necrosis by reducing flow in femoral head blood vessels. The contact pressure we simulated can plausibly account for both the therapeutic effects and main adverse effect of abduction harness treatment for developmental dysplasia of the hip. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res., (© 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Aim: To determine the dose of monosodium iodoacetate (MIA) required to induce oxidative stress, as well as pain and edema; to confirm the induction of knee osteoarthritis (OA) symptoms in rats by the presence of reactive oxygen species (ROS) and reduction of antioxidant agents; and to verify the presence of histopathological injury in these affected joints., Method: Biological markers of oxidative stress, pain, knee edema, and cartilage degeneration provided by different doses of MIA (0.5; 1.0 or 1.5 mg) in rat knee joints were analyzed. The animal evaluations were conducted during 15 days for mechanical and cold hypersensitivity, spontaneous pain and edema. After that, blood serum, intra-articular lavage and structures of knee, spinal cord and brainstem were collected for biochemical analysis; moreover, the knees were removed for histological evaluation., Results: This study demonstrates that the highest dose of MIA (1.5 mg) increased the oxidative stress markers and reduced the antioxidant reactions, both in the focus of the lesion and in distant sites. MIA also induced the inflammatory process, characterized by pain, edema, increase in neutrophil count and articular damage., Conclusion: This model provides a basis for the exploration of underlying mechanisms in OA and the identification of mechanisms that may guide therapy and the discovery of OA signals and symptoms., (© 2018 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Magnetic resonance imaging (MRI) of the hip joint is performed for the diagnostics of many clinical pathologies. For clarification of pathologies of the hip joint conventional MRI and MR arthrography are used. The use of MRI either with or without the intravenous administration of contrast material is performed to diagnose bone marrow lesions, necrosis of the femoral head, inflammatory and tumorous lesions affecting the hip joint and its components. After the intra-articular administration of a diluted solution of contrast material, which results in distension of the joint, MR arthrography is performed for the diagnosis of intra-articular pathologies, such as lesions of the labrum acetabulare, chondral lesions and free intra-articular bodies. In recent times, MR arthrography is carried out with continuous traction of the limb to be examined because this leads to a distension of the joint and its components and in this way particularly lesions of the labrum with involvement of cartilage can be visualized even better. This article gives an overview of MRI and the accuracy of detecting lesions of the labrum acetabulare and the influence on the therapeutic approach.

Objective: To review recent biomechanics literature focused on the interactions between biomechanics and articular cartilage health, particularly focused on macro-scale and human studies., Design: A literature search was conducted in PubMed using the search terms (biomechanics AND osteoarthritis) OR (biomechanics AND cartilage) OR (mechanics AND osteoarthritis) OR (mechanics AND cartilage) for publications from April 2017 to April 2018., Results: Abstracts from the 559 articles generated from the literature search were reviewed. Due to the wide range of topics, 62 full texts with a focus on in vivo biomechanical studies were included for further discussion. Several overarching themes in the recent literature were identified and are summarized, including 1) new methods to detect early osteoarthritis (OA) development, 2) studies describing healthy and OA cartilage and biomechanics, 3) ACL injury and OA development, 4) meniscus injury and OA development, and 5) OA prevention, treatment, and management., Conclusions: Mechanical loading is a critical factor in the maintenance of joint health. Abnormal mechanical loading can lead to the onset and progression of OA. Thus, recent studies have utilized various biomechanical models to better describe the etiology of OA development and the subsequent effects of OA on the mechanics of joint tissues and whole body biomechanics., (Copyright © 2018 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

The articular cartilage is exquisitely sensitive to mechanical load. Its structure is largely defined by the mechanical environment and destruction in osteoarthritis is the pathophysiological consequence of abnormal mechanics. It is often overlooked that disuse of joints causes profound loss of volume in the articular cartilage, a clinical observation first described in polio patients and stroke victims. Through the 1980s, the results of studies exploiting experimental joint immobilisation supported this. Importantly, this substantial body of work was also the first to describe metabolic changes that resulted in decreased synthesis of matrix molecules, especially sulfated proteoglycans. The molecular mechanisms that underlie disuse atrophy are poorly understood despite the identification of multiple mechanosensing mechanisms in cartilage. Moreover, there has been a tendency to equate cartilage loss with osteoarthritic degeneration. Here, we review the historic literature and clarify the structural, metabolic and clinical features that clearly distinguish cartilage loss due to disuse atrophy and those due to osteoarthritis. We speculate on the molecular sensing pathways in cartilage that may be responsible for cartilage mechanoadaptation., (© 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.)

The gene encoding the proteoglycan aggrecan ( Agc1 ) is abundantly expressed in cartilage during development and adulthood, and the loss or diminished deposition of the protein results in a wide range of skeletal malformations. Furthermore, aggrecan degradation is a hallmark of cartilage degeneration occurring in osteoarthritis. In the present study, we investigated the consequences of a partial loss of aggrecan in the postnatal skeleton and in the articular cartilage of adult mice. We took advantage of the previously described Agc1 tm(IRES-CreERT2) mouse line, which allows for conditional and timely-regulated deletion of floxed, cartilage-expressed genes. As previously reported, the introduction of the CreER T2 cassette in the 3'UTR causes a disruption of the normal expression of Agc1 resulting in a hypomorphic deposition of the protein. In homozygous mice, we observed a dwarf phenotype, which persisted throughout adulthood supporting the evidence that reduced aggrecan amount impairs skeletal growth. Homozygous mice exhibited reduced proteoglycan staining of the articular cartilage at 6 and 12 months of age, increased stiffening of the extracellular matrix at six months, and developed severe cartilage erosion by 12 months. The osteoarthritis in the hypomorph mice was not accompanied by increased expression of catabolic enzymes and matrix degradation neoepitopes. These findings suggest that the degeneration found in homozygous mice is likely due to the compromised mechanical properties of the cartilage tissue upon aggrecan reduction.

Cartilage metabolism-both the synthesis and breakdown of cartilage constituents and architecture-is influenced by its mechanical loading. Therefore, physical activity is often recommended to maintain cartilage health and to treat or slow the progression of osteoarthritis, a debilitating joint disease causing cartilage degeneration. However, the appropriate exercise frequency, intensity, and duration cannot be prescribed because direct in vivo evaluation of cartilage following exercise has not yet been performed. To address this gap in knowledge, we developed a cartilage stress test to measure the in vivo strain response of healthy human subjects' tibial cartilage to walking exercise. We varied both walk duration and speed in a dose-dependent manner to quantify how these variables affect cartilage strain. We found a nonlinear relationship between walk duration and in vivo compressive strain, with compressive strain initially increasing with increasing duration, then leveling off with longer durations. This work provides innovative measurements of cartilage creep behavior (which has been well-documented in vitro but not in vivo) during walking. This study showed that compressive strain increased with increasing walking speed for the speeds tested in this study (0.9-2.0 m/s). Furthermore, our data provide novel measurements of the in vivo strain response of tibial cartilage to various doses of walking as a mechanical stimulus, with maximal strains of 5.0% observed after 60 minutes of walking. These data describe physiological benchmarks for healthy articular cartilage behavior during walking and provide a much-needed baseline for studies investigating the effect of exercise on cartilage health.

Femoroacetabular impingement syndrome (FAIS) consists of abnormal hip joint morphology and pain during activities of daily living. Abnormal gait mechanics and potentially abnormal muscle forces within FAI patients leads to articular cartilage damage. Therefore, there is a necessity to understand the effects of FAI on hip joint muscle forces during gait and the link between muscle forces, patient reported outcomes (PRO) and articular cartilage health. The purposes of this study were to assess: (1) hip muscle forces between FAI patients and healthy controls and (2) the associations between hip muscle forces with PRO and cartilage composition (T 1ρ /T 2 mapping) within FAI patients. Musculoskeletal simulations were used to estimate peak muscle forces during the stance phase of gait in 24 FAI patients and 24 healthy controls. Compared to controls, FAI patients ambulated with lower vasti (30% body-weight, p = 0.01) and higher sartorius (4.0% body-weight, p < 0.01) forces. Within FAI patients, lower peak gluteus medius, gluteus minimus, sartorius and iliopsoas forces were associated with worse hip joint pain and function (R = 0.43-0.70, p = 0-0.04), while lower muscle forces were associated with increased T 1ρ and T 2 values (i.e. altered cartilage composition) within the hip joint cartilage (R = -0.44 to -0.58, p = 0.006-0.05). Although FAI patients demonstrate abnormal muscle forces, it is unknown whether or not these altered muscle force patterns are associated with pain avoidance or weak musculature. Further investigation is required in order to better understand the effects of FAI on hip joint muscle forces and the associations with hip joint cartilage degeneration., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Preclinical osteoarthritis models where damage occurs spontaneously may better reflect the initiation and development of human osteoarthritis. The aim was to assess the commercial pig as a model of spontaneous osteoarthritis development by examining pain-associated behaviour, joint cartilage integrity, as well as the use of porcine cartilage explants and isolated chondrocytes and osteoblasts for ex vivo and in vitro studies., Methods: Female pigs (Large white x Landrace x Duroc) were examined at different ages from 6 weeks to 3-4 years old. Lameness was assessed as a marker of pain-associated behaviour. Femorotibial joint cartilage integrity was determined by chondropathy scoring and histological staining of proteoglycan. IL-6 production and proteoglycan degradation was assessed in cartilage explants and primary porcine chondrocytes by ELISA and DMMB assay. Primary porcine osteoblasts from damaged and non-damaged joints, as determined by chondropathy scoring, were assessed for mineralisation, proliferative and mitochondrial function as a marker of metabolic capacity., Results: Pigs aged 80 weeks and older exhibited lameness. Osteoarthritic lesions in femoral condyle and tibial plateau cartilage were apparent from 40 weeks and increased in severity with age up to 3-4 years old. Cartilage from damaged joints exhibited proteoglycan loss, which positively correlated with chondropathy score. Stimulation of porcine cartilage explants and primary chondrocytes with either IL-1β or visfatin induced IL-6 production and proteoglycan degradation. Primary porcine osteoblasts from damaged joints exhibited reduced proliferative, mineralisation, and metabolic capacity., Conclusion: In conclusion, the commercial pig represents an alternative model of spontaneous osteoarthritis and an excellent source of tissue for in vitro and ex vivo studies.

A major goal of regenerative medicine is to stimulate tissue regeneration after traumatic injury. We previously discovered that treating digit amputation wounds with BMP2 in neonatal mice stimulates endochondral ossification to regenerate the stump bone. Here we show that treating the amputation wound with BMP9 stimulates regeneration of a synovial joint that forms an articulation with the stump bone. Regenerated structures include a skeletal element lined with articular cartilage and a synovial cavity, and we demonstrate that this response requires the Prg4 gene. Combining BMP2 and BMP9 treatments in sequence stimulates the regeneration of bone and joint. These studies provide evidence that treatment of growth factors can be used to engineer a regeneration response from a non-regenerating amputation wound.

The purpose of this study was to evaluate the effects of variations in quadriceps muscle forces on patellofemoral stress. We created subject-specific finite element models for 21 individuals with chronic patellofemoral pain and 16 pain-free control subjects. We extracted three-dimensional geometries from high resolution magnetic resonance images and registered the geometries to magnetic resonance images from an upright weight bearing squat with the knees flexed at 60°. We estimated quadriceps muscle forces corresponding to 60° knee flexion during a stair climb task from motion analysis and electromyography-driven musculoskeletal modelling. We applied the quadriceps muscle forces to our finite element models and evaluated patellofemoral cartilage stress. We quantified cartilage stress using an energy-based effective stress, a scalar quantity representing the local stress intensity in the tissue. We used probabilistic methods to evaluate the effects of variations in quadriceps muscle forces from five trials of the stair climb task for each subject. Patellofemoral effective stress was most sensitive to variations in forces in the two branches of the vastus medialis muscle. Femur cartilage effective stress was most sensitive to variations in vastus medialis forces in 29/37 (78%) subjects, and patella cartilage effective stress was most sensitive to variations in vastus medialis forces in 21/37 (57%) subjects. Femur cartilage effective stress was more sensitive to variations in vastus medialis longus forces in subjects classified as maltrackers compared to normal tracking subjects (p = 0.006). This study provides new evidence of the importance of the vastus medialis muscle in the treatment of patellofemoral pain.

We sought to determine the relationship between (i) full-thickness cartilage defects and tibiofemoral subchondral surface ratio (SSR) and (ii) disability and quality of life in patients with mild radiographic osteoarthritis (OA) (Kellgren-Lawrence grade 2) or without radiographic OA (Kellgren-Lawrence grades 0 or 1)? A total of 642 participants from the Osteoarthritis Initiative (OAI) with baseline knee MRIs and a Kellgren-Lawrence grade 2 or less on both bilateral screening radiographs were included. The independent relationship was assessed between (i) full-thickness cartilage defect presence and tibiofemoral SSR and (ii) Knee Injury and Osteoarthritis Outcome Score (KOOS) quality of life (QOL), KOOS function in sports and recreation (KOOS-sport/rec), and Western Ontario and McMaster Universities Arthritis Index (WOMAC) disability score after adjustment for relevant confounders with multivariate regression modeling. The prevalence of medial full-thickness defects was 10.4% (67/642) and lateral was 18.1% (116/642). Lateral defect presence was associated with worse KOOS-QOL (beta -3.61 SE 1.04; p = 0.001), KOOS-sport/rec (beta -4.70 SE 1.38; p = 0.001) and WOMAC-disability scores (beta 0.02 SE 0.01; p = 0.001); these associations were not influenced by defect size. A larger medial compartment SSR was associated with worse KOOS-QOL (beta -27.20 SE 6.80; p < 0.001), KOOS-sports/rec (beta -22.30 SE 9.01; p = 0.01) and WOMAC-disability scores (beta 0.16 SE 0.04; p < 0.001). In older adults with little to no radiographic osteoarthritis, lateral full-thickness cartilage defects, irrespective of size, and a larger medial compartment tibiofemoral SSR are potential sources of knee-related symptoms that are not appreciated on standard radiographs. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:378-385, 2019., (© 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)