Cartilage Pathology Research Articles

Measuring Outcomes in Knee Articular Cartilage Pathology

Measuring outcomes following treatment of knee articular cartilage lesions is crucial to determine the natural history of disease and the efficacy of treatments. Outcome assessments for articular cartilage treatments can be clinical (based on failure, lack of healing, reoperation, need for arthroplasty), radiographic (X-ray, MRI), histologic, or patient reported and functional. The purpose of this review is to discuss the application and properties of patient-reported outcomes (PROs) with a focus on articular cartilage injuries and surgery in the knee. The most frequently used and validated PROs for knee articular cartilage studies include: the Knee injury and Osteoarthritis and Outcome Score, International Knee Documentation Committee Subjective Knee Form, and Lysholm score as knee-specific measures; the Marx Activity Rating Scale and Tegner Activity Scale as activity measures; and EQ-5D and SF-36/12 as generic quality-of-life measures. Incorporating these validated PROs in studies pertaining to knee articular cartilage lesions will allow researchers to fully capture clinically relevant outcomes that are most important to patients.

Cartilage and Meniscus Injuries Are More Common in Patients Undergoing Delayed Multiligament Reconstruction.

The purpose of this study was to describe the pattern of meniscus and cartilage pathology in multiligament knee injuries (MLKIs) and determine the relationship between surgical timing and injury mechanism with degree of intra-articular injury. Patients with surgically treated MLKIs over a 15-year period were retrospectively reviewed and grouped based on surgical intervention, time to intervention, and injury mechanism. The presence or absence of meniscus and chondral injury were recorded at the time of surgery. Surgical intervention within 6 weeks of injury was deemed acute, while surgery occurring more than 6 weeks from injury was classified as delayed. Over the 15-year study period, 207 patients with MLKIs were identified. Compared with acutely managed patients, the delayed intervention group had significantly more meniscus (p = 0.03) and cartilage (p < 0.01) pathology. Meniscus injury rates in MLKIs sustained during sporting activity did not differ from nonsporting injuries (p = 0.63). However, the nonsporting group had significantly more chondral injuries (p < 0.01). High-energy injury mechanism was associated with increased cartilage (p = 0.02), but not meniscus (p = 0.61) injury rates. In conclusion, surgical reconstruction of MLKIs delayed for more than 6 weeks was associated with increased meniscus and cartilage pathology.

Genetics in Cartilage Lesions: Basic Science and Therapy Approaches.

Cartilage lesions have a multifactorial nature, and genetic factors are their strongest determinants. As biochemical and genetic studies have dramatically progressed over the past decade, the molecular basis of cartilage pathologies has become clearer. Several homeostasis abnormalities within cartilaginous tissue have been found, including various structural changes, differential gene expression patterns, as well as altered epigenetic regulation. However, the efficient treatment of cartilage pathologies represents a substantial challenge. Understanding the complex genetic background pertaining to cartilage pathologies is useful primarily in the context of seeking new pathways leading to disease progression as well as in developing new targeted therapies. A technology utilizing gene transfer to deliver therapeutic genes to the site of injury is quickly becoming an emerging approach in cartilage renewal. The goal of this work is to provide an overview of the genetic basis of chondral lesions and the different approaches of the most recent systems exploiting therapeutic gene transfer in cartilage repair. The integration of tissue engineering with viral gene vectors is a novel and active area of research. However, despite promising preclinical data, this therapeutic concept needs to be supported by the growing body of clinical trials.

A roadmap to target interleukin-6 in osteoarthritis

Joint inflammation is present in the majority of OA patients and pro-inflammatory mediators, such as IL-6, are actively involved in disease progression. Increased levels of IL-6 in serum or synovial fluid from OA patients correlate with disease incidence and severity, with IL-6 playing a pivotal role in the development of cartilage pathology, e.g. via induction of matrix-degrading enzymes. However, IL-6 also increases expression of anti-catabolic factors, suggesting a protective role. Until now, this dual role of IL-6 is incompletely understood and may be caused by differential effects of IL-6 classic vs trans-signalling. Here, we review current evidence regarding the role of IL-6 classic- and trans-signalling in local joint pathology of cartilage, synovium and bone. Furthermore, we discuss targeting of IL-6 in experimental OA models and provide future perspective for OA treatment by evaluating currently available IL-6 targeting strategies.

Classification, Categorization, and Algorithms for Articular Cartilage Defects.

There is a critical unmet need in the clinical implementation of valid preventative and therapeutic strategies for patients with articular cartilage pathology based on the significant gap in understanding of the relationships between diagnostic data, disease progression, patient-related variables, and symptoms. In this article, the current state of classification and categorization for articular cartilage pathology is discussed with particular focus on machine learning methods and the authors propose a bedside-bench-bedside approach with highly quantitative techniques as a solution to these hurdles. Leveraging computational learning with available data toward articular cartilage pathology patient phenotyping holds promise for clinical research and will likely be an important tool to identify translational solutions into evidence-based clinical applications to benefit patients. Recommendations for successful implementation of these approaches include using standardized definitions of articular cartilage, to include characterization of depth, size, location, and number; using measurements that minimize subjectivity or validated patient-reported outcome measures; considering not just the articular cartilage pathology but the whole joint, and the patient perception and perspective. Application of this approach through a multistep process by a multidisciplinary team of clinicians and scientists holds promise for validating disease mechanism-based phenotypes toward clinically relevant understanding of articular cartilage pathology for evidence-based application to orthopaedic practice.

Endogenous CCN family member WISP1 inhibits trauma-induced heterotopic ossification.

Heterotopic ossification (HO) is defined as abnormal differentiation of local stromal cells of mesenchymal origin, resulting in pathologic cartilage and bone matrix deposition. Cyr61, CTGF, Nov (CCN) family members are matricellular proteins that have diverse regulatory functions on cell proliferation and differentiation, including the regulation of chondrogenesis. However, little is known regarding CCN family member expression or function in HO. Here, a combination of bulk and single-cell RNA sequencing defined the dynamic temporospatial pattern of CCN family member induction within a mouse model of trauma-induced HO. Among CCN family proteins, Wisp1 (also known as Ccn4) was most upregulated during the evolution of HO, and Wisp1 expression corresponded with chondrogenic gene profile. Immunohistochemistry confirmed WISP1 expression across traumatic and genetic HO mouse models as well as in human HO samples. Transgenic Wisp1LacZ/LacZ knockin animals showed an increase in endochondral ossification in HO after trauma. Finally, the transcriptome of Wisp1-null tenocytes revealed enrichment in signaling pathways, such as the STAT3 and PCP signaling pathways, that may explain increased HO in the context of Wisp1 deficiency. In sum, CCN family members, and in particular Wisp1, are spatiotemporally associated with and negatively regulate trauma-induced HO formation.

Meniscal and Articular Cartilage Predictors of Outcome following Revision ACL Reconstruction: A 6-Year Follow-up Study

Objectives:Previous work has shown that having a lateral meniscectomy prior to revision ACL surgery, as well as grade 3-4 chondral damage to the trochlea at the time of revision ACL surgery results in poorer outcomes at 2 years. Alternatively, meniscal or articular cartilage (AC) pathology documented at the time of a revision surgery were not found to be significant risk factors for 2-year activity levels. The purpose of this study was to follow this cohort for a longer time period, to determine if either meniscal and/or articular cartilage pathology noted at the time of revision ACL surgery significantly affects a patient’s activity level, sports function, and OA symptoms at 6-year follow-up.Methods:Revision ACL reconstruction patients were identified and prospectively enrolled between 2006 and 2011. Data collected included baseline demographics, surgical technique and pathology, and a series of validated patient reported outcome instruments (IKDC, KOOS, WOMAC, and Marx activity rating score). Patients were followed up for 6 years and asked to complete the identical set of outcome instruments.Regression analysis was used to control for age, gender, BMI, smoking status, activity level, baseline outcome scores, revision number, time since their last ACL reconstruction, graft choice, and previous and current meniscal and articular cartilage pathology, in order to assess the meniscal and AC pathology risk factors for clinical outcomes 6 years after revision ACL reconstruction.Results:1234 patients met the inclusion criteria and were successfully enrolled, with 716 (58%) males and a median cohort age of 26 years. The median time since their last ACL reconstruction was 3.4 years. Surgeons noted previous pathology in the medial meniscus (39%), lateral meniscus (20%), and articular surfaces (12%) at the time of revision surgery. Surgeons reported current pathology at the time of revision surgery in the medial meniscus (45%), lateral meniscus (36%), medial femoral condyle (MFC; 43%), lateral femoral condyle (LFC; 29%), medial tibial plateau (MTP; 11%), lateral tibial plateau (LTP; 17%), patella (30%), and trochlea (21%). At 6 years, follow-up was obtained on 77% (949/1234). Previous and current meniscal pathology (both medial and lateral), as well as current AC pathology (in the MFC, LTP, trochlea, and patella) were found to be significant drivers of poorer outcomes at 6 years. The most consistent cartilage-related factors driving outcome in revision patients were either a previous or current repair or excision of the medial meniscus and patellofemoral AC pathology. Six-year Marx activity levels were negatively impacted by having either a repair or an excision of the medial meniscus (odds ratio range =0.58-66; 95% CI=0.38-0.91; p=0.01) or having grade 3-4 patellar chondrosis (OR=0.57; 95% CI= 0.35-0.95; p=0.03). Conversely, 6-year activity levels significantly improved by having either a lateral meniscus repair or excision (OR=1.49-2.22; 95% CI=1.07-4.04; p=0.005). Previous medial or lateral meniscal pathology negatively affected all KOOS subscales except for sports/recreation (p<0.05). Articular pathology significantly impaired KOOS symptoms, sports/recreation and the quality of life subscales (p<0.05). The KOOS sports/recreation subscale was significantly affected by articular cartilage pathology (LTP, patella, trochlea; p<0.03). Lower baseline outcome scores, lower baseline activity level, and being a smoker all significantly increased the odds of reporting poorer clinical outcomes at 6 years.Conclusion:Meniscal and articular cartilage pathology was found to have a larger impact at 6 years following revision ACL surgery, as compared to 2-year follow-up. In contrast to 2-year follow-up, incidence of medial meniscal and AC pathology at the time of a patient’s revision surgery were found to significantly diminish a patient’s activity level at 6 years, whereas the incidence of lateral meniscal repair or excision was found to improve a patient’s activity level. Having a previous medial meniscal repair or excision or exhibiting grade 2-4 chondral damage noted at the time of ACL revision reconstruction results in poorer IKDC and KOOS scores and worse WOMAC pain and ADL scores at 6 years following revision surgery.

Clinical Application of the Basic Science of Articular Cartilage Pathology and Treatment.

The joint is an organ with each tissue playing critical roles in health and disease. Intact articular cartilage is an exquisite tissue that withstands incredible biologic and biomechanical demands in allowing movement and function, which is why hyaline cartilage must be maintained within a very narrow range of biochemical composition and morphologic architecture to meet demands while maintaining health and integrity. Unfortunately, insult, injury, and/or aging can initiate a cascade of events that result in erosion, degradation, and loss of articular cartilage such that joint pain and dysfunction ensue. Importantly, articular cartilage pathology affects the health of the entire joint and therefore should not be considered or addressed in isolation. Treating articular cartilage lesions is challenging because left alone, the tissue is incapable of regeneration or highly functional and durable repair. Nonoperative treatments can alleviate symptoms associated with cartilage pathology but are not curative or lasting. Current surgical treatments range from stimulation of intrinsic repair to whole-surface and whole-joint restoration. Unfortunately, there is a relative paucity of prospective, randomized controlled, or well-designed cohort-based clinical trials with respect to cartilage repair and restoration surgeries, such that there is a gap in knowledge that must be addressed to determine optimal treatment strategies for this ubiquitous problem in orthopedic health care. This review article discusses the basic science rationale and principles that influence pathology, symptoms, treatment algorithms, and outcomes associated with articular cartilage defects in the knee.

Sonography: a sensitive and specific method for detecting trochlear cartilage pathologies.

MRI is now the modality of choice for evaluating articular cartilage. Nevertheless, it has some general drawbacks. Some patients cannot undergo MRI, and in others US scan could be the first examination and cartilage should be evaluated. Ultrasound could be a useful method for detecting trochlear cartilage low-grade lesions. In this study, our goal was to evaluate the efficacy of ultrasonography in detecting these lesions. All patients referred to our hospital, from July 2018 to July 2019, who were arthroscopic candidates due to sport-related pathologies, underwent ultrasound scan 1day prior to surgery. Ultrasound assessment was performed by an expert radiologist, with a 13-MHz probe, located transversely proximal to the patella in different degrees of knee flexion to assess trochlear lesion grade and thickness. Arthroscopic examination of all patients was performed by an experienced orthopedic knee surgeon (second author). Sensitivity and specificity of ultrasound were calculated. A total of 48 patients were involved in the study with a mean age of 33.2years (SD: 9.7), between 19 and 51years of age. Patients were 81% male (39 patients). The sensitivity of ultrasound in grading of trochlear cartilage lesion was 100%, meanwhile its specificity was 88.2% (30 cases had normal cartilage while this figure was 34 in arthroscopy). Sonography is a low-cost, accessible diagnostic tool with high sensitivity and specificity for early detection of trochlear cartilage pathologies. It can play an important role as an outpatient diagnostic workup in patients with anterior knee pain.

Evaluation of distal femoral cartilage by B-mode ultrasonography and shear wave elastography in patients with knee osteoarthritis: a preliminary study

Degenerative change in articular cartilage is one of the most important factors in the development of osteoarthritis. Shear wave elastography can be used to identify pathologic cartilage. To evaluate distal femoral cartilage by shear wave elastography in patients with symptomatic knee osteoarthritis. Twenty patients with bilateral knee osteoarthritis (study group) and 20 volunteers with the same demographic characteristics but without symptomatic knee pain (control group) were included in the study. A total of 80 knee joints of 40 individuals were evaluated. At the medial, intercondylar, and lateral condylar levels distal femoral cartilage thickness was measured by B-mode ultrasonography and stiffness was measured by shear wave elastography. The medial, intercondylar, and lateral cartilage thickness measurements were similar between the two groups and no statistically significant difference was observed (P = 0.711, P = 0.766, and P = 0.575, respectively). The shear wave velocity values in the medial and intercondylar cartilage were significantly higher in the study group (P = 0.002). Shear wave velocity values measured from lateral cartilage were higher in the study group and the difference between the groups had a borderline statistical significance (P = 0.053). Shear wave elastography seems to be a reliable, non-invasive, and acceptable method for the assessment of pathologic cartilage.

Odiparcil, a potential glycosaminoglycans clearance therapy in mucopolysaccharidosis VI-Evidence from in vitro and in vivo models.

Mucopolysaccharidoses are a class of lysosomal storage diseases, characterized by enzymatic deficiency in the degradation of specific glycosaminoglycans (GAG). Pathological accumulation of excess GAG leads to multiple clinical symptoms with systemic character, most severely affecting bones, muscles and connective tissues. Current therapies include periodic intravenous infusion of supplementary recombinant enzyme (Enzyme Replacement Therapy–ERT) or bone marrow transplantation. However, ERT has limited efficacy due to poor penetration in some organs and tissues. Here, we investigated the potential of the β-D-xyloside derivative odiparcil as an oral GAG clearance therapy for Maroteaux–Lamy syndrome (Mucopolysaccharidosis type VI, MPS VI). In vitro, in bovine aortic endothelial cells, odiparcil stimulated the secretion of sulphated GAG into culture media, mainly of chondroitin sulphate (CS) /dermatan sulphate (DS) type. Efficacy of odiparcil in reducing intracellular GAG content was investigated in skin fibroblasts from MPS VI patients where odiparcil was shown to reduce efficiently the accumulation of intracellular CS with an EC50 in the range of 1 μM. In vivo, in wild type rats, after oral administrations, odiparcil was well distributed, achieving μM concentrations in MPS VI disease-relevant tissues and organs (bone, cartilage, heart and cornea). In MPS VI Arylsulphatase B deficient mice (Arsb-), after chronic oral administration, odiparcil consistently stimulated the urinary excretion of sulphated GAG throughout the treatment period and significantly reduced tissue GAG accumulation in liver and kidney. Furthermore, odiparcil diminished the pathological cartilage thickening observed in trachea and femoral growth plates of MPS VI mice. The therapeutic efficacy of odiparcil was similar in models of early (treatment starting in juvenile, 4 weeks old mice) or established disease (treatment starting in adult, 3 months old mice). Our data demonstrate that odiparcil effectively diverts the synthesis of cellular glycosaminoglycans into secreted soluble species and this effect can be used for reducing cellular and tissue GAG accumulation in MPS VI models. Therefore, our data reveal the potential of odiparcil as an oral GAG clearance therapy for MPS VI patients.

Characterization of the interleukin-17 effect on articular cartilage in a translational model: an explorative study

BackgroundOsteoarthritis (OA) is a progressive, chronic disease characterized by articular cartilage destruction. The pro-inflammatory cytokine IL-17 levels have been reported elevated in serum and synovial fluid of OA patients and correlated with increased cartilage defects and bone remodeling. The aim of this study was to characterize an IL-17-mediated articular cartilage degradation ex-vivo model and to investigate IL-17 effect on cartilage extracellular matrix protein turnover.MethodsFull-depth bovine femoral condyle articular cartilage explants were cultured in serum-free medium for three weeks in the absence, or presence of cytokines: IL-17A (100 ng/ml or 25 ng/ml), or 10 ng OSM combined with 20 ng/ml TNFα (O + T). RNA isolation and PCR analysis were performed on tissue lysates to confirm IL-17 receptor expression. GAG and ECM-turnover biomarker release into conditioned media was assessed with dimethyl methylene blue and ELISA assays, respectively. Gelatin zymography was used for matrix metalloproteinase (MMP) 2 and MMP9 activity assessment in conditioned media, and shotgun LC-MS/MS for identification and label-free quantification of proteins and protein fragments in conditioned media. Western blotting was used to validate MS results.ResultsIL-17RA mRNA was expressed in bovine full-depth articular cartilage and the treatment with IL-17A did not interfere with metabolic activity of the model. IL-17A induced cartilage breakdown; conditioned media GAG levels were 3.6-fold-elevated compared to untreated. IL-17A [100 ng/ml] induced ADAMTS-mediated aggrecan degradation fragment release (14-fold increase compared to untreated) and MMP-mediated type II collagen fragment release (6-fold-change compared to untreated). MS data analysis revealed 16 differentially expressed proteins in IL-17A conditioned media compared to untreated, and CHI3L1 upregulation in conditioned media in response to IL-17 was confirmed by Western blotting.ConclusionsWe showed that IL-17A has cartilage modulating potential. It induces collagen and aggrecan degradation indicating an upregulation of MMPs. This was confirmed by zymography and mass spectrometry data. We also showed that the expression of other cytokines is induced by IL-17A, which provide further insight to the pathways that are active in response to IL-17A. This exploratory study confirms that IL-17A may play a role in cartilage pathology and that the applied model may be a good tool to further investigate it.

Asiatic acid attenuates hypertrophic and fibrotic differentiation of articular chondrocytes via AMPK/PI3K/AKT signaling pathway

BackgroundOsteoarthritis (OA), the most common joint disorder, is characterized by a progressive degradation of articular cartilage. Increasing evidence suggests that OA is closely associated with cartilage pathologies including chondrocyte hypertrophy and fibrosis.MethodsIn this study, we showed that asiatic acid (AA) treatment reduced chondrocyte hypertrophy and fibrosis. First, the cytotoxicity of AA (0, 5, 10, and 20 μM) to chondrocytes was evaluated, and 5 μM was selected for subsequent experiments. Then, we detected the gene and protein level of chondrocyte hypertrophic markers including type X collagen (COL-X), matrix metalloproteinase-13 (MMP-13), alkaline phosphatase (ALP), and runt-related transcription factor 2 (Runx2); chondrocyte fibrosis markers including type I collagen (COL-Ι) and alpha-smooth muscle actin (α-SMA); and chondrogenic markers including SRY-related HMG box 9 (SOX9), type II collagen (COL-II), and aggrecan (ACAN). Further, we tested the mechanism of AA on inhibiting chondrocyte hypertrophy and fibrosis. Finally, we verified the results in an anterior cruciate ligament transection (ACLT) rat OA model.ResultsWe found that AA treatment inhibited the hypertrophic and fibrotic phenotype of chondrocytes, without affecting the chondrogenic phenotype. Moreover, we found that AA treatment activated AMP-activated protein kinase (AMPK) and inhibited phosphoinositide-3 kinase/protein kinase B (PI3K/AKT) signaling pathway in vitro. The results in an ACLT rat OA model also indicated that AA significantly attenuated chondrocyte hypertrophy and fibrosis.ConclusionAA treatment could reduce hypertrophic and fibrotic differentiation and maintain the chondrogenic phenotype of articular chondrocytes by targeting the AMPK/PI3K/AKT signaling pathway. Our study suggested that AA might be a prospective drug component that targets hypertrophic and fibrotic chondrocytes for OA treatment.

Bone Marrow Aspirate Concentrate: Its Uses in Osteoarthritis.

Human bone marrow (BM) is a kind of source of mesenchymal stem cells (MSCs) as well as growth factors and cytokines that may aid anti-inflammation and regeneration for various tissues, including cartilage and bone. However, since MSCs in BM usually occupy only a small fraction (0.001%) of nucleated cells, bone marrow aspirate concentrate (BMAC) for cartilage pathologies, such as cartilage degeneration, defect, and osteoarthritis, have gained considerable recognition in the last few years due to its potential benefits including disease modifying and regenerative capacity. Although further research with well-designed, randomized, controlled clinical trials is needed to elucidate the exact mechanism of BMAC, this may have the most noteworthy effect in patients with osteoarthritis. The purpose of this article is to review the general characteristics of BMAC, including its constituent, action mechanisms, and related issues. Moreover, this article aims to summarize the clinical outcomes of BMAC reported to date.

Doxycycline improves tendon and cartilage pathologies in preclinical studies: current concepts

Matrix metalloproteinases (MMPs) are enzymes that are elevated during states of inflammation and have specifically been linked to cartilage, tendon and bone pathologies. Concentrations of these enzymes fluctuate naturally with various injury states, and these enzymes have been shown to be directly inhibited by doxycycline. Historically, doxycycline has been used exclusively for its antimicrobial properties, but recent studies have investigated the anti-inflammatory properties of doxycycline and its effects on musculoskeletal pathologies. This study sought to describe the current use of doxycycline for its MMP inhibitory properties in the setting of musculoskeletal pathologies. During preclinical studies, improved healing properties were noted acutely in tendon injuries following surgical repair and chronically in cartilage injuries, demonstrating decreased rates of joint space narrowing and improved cartilage quality. There is only one known clinical trial that has examined doxycycline use, and it reported that doxycycline can decrease the rate of joint space narrowing in patients with osteoarthritis. Furthermore, doxycycline was well tolerated with minimal side effects reported in both animal and human studies. While it can be reasonably inferred that the positive effects of doxycycline are related to its ability to inhibit MMP activity, further clinical research is warranted to investigate the use of doxycycline in orthopaedic and musculoskeletal pathologies. Level of Evidence: Current Concepts, Level IV.

Inflammatory priming enhances mesenchymal stromal cell secretome potential as a clinical product for regenerative medicine approaches through secreted factors and EV-miRNAs: the example of joint disease

BackgroundMesenchymal stromal cell (MSC)-enriched products showed positive clinical outcomes in regenerative medicine, where tissue restoration and inflammation control are needed. GMP-expanded MSCs displayed an even higher potential due to exclusive secretion of therapeutic factors, both free and conveyed within extracellular vesicles (EVs), collectively termed secretome. Moreover, priming with biochemical cues may influence the portfolio and biological activities of MSC-derived factors. For these reasons, the use of naive or primed secretome gained attention as a cell-free therapeutic option. Albeit, at present, a homogenous and comprehensive secretome fingerprint is still missing. Therefore, the aim of this work was to deeply characterize adipose-derived MSC (ASC)-secreted factors and EV-miRNAs, and their modulation after IFNγ preconditioning. The crucial influence of the target pathology or cell type was also scored in osteoarthritis to evaluate disease-driven potency.MethodsASCs were isolated from four donors and cultured with and without IFNγ. Two-hundred secreted factors were assayed by ELISA. ASC-EVs were isolated by ultracentrifugation and validated by flow cytometry, transmission electron microscopy, and nanoparticle tracking analysis. miRNome was deciphered by high-throughput screening. Bioinformatics was used to predict the modulatory effect of secreted molecules on pathologic cartilage and synovial macrophages based on public datasets. Models of inflammation for both macrophages and chondrocytes were used to test by flow cytometry the secretome anti-inflammatory potency.ResultsData showed that more than 60 cytokines/chemokines could be identified at varying levels of intensity in all samples. The vast majority of factors are involved in extracellular matrix remodeling, and chemotaxis or motility of inflammatory cells. IFNγ is able to further increase the capacity of the secretome to stimulate cell migration signals. Moreover, more than 240 miRNAs were found in ASC-EVs. Sixty miRNAs accounted for > 95% of the genetic message that resulted to be chondro-protective and M2 macrophage polarizing. Inflammation tipped the balance towards a more pronounced tissue regenerative and anti-inflammatory phenotype. In silico data were confirmed on inflamed macrophages and chondrocytes, with secretome being able to increase M2 phenotype marker CD163 and reduce the chondrocyte inflammation marker VCAM1, respectively. IFNγ priming further enhanced secretome anti-inflammatory potency.ConclusionsGiven the portfolio of soluble factors and EV-miRNAs, ASC secretome showed a marked capacity to stimulate cell motility and modulate inflammatory and degenerative processes. Preconditioning is able to increase this ability, suggesting inflammatory priming as an effective strategy to obtain a more potent clinical product which use should always be driven by the molecular mark of the target pathology.

What are the rates of hip arthroscopy in Victoria, Australia and Denmark from 2012 to 2018

Purpose: Hip pain is associated with reduced quality of life, function and compromised occupational and daily tasks. Bony variations such as cam morphology at the femoral head-neck junction are thought to cause femoroacetabular impingement (FAI) when associated with hip pain. FAI can increase the risk of progression to early hip osteoarthritis. Hip arthroscopy is an intervention commonly used therapeutically to manage hip symptoms by modification of cam morphology or hip joint structures thought to contribute to symptoms such as labral tears and cartilage pathology.

Degeneration-dependent changes in human meniscus functionality as assessed by quantitative MRI techniques

Purpose: In OA, there is a close association of meniscus and cartilage pathologies. Meniscus degeneration and lesioning are critical risk factors for development of early OA. Hence, this ex-vivo study assessed the responses to standardized loading of human meniscus samples as a function of degeneration and based on changes in their T1, T2 and T1ρ maps (as surrogate parameters of the tissue’s functionality).

Synovial inflammation in anterior cruciate ligament injury knees in mice: surgical vs non-surgical models

Purpose: Anterior-cruciate-ligament (ACL) rupture is one of the most common knee injuries, resulting in pain, disability, and increased risk of developing OA. However, only ∼50% of individuals with ACL rupture develop OA, and the factors underlying this variable risk remain unclear. Changes in joint stability as a result of ACL deficiency drive mechanobiological dysfunction and the development of OA. However, specific factors are known to increase OA risk such as concurrent injury to the meniscus, cartilage, and subchondral bone. Also, the degree of initial joint inflammation and its resolution are implicated in long-term outcomes. Surgical and nonsurgical models of ACL rupture in mice result in similar joint instability but distinct risks or trajectories of OA. We used these two models to investigate if differences in synovial inflammatory response are associated with this risk of OA disease progression Methods: Ten-week-old, male C57BL/6 mice were randomly assigned to ACL transection (ACLT), ACL rupture (ACLR), sham-surgery or uninjured groups. Mice in the ACLT and sham-operated groups were subjected to anaesthesia, right unilateral medial arthrotomy, patella luxation, and fat-pad elevation to visualise the ACL, at which time the surgeon was informed to transect or spare the ACL before joint closure. Uninjured and ACLR animals were anaesthetised, the latter having a single compressive load (9-12N) to posteriorly displace the femur and traumatically rupture the ACL. Animals were housed in mixed injury groups (up to 5/cage) and allowed unrestricted activity. At 1, 2, 4 and 8 weeks post-injury, mice were euthanised and joints harvested for fixation, paraffin embedding, sectioning and OA histopathology scoring (n=7/group/timepoint); or synovial tissue (en bloc fat-pad, synovial lining and joint capsule anterior to the collateral ligaments) isolation for RNA extraction and quantitative RT-PCR analysis of cytokines (IL1, IL6, TNF), inflammatory cell markers (CD11b, CD4, CD8), and enzymes implicated in OA pathophysiology (ADAMTS4, ADAMTS5, MMP3, MMP9, MMP13) (n=6/group/time point). Results: ACL injury resulted in progressive OA pathology with cartilage pathology significantly greater in ACLR compared with ACLT at 2 and 4 weeks (p<0.001), but by 8 weeks was equivalent in the two models; posterior osteochondral erosion significantly worse in ACLR than ACLT at 4 and 8 weeks (p<0.01); and osteophyte size (p<0.001) and maturity (p<0.01) greater at 1 and 2 weels in ACLR compared with ACLT. Synovitis was increased acutely in both ACL-injuries and then decreased with time, with ACLT>ACLR (p=0.003) at week-1 but similar thereafter; both still greater than uninjured joints through to week 8 (p<0.001). Sham and ACLT had similar synovitis scores until week 8 when the latter was more severe. Despite histomorphological similarities in synovitis in ACLT and ACLR, there were differences in gene expression patterns. Synovial expression of TNF, CD11b and CD8 was unchanged at any time when comparing between groups. Surgery alone (ACLT and Sham) increased synovial IL6 (week-1: ACLT p=0.02, Sham p<0.001 vs uninjured) while ACLR did not. While CD4 was also increased by surgery (week-1 and -2: ACLT p<0.01, Sham p<0.05 vs uninjured), it was also increased in ACLR versus uninjured at these times (p<0.05; Figure 1). ADAMTS5 expression was not detected in synovial tissue, and MMP9 mRNA did not differ between groups. In contrast, ADAMTS4, MMP3, and MMP13 expression were increased by surgery (ACLT/Sham) and ACLR at week-1 and -2 compared with uninjured joint, although both surgeries>ACLR (Table 1). Conclusions: While both models caused joint instability, OA trajectory and ultimate severity were greater in ACLR. In contrast, surgery induced greater histo-pathological synovitis acutely but was similar in both injuries thereafter. There was a difference in the “phenotype” of the synovial inflammation in the two injury models. In ACLT there was upregulation of IL6 not evident in ACLR but similar to Sham, suggesting this was a response to surgery and wound healing. While helper T-cell (CD4) increase was greater in ACLT and Sham, this also occurred in ACLR suggesting a role of adaptive immunity in OA after nonsurgical injury. Expression of ADAMTS4, MMP3 and MMP13 were similarly increased acutely in both injury models, suggesting synovial tissues as a source of these enzymes implicated in the structural pathology of OA. While their expression was not correlated with ultimate pathological severity they may be broad-spectrum target across varying phenotypes of post-traumatic OA. Our data suggest that synovitis severity per se was not associated with differential OA risk with ACL injury; it likely still contributes to long-term OA structural pathology.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

DELAY IN DIAGNOSIS AND MANAGEMENT OF ADOLESCENT ANTERIOR CRUCIATE LIGAMENT INJURIES IN A PUBLICLY FUNDED HEALTHCARE SYSTEM

Background:Delay to surgical anterior cruciate ligament (ACL) reconstruction after injury has been associated with increased frequency and severity of meniscal and articular cartilage pathology. Patient factors that contribute to delayed ACL reconstruction are not well understood.Hypothesis/Purpose:Identify patient factors contributing to delayed ACL reconstruction in a publicly funded healthcare system.Methods:A retrospective review of all patients who had a primary ACL reconstruction at a single institution between 2014 and 2018 was completed. Patient demographic data, side, history of physical therapy, and intraoperative status of the meniscus and articular cartilage were collected. Household income was determined based on federal census data of mean household income by postal code. Time from injury to orthopedic referral (W0), consult (W1), and ACL reconstruction (W2) was calculated. A logistic regression model was constructed to determine the impact of household income, age, and sex on W0, W1, and W2.Results:Eighty-three patients were identified with a mean age of 14 years (range, 9-17). Twenty-eight patients were male (33.7%). Mean time from injury to orthopedic consult was 124 days (range, 0-1096). Mean time from injury to reconstruction was 286 days (range, 51-1623). Eleven patients (13%) had ligament reconstruction within 90 days of injury. Fifty-three patients (63.8%) had meniscal or articular cartilage damage at the time of ACL reconstruction. There was no significant effect of patient sex, age, or history of physical therapy on time to ACL reconstruction. Household income was found to have a significant effect on time to ACL reconstruction. For every $10,000.00 increase in household income, time to reconstruction was reduced by 19%. Using median time to reconstruction (223 days), this represents a decrease of 42 days. Household income only had an effect on W0 with a decrease of 38.4% for every $10,000.00 incremental increase in household income. No association was found between time to ACL reconstruction and odds of meniscal or articular cartilage damage.Conclusion:At a pediatric tertiary care hospital in a public health care system, most adolescent patients are having their ACL reconstructed in a delayed fashion contributing to an increased frequency of intra-articular pathology. Increase in household income was associated with a significant decrease in time to orthopaedic referral. There was no difference in wait time for consultation (W1) or wait time for surgery (W2). Further research is needed to determine specific factors causing this discrepancy in access to healthcare within a publicly funded system.