An Atlas of the Knee Joint Proteins and Their Role in Osteoarthritis Defined by Literature Mining.

Osteoarthritis (OA) is the most prevalent rheumatic pathology. However, OA is not simply a process of wear and tear affecting articular cartilage but rather a disease of the entire joint. One of the most common locations of OA is the knee. Knee tissues have been studied using molecular strategies, generating a large amount of complex data. As one of the goals of the Rheumatic and Autoimmune Diseases initiative of the Human Proteome Project, we applied a text-mining strategy to publicly available literature to collect relevant information and generate a systematically organized overview of the proteins most closely related to the different knee components. To this end, the PubPular literature-mining software was employed to identify protein-topic relationships and extract the most frequently cited proteins associated with the different knee joint components and OA. The text-mining approach searched over eight million articles in PubMed up to November 2022. Proteins associated with the six most representative knee components (articular cartilage, subchondral bone, synovial membrane, synovial fluid, meniscus, and cruciate ligament) were retrieved and ranked by their relevance to the tissue and OA. Gene ontology analyses showed the biological functions of these proteins. This study provided a systematic and prioritized description of knee-component proteins most frequently cited as associated with OA. The study also explored the relationship of these proteins to OA and identified the processes most relevant to proper knee function and OA pathophysiology.

Lef1 ablation alleviates cartilage mineralization following posttraumatic osteoarthritis induction.

Cartilage mineralization is a tightly controlled process, imperative for skeletal growth and fracture repair. However, in osteoarthritis (OA), cartilage mineralization may impact the joint range of motion, inflict pain, and increase chances for joint effusion. Here we attempt to understand the link between inflammation and cartilage mineralization by targeting Sirtuin 1 (SIRT1) and lymphoid enhancer binding factor 1 (LEF1), both reported to have contrasting effects on cartilage. We find that inflammatory-dependent cleavage of SIRT1 or its cartilage-specific genetic ablation, directly enhanced LEF1 expression accompanied by a catabolic response. Applying a posttraumatic OA (PTOA) model to cartilage-specific Sirt1 nulls displayed severe OA, which was accompanied by synovitis, meniscal mineralization, and osteophyte formation of the lateral joint compartment. Alternatively, cartilage-specific Lef1 nulls presented reduced lateral mineralization, OA severity, and local pain. Differential gene expression analysis revealed that Lef1 ablation reduced nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Toll-like receptor (Tlr) pathways, while enhancing SRY-Box transcription factor 9 (Sox9) and cartilaginous extracellular matrix genes. The results support a link between inflammation and Lef1-dependent cartilage mineralization, mediated by the inactivation of Sirt1. By ablating Lef1 in a PTOA model, the structural and pain-related phenotypes of OA were reduced, in part, by preventing cartilage mineralization of the lateral joint compartment, partially manifested by meniscal tissue mineralization. Overall, these data provide a molecular axis to link between inflammation and cartilage in a PTOA model.

Shedding light on the effects of blood on meniscus tissue: the role of mononuclear leukocytes in mediating meniscus catabolism.

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

Unraveling sex-specific risks of knee osteoarthritis before menopause: Do sex differences start early in life?

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

Krüppel-like factor 15 deficiency exacerbates osteoarthritis through reduced expression of peroxisome proliferator-activated receptor gamma signaling in mice.

OBJECTIVE: Krüppel-like zinc finger transcription factors (KLFs) play diverse roles in mammalian cell differentiation and development. In this study, we investigated the function of KLF15 in the progression of osteoarthritis (OA). METHODS: 0Destabilization of the medial meniscus (DMM) surgery was performed in 10-week-old male wild-type control (WT) mice and cartilage-specific KLF15 knockout (KO) mice. Histological analysis, immunohistochemistry, and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling staining were performed. Morphological changes were measured using microcomputed tomography. Six mice from each group were analyzed (total number of mice analyzed: 60). In vitro, immunofluorescence, quantitative reverse transcription-polymerase chain reaction, and western blot analyses were performed. RESULTS: KLF15 KO DMM mice exhibited significant cartilage degradation compared to WT mice. According to the Osteoarthritis Research Society International cartilage OA-histopathology scoring system, the mean sum score in KLF15 KO mice was significantly higher than that in WT mice at 8 weeks after surgery. Immunohistochemistry results revealed KLF15 KO mice exhibited reduced peroxisome proliferator-activated receptor gamma (PPARγ) expression, increased pIKKα/ß, a disintegrin-like and metalloproteinase with thrombospondin motifs (ADAMTS) 5, and Matrix metalloproteinases (MMP13) expression, and reduced Forkhead box O (FOXO1) and Light chain 3B (LC3B) expression. Inhibition of PPARγ phosphorylation accelerated the effects of interleukin (IL) 1ß-treatment in both KLF15 KO and WT chondrocytes, and activation of PPARγ expression canceled the IL1ß-induced catabolic effects. CONCLUSION: Our results indicated that the OA phenotype of KLF15 KO DMM mice was influenced by reduced PPARγ expression, including enhanced pIKKα/ß, ADAMTS5, and MMP13 expression, reduced autophagy, and increased apoptosis. KLF15 regulation may constitute a possible therapeutic strategy for the treating OA.

Prevalence and classification of meniscal calcifications in the human knee.

OBJECTIVE: To investigate the occurrence of meniscal calcifications in individuals with and without knee osteoarthritis (OA). Additionally, we aim to identify the specific types of calcifications: basic calcium phosphate (BCP) and calcium pyrophosphate dihydrate (CPP). METHOD: We analyzed 82 meniscal posterior horn samples (medial and lateral) collected from 41 human subjects. Among them, 20 individuals underwent total knee replacement due to medial compartment OA, while 21 deceased donors had no known knee OA. The assessment of meniscal calcifications and Pauli's histopathological scoring was conducted using histological sections. Furthermore, adjacent sections underwent measurement using Raman spectroscopy to characterize BCP and CPP calcifications based on their distinct spectral fingerprints. RESULTS: All OA individuals exhibited calcifications in at least one meniscus, compared to 9.5% (95%CI 1%, 30%) of donors. Among 35 OA menisci with calcifications, 28(80%) had BCP, 5(14%) had CPP and 2(6%) had both types. In 4 donor menisci, 3(75%) had CPP while 1(25%) had both types. We estimated the association between Pauli score and presence of BCP in OA individuals, yielding an odds ratio of 2.1 (95%CI 0.8, 5.3) per 1 Pauli score. The association between Pauli score and presence of CPP (in whole study sample) seemed weaker, with odds ratio of 1.3 (95%CI 1.1, 1.7). CONCLUSION: The presence of BCP was predominant in menisci of OA individuals, whereas CPP exhibited similar prevalence in individuals with and without OA. The formation of BCP crystals in menisci may represent an important and specific characteristic of OA disease process that warrants further attention.

Effect of arthroscopic partial meniscectomy on structural degeneration of the knee - A 5-year MRI-based follow-up of the placebo-surgery controlled FIDELITY (Finnish Degenerative Meniscus Lesion Study) trial.

OBJECTIVE: To assess the 5-year effects of arthroscopic partial meniscectomy (APM) vs. placebo surgery on the development of the structural changes of the knee by magnetic resonance imaging (MRI). DESIGN: This multicentre, randomized, participant- and outcome-assessor-blinded, placebo-surgery-controlled trial was carried out in Finland. We randomized 146 adults, mean age 52 years (range 35 to 65) to undergo either APM or placebo surgery. The subjects had symptoms of degenerative medial meniscus tear, a tear verified in MRI and arthroscopy, and no advanced osteoarthritis at baseline. We compared the baseline and 5-year follow-up MRIs using MRI Osteoarthritis Knee Score scoring to derive subregional data on cartilage damage, osteophytes and bone marrow lesions (BMLs). Progression of structural cartilage changes analyzed per subregion was the main outcome, that of osteophytes and BMLs secondary outcomes. We analyzed the progression with multilevel logistic regression model on subregion-level data, adjusted for randomization stratification factors, and using robust standard errors. RESULTS: Sixty-three (90%) subjects in the APM and 73 (96%) in the placebo-surgery group had MRI at both time points. The adjusted odds ratio (APM vs. placebo-surgery) was 1.31 (95% confidence interval 0.81, 1.94) for progression of cartilage damage, 2.86 (1.16, 6.21) for osteophytes, and 1.43 (0.84, 2.43) for BMLs. CONCLUSIONS: We found a slightly greater risk for progression of osteophytes in the APM group compared to the placebo-surgery group at 5 years after surgery. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01052233 and NCT00549172).

Artificial intelligence applied to magnetic resonance imaging reliably detects the presence, but not the location, of meniscus tears: a systematic review and meta-analysis.

OBJECTIVES: To review and compare the accuracy of convolutional neural networks (CNN) for the diagnosis of meniscal tears in the current literature and analyze the decision-making processes utilized by these CNN algorithms. MATERIALS AND METHODS: PubMed, MEDLINE, EMBASE, and Cochrane databases up to December 2022 were searched in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement. Risk of analysis was used for all identified articles. Predictive performance values, including sensitivity and specificity, were extracted for quantitative analysis. The meta-analysis was divided between AI prediction models identifying the presence of meniscus tears and the location of meniscus tears. RESULTS: Eleven articles were included in the final review, with a total of 13,467 patients and 57,551 images. Heterogeneity was statistically significantly large for the sensitivity of the tear identification analysis (I2 = 79%). A higher level of accuracy was observed in identifying the presence of a meniscal tear over locating tears in specific regions of the meniscus (AUC, 0.939 vs 0.905). Pooled sensitivity and specificity were 0.87 (95% confidence interval (CI) 0.80-0.91) and 0.89 (95% CI 0.83-0.93) for meniscus tear identification and 0.88 (95% CI 0.82-0.91) and 0.84 (95% CI 0.81-0.85) for locating the tears. CONCLUSIONS: AI prediction models achieved favorable performance in the diagnosis, but not location, of meniscus tears. Further studies on the clinical utilities of deep learning should include standardized reporting, external validation, and full reports of the predictive performances of these models, with a view to localizing tears more accurately. CLINICAL RELEVANCE STATEMENT: Meniscus tears are hard to diagnose in the knee magnetic resonance images. AI prediction models may play an important role in improving the diagnostic accuracy of clinicians and radiologists. KEY POINTS: • Artificial intelligence (AI) provides great potential in improving the diagnosis of meniscus tears. • The pooled diagnostic performance for artificial intelligence (AI) in identifying meniscus tears was better (sensitivity 87%, specificity 89%) than locating the tears (sensitivity 88%, specificity 84%). • AI is good at confirming the diagnosis of meniscus tears, but future work is required to guide the management of the disease.

The analysis of tear meniscus parameters during daily soft contact lens wear using optical coherence tomography.

PURPOSE: To evaluate tear meniscus parameters in soft contact lens wearers (SCL) using optical coherence tomography (OCT) and ImageJ software. METHODS: This prospective study included 50 soft contact lens wearers (group 1: 25 symptomatic SCL wearers (SCLW), group 2: 25 asymptomatic SCL wearers (ASCW)) and 25 healthy non-CL wearers (group 3 (NCLW)). SCLs were fitted on each eye of CL wearers, and the lower tear meniscus was imaged using OCT before CL insertion, immediately afterward, and reimaged 2, 5 and 10 h after insertion. Tear meniscus parameters, including tear meniscus height (TMH), depth (TMD), turbidity, and percentage area occupied by particles (PAOP) were measured in all groups. RESULTS: Turbidity and PAOP measurements at baseline in SCLW were significantly higher than in other groups (p < 0.05). There was no significant difference between TMH, TMD, turbidity, and PAOP parameters calculated at baseline visit and two hours after SCL insertion in all groups (p > 0.05 for 2 comparisons). The symptomatic SCL users had a significant decrease in TMH and TMD in the fifth hour. The turbidity and PAOP measurements of SCLW and ASCW at the fifth and tenth hours were significantly higher than those of NCLW (p < 0.05). CONCLUSION: TMD and height TMH decrease throughout the day in all participants; however, a significant decrease in these parameters was observed only in symptomatic SCL users at the fifth hour, at the earliest. As the duration of CL wear increases, turbidity and PAOP even in asymptomatic SCL wearers become significantly higher than those in healthy non-CL wearers. KEY MESSAGES: What Is Known • Contact lens wear is associated with an increased risk of dry eye. • Tear volume decreases gradually during contact lens wear. What Is New • Tear meniscus turbidity and particle area occupied by particles (PAOP) were higher in symptomatic contact lens wearers and they increase gradually during contact lens wear. • Tear meniscus turbidity and PAOP may be measures of how well the tear film and meniscus are functioning in contact lens wearers.

Quantitative MRI methods for the assessment of structure, composition, and function of musculoskeletal tissues in basic research and preclinical applications.

Osteoarthritis (OA) is a disabling chronic disease involving the gradual degradation of joint structures causing pain and dysfunction. Magnetic resonance imaging (MRI) has been widely used as a non-invasive tool for assessing OA-related changes. While anatomical MRI is limited to the morphological assessment of the joint structures, quantitative MRI (qMRI) allows for the measurement of biophysical properties of the tissues at the molecular level. Quantitative MRI techniques have been employed to characterize tissues' structural integrity, biochemical content, and mechanical properties. Their applications extend to studying degenerative alterations, early OA detection, and evaluating therapeutic intervention. This article is a review of qMRI techniques for musculoskeletal tissue evaluation, with a particular emphasis on articular cartilage. The goal is to describe the underlying mechanism and primary limitations of the qMRI parameters, their association with the tissue physiological properties and their potential in detecting tissue degeneration leading to the development of OA with a primary focus on basic and preclinical research studies. Additionally, the review highlights some clinical applications of qMRI, discussing the role of texture-based radiomics and machine learning in advancing OA research.