Osteoarthritis Research Research Articles

Medial Meniscus Posterior Root Repair Reduces but Does Not Avoid Histologic Progression of Osteoarthritis: Randomized In Vivo Experimental Study in a Rabbit Model

Background: The optimal treatment option for meniscus root tears is still challenging, and whether the meniscus root repair ultimately can arrest or delay osteoarthritic changes is still a concern. Purpose/Hypothesis: The purpose of this study was 2-fold: (1) to describe and compare histopathologic findings of 3 different therapeutic options for medial meniscus posterior root tear: nonoperative management, partial meniscectomy, and meniscus root repair; and (2) to test the hypothesis that meniscus root tears treated nonoperatively predispose to a lower risk of osteoarthritic progression compared with partial meniscectomy. Study Design: Controlled laboratory study. Methods: Posteromedial meniscus root tears were carried out in 39 New Zealand White rabbits. Animals were randomly assigned into 3 experimental groups: partial meniscectomy after root tear (PM; n = 13), root tears treated conservatively (CT; n = 13), and transtibial root repair (RR; n = 13). Contralateral limbs were used as healthy controls. The animals were euthanized at 16 weeks postoperatively; tissue samples of femoral and tibial articular cartilage were collected and processed for macro- and microscopic assessment to detect signs of early osteoarthritis (OA). Each sample was histopathologically assessed using the Osteoarthritis Research Society International grading and staging system. Results: Osteoarthritic changes were the hallmark in all 3 experimental groups. The RR group had the lowest scores for cartilage damage (mean, 2.5; range, 2-3), and the PM group exhibited higher and more severe signs of OA (mean, 16; range, 9-16) compared with the CT group (mean, 5; range, 4-6). The between-group comparison revealed significant differences, as the PM group showed a significantly higher rate of macro- and microscopic osteoarthritic changes compared with the RR (P < .001) and CT (P < .001) groups. The weightbearing area of the medial femoral condyle was the most severely affected, and tidemark disruption was evident in all tissue samples. Conclusion: Meniscus root repair cannot completely arrest the histopathologic progression of knee OA but leads to significantly less severe degenerative changes than partial meniscectomy and nonoperative treatment. Partial meniscectomy leads to the most severe osteoarthritic progression, while stable radial tears left in situ have lower progression compared with partial meniscectomy. Clinical Relevance: Histologic assessment is an essential tool and metric for guiding and understanding osteoarthritic features, providing insight into the disease development and progression. This study provides histopathologic evidence on osteoarthritic progression after medial meniscus posterior root repair. This knowledge can help to set more realistic expectations and can lead to the future development of augmented techniques.

High-Resolution N-Glycan MALDI Mass Spectrometry Imaging of Subchondral Bone Tissue Microarrays in Patients with Knee Osteoarthritis.

N-glycan alterations contribute to the progression of several joint diseases, including knee osteoarthritis (KOA). However, molecular changes in KOA subchondral trabecular bone, when exposed to different joint loading forces, are still unknown. The aim of this study was, therefore, to demonstrate the feasibility to differentiate N-glycan changes in subchondral trabecular bone from four different joint loading forces of the tibial plateau regions (i.e., Lateral Anterior (L-A), Lateral Posterior (L-P), Medial Anterior (M-A), and Medial Posterior (M-P)) in KOA patients (n = 10) using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) at 20 μm spatial resolution. The degree of cartilage degeneration was evaluated histologically, and the subchondral bone tissue microarrays (TMAs) were subsequently manually constructed from formalin-fixed paraffin-embedded (FFPE) KOA osteochondral (i.e., cartilage-subchondral bone) tissues. Overall, the Osteoarthritis Research Society International (OARSI) histological grade was significantly higher and the size of chondrocytes in the superficial zone was much larger for both M-A and M-P compared to L-A and L-P of cartilage (p = 0.006, p = 0.030, p = 0.028, and p = 0.010; respectively). Among the 65 putative N-glycans observed by MALDI-MSI, 2 core fucosylated bi-antennary N-glycans, m/z 1809.64; (Hex)5(HexNAc)4(Fuc)1 and 2100.73; (NeuAc)1(Hex)5(HexNAc)4(Fuc)1, were significantly higher in intensity in M-A compared to L-A of the trabecular bone (p = 0.027, and p = 0.038, respectively). These N-glycans were then further structurally characterized by in situ MS/MS fragmentation post-MALDI-MSI. Our results demonstrate, for the first time, N-glycan alterations can occur at different joint loading forces in the KOA tibial plateau and the feasibility of subchondral bone TMA construction for N-glycan MALDI-MSI.

Tranexamic acid administered intraarticularly to the knee is safer for the articular cartilage and anterior cruciate ligament compared to intravenous administration: Histological analysis of an experimental rat model.

In this study, the effects of tranexamic acid (TXA) on the knee's articular cartilage, anterior cruciate ligament (ACL), and joint capsule were assessed histologically. There were 15 rats in each of the 3 groups, totaling 45 rats. Intraarticular (IA) saline injections were applied for the first group, IA TXA injections for the second group, and intravenous (IV) TXA injections for the third group. Using samples taken from the knee joint 3weeks later, the medial/lateral femoral condyle and medial/lateral tibial plateau articular cartilages were evaluated with Osteoarthritis Research Society International (OARSI) scoring, while ACL diameter and joint capsule thickness were analyzed histologically. In comparisons of OARSI scores for the medial/lateral femoral condyle and medial/lateral tibial plateau cartilage regions, the scores obtained for the IV TXA group were significantly higher than those of the IA saline group (P < 0.001, P = 0.001, P = 0.003, P = 0.011). In comparisons of medial/lateral femoral condyle and medial/lateral tibial plateau OARSI scores, the scores obtained for the IV TXA group were again significantly higher than those of the IA TXA group (P < 0.001, P < 0.001, P < 0.001, P = 0.002). When ACL diameters were compared, a significant decrease was observed in the ACL diameters of the IV TXA group compared to the IA saline and IA TXA groups (P < 0.001, P = 0.039). Histologically, IV TXA damages the articular cartilage and ACL more than IA TXA. IA administration of TXA is more protective when the articular cartilage and ACL are preserved.

Machine Learning Approaches to the Prediction of Osteoarthritis Phenotypes and Outcomes.

Osteoarthritis (OA) is a complex heterogeneous disease with no effective treatments. Artificial intelligence (AI) and its subfield machine learning (ML) can be applied to data from different sources to (1) assist clinicians and patients in decision making, based on machine-learned evidence, and (2) improve our understanding of pathophysiology and mechanisms underlying OA, providing new insights into disease management and prevention. The purpose of this review is to improve the ability of clinicians and OA researchers to understand the strengths and limitations of AI/ML methods in applications to OA research. AI/ML can assist clinicians by prediction of OA incidence and progression and by providing tailored personalized treatment. These methods allow using multidimensional multi-source data to understand the nature of OA, to identify different OA phenotypes, and for biomarker discovery. We described the recent implementations of AI/ML in OA research and highlighted potential future directions and associated challenges.

The relationship between inadequate response to physical therapy and central sensitization in patients with knee osteoarthritis: A prospective cohort study.

Objectives: This study aims to investigate the relationship between physical therapy response and the presence of central sensitization (CS) in patients with painful knee osteoarthritis (OA). Patients and methods: Between May 2019 and March 2020, a total of 84 patients with knee OA (12 males, 72 females; mean age: 60.7±7.7 years; range 50 to 74 years) and 30 age and sex-matched controls (6 males, 24 females; mean age: 59.2±8.9 years; range 50 to 75 years) were included in this study. Knee pain and functional status were evaluated by Visual Analog Scale (VAS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Structural damage was assessed by knee radiography. The Central Sensitization Inventory (CSI), Beck Depression Inventory (BDI), Insomnia Severity Index (ISI), Pain Catastrophizing Scale (PCS), and PainDETECT Questionnaire (PDQ) were applied at baseline. Pain pressure thresholds (PPTs) of the patients were measured and compared with the control group. All patients underwent a total of 15 sessions of physical therapy program for five sessions/weekly. After treatment, the patients were divided into two groups as responders and non-responders according to the Osteoarthritis Research Society International (OARSI) criteria. Results: The CSI score of the patients in non-responder group was significantly higher compared to the responder group (p=0.004). Using a cut-off value of ≥40, the proportion of patients with CSI scores of ≥40 was significantly lower in the responder group compared to non-responder group (p=0.021). The PPT measurement values were significantly lower in the non-responder group compared to the responder and control groups (p <0.01). There was a significant difference in the frequency of hyperalgesia between the groups (p=0.021). Central sensitization and depression were the most significant predictors of non-response to physical therapy (p=0.045 and p=0.024, respectively). Conclusion: Our study results suggest the presence of CS and depression may result in an inadequate response to physical therapy in patients with knee OA. Clinicians should consider the findings of CS and depression in treatment planning.

Complex Approach in Examination of Function of the Knee Joint in Patients with Osteoarthritis

INTRODUCTION: Osteoarthritis (OA) of the knee joint (KJ) is a common problem. The basic factors impairing the function of the KJ are pain and restriction of movement. Evaluation of function of the KJ in OA is an indispensable part of the diagnostic and treatment process. There exists a problem of a quantitative evaluation of pain and restriction of movement of the KJ in OA, associated with the absence of a single standard for evaluation of the KJ function. In the article, the data are given on the modern possibilities for evaluation of the KJ function in OA. The KJ function is evaluated in clinical examination, functional tests, numerous functional questionnaires, as well as with the use of devices for record of movements. Clinical picture of OA of the KJ is evaluated in the clinical examination which includes diagnostic tests, evaluation of the volume of movement, force of muscles, with conclusions about the phenotype of the disease. Functional tests recommended by OARSI (Osteoarthritis Research Society International) are preferable for express-testing, but not all of them have reference values. Functional questionnaires for evaluation of the KJ function exist in many variants, which impedes their choice and interaction between specialists, and they are characterized by different labor intensity in use. There exists a diversity of devices for evaluation of function of the KJ, some of which are expensive, require special rooms, training of the specialist, and take considerable time. Others are simpler in use and inexpensive, but give less reliable results.&#x0D; CONCLUSION: The authors showed the possibilities of a comprehensive evaluation, described the problem of the lack of a single standard for investigation of the KJ function. A conclusion is made about the necessity to develop a software-hardware complex that maximally satisfies the criteria of objectivity, accessibility and quickness of use for evaluation of function of the KJ in OA.

Ginsenoside compound K alleviates osteoarthritis by inhibiting NLRP3‑mediated pyroptosis.

Ginsenoside compound K (GCK) has been previously reported to be a potent antiarthritic and bone-protective agent. Therefore, the present study aimed to explore the potential effects of GCK on osteoarthritis and its regulatory effects on the pyroptosis of chondrocytes. Primary mouse chondrocytes (PMCs) were used for in vitro analysis. ELISA assays revealed that compared with the untreated cells, TNF-α induced a significant increase in IL-6, MMP13, A disintegrin and metalloproteinase with thrombospondin motifs 5 and MMP3 expression but induced a significant decrease in aggrecan and collagen II expression. By contrast, GCK reversed the aforementioned alterations in a dose-dependent manner. Experimental osteoarthritis was subsequently induced in mice through transection of the medial meniscotibial ligament and medial collateral ligament in the right knee [destabilization of the medial meniscus (DMM) mice]. GCK was found to reduce cartilage degradation in vivo in DMM mice, which was assessed using the Osteoarthritis Research Society International (OARSI) score, collagen II and MMP13 expression. Cartilage degradation is associated with higher OARSI score, decreased collagen II and increased MMP13 expression. In PMCs, TNF-α treatment stimulated an increase in the expression of NLR family pyrin domain containing 3 (NLRP3), Gasdermin D-N terminal (GSDMD-NT), cleaved caspase-1 and mature IL-1β, markers that indicate the occurrence of pyroptosis. However, GCK treatment suppressed the increase of the aforementioned proteins in a dose-dependent manner. Immunohistochemistry staining of the knee joint tissue sections from the DMM mice confirmed that GCK attenuated the NLRP3 and GSDMD-NT expression that was induced by DMM surgery. In conclusion, the present study revealed that GCK can reduce cartilage degradation in an osteoarthritis model by inhibiting the NLRP3-inflammasome activation and subsequent pyroptosis.

Targeting macrophagic PIM-1 alleviates osteoarthritis by inhibiting NLRP3 inflammasome activation via suppressing mitochondrial ROS/Cl− efflux signaling pathway

BackgroundOsteoarthritis (OA), in which macrophage-driven synovitis is considered closely related to cartilage destruction and could occur at any stage, is an inflammatory arthritis. However, there are no effective targets to cure the progression of OA. The NOD-, LRR-,and pyrin domain-containing protein 3 (NLRP3) inflammasome in synovial macrophages participates in the pathological inflammatory process and treatment strategies targeting it are considered to be an effective approach for OA. PIM-1 kinase, as a downstream effector of many cytokine signaling pathways, plays a pro-inflammatory role in inflammatory disease.MethodsIn this study, we evaluated the expression of the PIM-1 and the infiltration of synovial macrophages in the human OA synovium. The effects and mechanism of PIM-1 were investigated in mice and human macrophages stimulated by lipopolysaccharide (LPS) and different agonists such as nigericin, ATP, Monosodium urate (MSU), and Aluminum salt (Alum). The protective effects on chondrocytes were assessed by a modified co-culture system induced by macrophage condition medium (CM). The therapeutic effect in vivo was confirmed by the medial meniscus (DMM)-induced OA in mice.ResultsThe expression of PIM-1 was increased in the human OA synovium which was accompanied by the infiltration of synovial macrophages. In vitro experiments, suppression of PIM-1 by SMI-4a, a specific inhibitor, rapidly inhibited the NLRP3 inflammasome activation in mice and human macrophages and gasdermin-D (GSDME)-mediated pyroptosis. Furthermore, PIM-1 inhibition specifically blocked the apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization in the assembly stage. Mechanistically, PIM-1 inhibition alleviated the mitochondrial reactive oxygen species (ROS)/chloride intracellular channel proteins (CLICs)-dependent Cl− efflux signaling pathway, which eventually resulted in the blockade of the ASC oligomerization and NLRP3 inflammasome activation. Furthermore, PIM-1 suppression showed chondroprotective effects in the modified co-culture system. Finally, SMI-4a significantly suppressed the expression of PIM-1 in the synovium and reduced the synovitis scores and the Osteoarthritis Research Society International (OARSI) score in the DMM-induced OA model.ConclusionsTherefore, PIM-1 represented a new class of promising targets as a treatment of OA to target these mechanisms in macrophages and widened the road to therapeutic strategies for OA.

Complex-Type N-Glycans Are Associated with Cartilage Degeneration within Different Loading Sites of the Tibial Plateau for Knee Osteoarthritis Patients.

Abnormal N-glycosylation has been shown to play an important role in the pathogenesis of multiple diseases. However, little is known about the relationship between N-glycosylation and knee osteoarthritis (KOA) progression at the tissue level. Thus, the aim of this study was to quantify the cartilage histomorphometric changes in formalin-fixed paraffin-embedded (FFPE) tissue collected from the lateral and medial compartments of the tibial plateau KOA patients (n = 8). Subsequently, N-glycans were analyzed by matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) followed by in situ MS/MS fragmentation. Overall, the Osteoarthritis Research Society International (OARSI) histological grade and cartilage surface fibrillation index were significantly higher, and chondrocyte size in the superficial zone was much larger, for the medial high-loaded cartilage compared to the lateral less-loaded cartilage. Among 92 putative N-glycans observed by MALDI-MSI, 3 complex-type N-glycans, (Hex)4(HexNAc)3, (Hex)4(HexNAc)4, and (Hex)5(HexNAc)4, and 1 oligomannose-type N-glycan, (Hex)9(HexNAc)2, were significantly higher in intensity in the medial cartilage compared to the lateral cartilage, whereas 2 tetra-antennary fucosylated-type N-glycans, (Hex)3(HexNAc)6(Fuc)2 and (Hex)3(HexNAc)6(Fuc)3, were significantly higher in intensity in the lateral cartilage than the medial cartilage. Our findings indicate that complex-type N-glycans are associated with higher severity of cartilage degeneration and may influence the cellular processes of KOA.

Epigenetic regulatory mechanism of ADAMTS12 expression in osteoarthritis

BackgroundOsteoarthritis (OA) is a degenerative joint disease with lacking effective prevention targets. A disintegrin and metalloproteinase with thrombospondin motifs 12 (ADAMTS12) is a member of the ADAMTS family and is upregulated in OA pathologic tissues with no fully understood molecular mechanisms.MethodsThe anterior cruciate ligament transection (ACL-T) method was used to establish rat OA models, and interleukin-1 beta (IL-1β) was administered to induce rat chondrocyte inflammation. Cartilage damage was analyzed via hematoxylin-eosin, Periodic Acid-Schiff, safranin O-fast green, Osteoarthritis Research Society International score, and micro-computed tomography assays. Chondrocyte apoptosis was detected by flow cytometry and TdT dUTP nick-end labeling. Signal transducer and activator of transcription 1 (STAT1), ADAMTS12, and methyltransferase-like 3 (METTL3) levels were detected by immunohistochemistry, quantitative polymerase chain reaction (qPCR), western blot, or immunofluorescence assay. The binding ability was confirmed by chromatin immunoprecipitation-qPCR, electromobility shift assay, dual-luciferase reporter, or RNA immunoprecipitation (RIP) assay. The methylation level of STAT1 was analyzed by MeRIP-qPCR assay. STAT1 stability was investigated by actinomycin D assay.ResultsThe STAT1 and ADAMTS12 expressions were significantly increased in the human and rat samples of cartilage injury, as well as in IL-1β-treated rat chondrocytes. STAT1 is bound to the promoter region of ADAMTS12 to activate its transcription. METTL3/ Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) mediated N6-methyladenosine modification of STAT1 promoted STAT1 mRNA stability, resulting in increased expression. ADAMTS12 expression was reduced and the IL-1β-induced inflammatory chondrocyte injury was attenuated by silencing METTL3. Additionally, knocking down METTL3 in ACL-T-produced OA rats reduced ADAMTS12 expression in their cartilage tissues, thereby alleviating cartilage damage.ConclusionMETTL3/IGF2BP2 axis increases STAT1 stability and expression to promote OA progression by up-regulating ADAMTS12 expression.

MiR-1 Inhibits the Ferroptosis of Chondrocyte by Targeting CX43 and Alleviates Osteoarthritis Progression.

Dysregulation of miRNAs in chondrocytes has been confirmed to participate in osteoarthritis (OA) progression. Previous study has screen out several key miRNAs may play crucial role in OA based on bioinformatic analysis. Herein, we identified the downregulation of miR-1 in OA samples and inflamed chondrocytes. The further experiments revealed that miR-1 played an essential role in maintaining chondrocytes proliferation, migration, antiapoptosis, and anabolism. Connexin 43 (CX43) was further predicted and confirmed to be the target of miR-1, and mediated the promotion effects of miR-1 in regulating chondrocyte functions. Mechanistically, miR-1 maintained the expression of GPX4 and SLC7A11 by targeting CX43, attenuated the accumulation of intracellular ROS, lipid ROS, MDA, and Fe2+ in chondrocytes, thereby inhibiting the ferroptosis of chondrocytes. Finally, experimental OA model was constructed by anterior cruciate ligament transection surgery, and Agomir-1 was injected into the joint cavity of mice to assess the protective effect of miR-1 in OA progression. Histological staining, immunofluorescence staining and Osteoarthritis Research Society International score revealed that miR-1 could alleviate the OA progression. Therefore, our study elucidated the mechanism of miR-1 in OA in detail and provided a new insight for the treatment of OA.

Animal Models of Osteoarthritis: Updated Models and Outcome Measures 2016-2023.

Osteoarthritis (OA) is a global musculoskeletal disorder that affects primarily the knee and hip joints without any FDA-approved disease-modifying therapies. Animal models are essential research tools in developing therapies for OA; many animal studies have provided data for the initiation of human clinical trials. Despite this, there is still a need for strategies to recapitulate the human experience using animal models to better develop treatments and understand pathogenesis. Since our last review on animal models of osteoarthritis in 2016, there have been exciting updates in OA research and models. The main purpose of this review is to update the latest animal models and key features of studies in OA research. We used our existing classification method and screened articles in PubMed and bibliographic search for animal OA models between 2016 and 2023. Relevant and high-cited articles were chosen for inclusion in this narrative review. Recent studies were analyzed and classified. We also identified ex vivo models as an area of ongoing research. Each animal model offers its own benefit in the study of OA and there are a full range of outcome measures that can be assessed. Despite the vast number of models, each has its drawbacks that have limited translating approved therapies for human use. Depending on the outcome measures and objective of the study, researchers should pick the best model for their work. There have been several exciting studies since 2016 that have taken advantage of regenerative engineering techniques to develop therapies and better understand OA. Osteoarthritis (OA) is a chronic debilitating disease without any cure that affects mostly the knee and hip joints and often results in surgical joint replacement. Cartilage protects the joint from mechanical forces and degrades with age or in response to injury. The many contributing causes of OA are still being investigated, and animals are used for preclinical research and to test potential new treatments. A single consensus OA animal model for preclinical studies is non-existent. In this article, we review the many animal models for OA and provide a much-needed update on studies and model development since 2016.

Intra-articular injection of secretome, derived from umbilical cord mesenchymal stem cell, enhances the regeneration process of cartilage in early-stage osteo-arthritis: an animal study.

Mesenchymal stem cells (MSCs), both endogenous and exogenous, enhance chondrocyte proliferation by stimulating collagen type II. Secretome, an MSC derivate, has shown to also provide this mechanism through a paracrine effect. We aimed to evaluate the use of secretome and MSC in the management of early osteoarthritis (OA). 19 (1 control) male sheep (Ovies aries), which were operated on with total lateral meniscectomy to induce knee OA, were divided into 3 groups: the secretome group, hyaluronic acid group, and MSC group. Each group was injected with the respective substances and was evaluated macroscopically and microscopically. The Osteoarthritis Research Society International (OARSI) score was calculated for all subjects and a descriptive and comparative statistical analysis was undertaken. The macroscopic analysis of the treated groups revealed better OARSI score in the secretome group compared with the other 2 groups. The secretome group showed a significantly better microscopic score compared with the hyaluronic acid group (mean difference [MD] 6.0, 95% confidence interval [CI] 0.15-12), but no significant difference compared with the MSC group (MD 1.0, CI -4.8 to 6.8). Intra-articular injection of secretome is effective in managing early-stage osteoarthritis in the animal model compared with hyaluronic acid and has similar efficacy to MSC injection.

Subluxation of the first carpometacarpal joint and age are important factors in reduced hand strength in patients with hand osteoarthritis

Objective To investigate the determinants of hand strength in patients with hand osteoarthritis (OA). Method Pinch and cylinder grip strength were measured in 527 patients with hand OA diagnosed by their treating rheumatologist from the Hand OSTeoArthritis in Secondary care (HOSTAS) study. Radiographs of hands (22 joints) were scored 0–3 (scaphotrapeziotrapezoid and first interphalangeal joints 0–1) on osteophytes and joint space narrowing following the Osteoarthritis Research Society International atlas. The first carpometacarpal joint (CMC1) was scored 0–1 for subluxation. Pain was assessed with the Australian/Canadian Hand Osteoarthritis Index pain subscale, and health-related quality of life with the Short Form-36. Regression analysis served to investigate associations of hand strength with patient, disease, and radiographic features. Results Hand strength was negatively associated with female sex, age, and pain. Reduced hand strength was associated with reduced quality of life, although less after adjusting for pain. Radiographic features of hand OA were associated with reduced grip strength when solely adjusted for sex and body mass index, but only CMC1 subluxation in the dominant hand remained significantly associated with pinch grip adjusted additionally for age (−0.511 kg, 95% confidence interval −0.975; −0.046). Mediation analysis showed low and not significant percentages of mediation of hand OA in the association between age and grip strength. Conclusions Subluxation of CMC1 is associated with reduced grip strength, whereas associations with other radiographic features seem to be confounded by age. In the relationship between age and hand strength, radiographic hand OA severity is not an important mediator.

Reasons for the Sex Bias in Osteoarthritis Research: A Review of Preclinical Studies.

Osteoarthritis (OA) is one of the most common degenerative diseases of articular cartilage. During OA, all the elements that contribute to the joint undergo physiological and structural changes that impair the joint function and cause joint pain and stiffness. OA can arise naturally, with the aging population witnessing an increase in diagnoses of this pathology, but the root causes of OA have yet to be identified, and increasing interest is arising towards investigating biological sex as a risk factor. Clinical studies show increased prevalence and worse clinical outcomes for female patients, yet most clinical and preclinical studies have disproportionately focused on male subjects. This review provides a critical overview of preclinical practices in the context of OA, highlighting the underlying need for taking biological sex as both a risk factor and an important component affecting treatment outcome. A unique insight into the possible reasons for female underrepresentation in preclinical studies is offered, including factors such as lack of specific guidelines requiring the analysis of sex as a biological variable (SABV), research-associated costs and animal handling, and wrongful application of the reduction principle. Additionally, a thorough investigation of sex-related variables is provided, stressing how each of them could add valuable information for the understanding of OA pathophysiology, as well as sex-dependent treatment strategies.

Diverse parameters of ambulatory knee moments differ with medial knee osteoarthritis severity and are combinable into a severity index.

Objective: To characterize ambulatory knee moments with respect to medial knee osteoarthritis (OA) severity comprehensively and to assess the possibility of developing a severity index combining knee moment parameters. Methods: Nine parameters (peak amplitudes) commonly used to quantify three-dimensional knee moments during walking were analyzed for 98 individuals (58.7 ± 9.2years old, 1.69 ± 0.09m, 76.9 ± 14.5kg, 56% female), corresponding to three medial knee osteoarthritis severity groups: non-osteoarthritis (n = 22), mild osteoarthritis (n = 38) and severe osteoarthritis (n = 38). Multinomial logistic regression was used to create a severity index. Comparison and regression analyses were performed with respect to disease severity. Results: Six of the nine moment parameters differed statistically significantly among severity groups (p ≤ 0.039) and five reported statistically significant correlation with disease severity (0.23 ≤ |r| ≤ 0.59). The proposed severity index was highly reliable (ICC = 0.96) and statistically significantly different between the three groups (p < 0.001) as well as correlated with disease severity (r = 0.70). Conclusion: While medial knee osteoarthritis research has mostly focused on a few knee moment parameters, this study showed that other parameters differ with disease severity. In particular, it shed light on three parameters frequently disregarded in prior works. Another important finding is the possibility of combining the parameters into a severity index, which opens promising perspectives based on a single figure assessing the knee moments in their entirety. Although the proposed index was shown to be reliable and associated with disease severity, further research will be necessary particularly to assess its validity.

Meloxicam emulgel potently suppressed cartilage degradation in knee osteoarthritis: Optimization, formulation, industrial scalability and pharmacodynamic analysis

Background and objectiveMeloxicam (MLX) is prescribed for the management of pain and inflammation allied with osteoarthritis (OA). However, MLX causes intestinal damage in long term administration. Hence, meloxicam loaded emulgel (MLX-emulgel) was optimized, formulated and examined under stringent parameters in monosodium-iodoacetate (MIA) induced knee OA in Wistar rats. Methods and resultsNanoemulsion of MLX was fabricated by ultrasonication and microfluidization method with a droplet size of 66.81 ± 5.31-nm and zeta potential of −24.6 ± 0.72-mV. Further, MLX nanoemulsion was optimized with centrifugation, heating-cooling cycles and transmittance parameters in addition to scale-up feasibility with microfluidizer. Post optimization, MLX-nanoemulsion was tailored as emulgel with Carbopol Ultrez 10 NF and assessed for pH, rheology, textural properties, assay and stability features. The in-vitro release study revealed the Korsmeyer-Peppas release kinetics and ex-vivo skin permeation was improved by 6.71-folds. The skin distribution of MLX-emulgel evinced the transfollicular mode of permeation. In-vivo study indicated the protective action of MLX-emulegl expressed in terms of inflammatory cyctokines level, X-ray analysis of knee joints of rats, histopathology and OARSI (Osteoarthritis Research Society International) scoring. MLX-emulgel treated group displayed lower (P < 0.001) level of COX-2 intensity as compared to positive control group. However, it was comparable (P > 0.05) to the normal control group, MLX oral dispersion, i.v. solution and etoricoxib gel groups. MLX-emulgel showcased an alternative to the long term usage of analgesics for relieving the symptoms of knee OA. ConclusionMLX-emulgel may be a potential candidate for translating in to a clinically viable dosage form in the management of knee OA.

Automated Radiographic Measurements of Knee Osteoarthritis.

Herewith, we report the development of Orthopedic Digital Image Analysis (ODIA) software that is developed to obtain quantitative measurements of knee osteoarthritis (OA) radiographs automatically. Manual segmentation and measurement of OA parameters currently hamper large-cohort analyses, and therefore, automated and reproducible methods are a valuable addition in OA research. This study aims to test the automated ODIA measurements and compare them with available manual Knee Imaging Digital Analysis (KIDA) measurements as comparison. This study included data from the CHECK (Cohort Hip and Cohort Knee) initiative, a prospective multicentre cohort study in the Netherlands with 1,002 participants. Knee radiographs obtained at baseline of the CHECK cohort were included and mean medial/lateral joint space width (JSW), minimal JSW, joint line convergence angle (JLCA), eminence heights, and subchondral bone intensities were compared between ODIA and KIDA. Of the potential 2,004 radiographs, 1,743 were included for analyses. Poor intraclass correlation coefficients (ICCs) were reported for the JLCA (0.422) and minimal JSW (0.299). The mean medial and lateral JSW, eminence height, and subchondral bone intensities reported a moderate to good ICC (0.7 or higher). Discrepancies in JLCA and minimal JSW between the 2 methods were mostly a problem in the lateral tibia plateau. The current ODIA tool provides important measurements of OA parameters in an automated manner from standard radiographs of the knee. Given the automated and computerized methodology that has very high reproducibility, ODIA is suitable for large epidemiological cohorts with various follow-up time points to investigate structural progression, such as CHECK or the Osteoarthritis Initiative (OAI).

Bibliometric Analysis of Publications in Clinical Trials on Knee Osteoarthritis Between 2001 and 2022.

Clinical treatment of knee osteoarthritis has gained great interest, and numerous clinical studies have been reported. Few studies have described the detailed characterizations of clinical trials on knee osteoarthritis. This study is to identify, visualize, and characterize the clinical trials in knee osteoarthritis research. Articles published in recent two decades were extracted from the Web of Science core collection database using a query based on MeSH terms and topics of knee osteoarthritis and clinical trial. Basic characteristics of publications were analyzed based on the publication year, authors, institutions, counties, and keywords covered in the article. CiteSpace and VOS viewer were used for data visualization. The data were retrieved on May 28, 2022. A total of 1972 trials on knee osteoarthritis were identified. The number of publications has experienced rapid growth in the past two decades. America, England, and China had strong contributions in publication. Osteoarthritis and Cartilage, Annals of the Rheumatic Diseases and American Journal of Sports Medicine were highly cited and bellwether journals. Clustering mapping of the collaborative network, co-citation, and co-occurrence analyses showed that the research hotspots are mainly focused on disease-modifying medications, intra-articular injections, physical therapy for symptom control, lifestyle intervention, Chinese medicine treatment, and knee replacement. Clinical treatments of knee OA are evolving. Pharmacologic therapy, intra-articular therapy, nonpharmacologic therapy including exercise or diet, self-management programs, Chinese medicine treatment, and knee replacement were highly represented in clinical trials of knee OA. Adjustment of combination therapy may be the next study focus in the future.

Comparison of Kindlin-2 deficiency-stimulated osteoarthritis-like lesions induced by Prg4CreERT2 versus AggrecanCreERT2 transgene in mice

BackgroundGenetically modified mice are the most useful tools for investigating the gene functions in articular cartilage biology and the pathogenesis of osteoarthritis. The AggrecanCreERT2 mice are one of the most reported mouse lines used for this purpose. The Prg4 (proteoglycan 4) gene encodes the lubricin protein and is expressed selectively in chondrocytes located at the superficial layer of the articular cartilage. While the Prg4GFPCreERT2 knock-in inducible-Cre transgenic mice were generated a while ago, so far, few studies have used this mouse line to perform gene functional studies in cartilage biology. MethodsWe have recently reported that deleting the Fermt2 gene, which encodes the key focal adhesion protein Kindlin-2, in articular chondrocytes by using the AggrecanCreERT2 transgenic mice, results in spontaneous osteoarthritis (OA) lesions, which highly mimics the human OA pathologies. In this study, we have compared the Kindlin-2 deficiency-caused OA phenotypes induced by Prg4GFPCreERT2 with those caused by AggrecanCreERT2 using imaging and histological analyses. ResultsWe find that Kindlin-2 protein is deleted in about 75% of the superficial articular chondrocytes in the tamoxifen (TAM)-treated Prg4GFPCreERt2/+; Fermt2fl/fl mice compared to controls. At 6 months after TAM injections, the OARSI scores of AggrecanCreERT2/+; Fermt2fl/fl and Prg4GFPCreERt2/+; Fermt2fl/fl mice were 5 and 3, respectively. The knee joints histological osteophyte and synovitis scores were also significantly decreased in Prg4GFPCreERT2/+; Fermt2fl/fl mice compared to those in AggrecanCreERT2/+; Fermt2fl/fl mice. Furthermore, magnitudes of upregulation of the extracellular matrix-degrading enzymes Mmp13 and hypertrophic chondrocyte markers Col10a1 and Runx2 were decreased in Prg4GFPCreERT2/+; Fermt2fl/fl versus AggrecanCreERT2/+; Fermt2fl/fl mice. We finally examined the susceptibility of Prg4GFPCreERT2/+; Fermt2fl/fl mouse model to surgically induce OA lesions. The pathological features of OA in the TAM-DMM model exhibited significant enhancement in cartilage erosion, proteoglycan loss, osteophyte, and synovitis and an increase in OARSI score in articular cartilage compared with those in corn-oil DMM mice. ConclusionKindlin-2 loss causes milder OA-like lesions in Prg4GFPCreERT2/+;Fermt2fl/fl than in AggrecanCreERT2/+; Fermt2fl/fl mice. In contrast, Kindlin-2 loss similarly accelerates the destabilization of the medial meniscus-induced OA lesions in both mice.Translational Potential of this Article: Our study demonstrates that Prg4GFPCreERT2 is a useful tool for gene functional study in OA research. This study provides useful information for investigators to choose appropriate Cre mouse lines for their research in cartilage biology.