Phenotypes Of Knee Osteoarthritis Research Articles

Identifying multivariate disease trajectories and potential phenotypes of early knee osteoarthritis in the CHECK cohort.

To gain better understanding of osteoarthritis (OA) heterogeneity and its predictors for distinguishing OA phenotypes. This could provide the opportunity to tailor prevention and treatment strategies and thus improve care. Ten year follow-up data from CHECK (1002 early-OA subjects with first general practitioner visit for complaints ≤6 months before inclusion) was used. Data were collected on WOMAC (pain, function, stiffness), quantitative radiographic tibiofemoral (TF) OA characteristics, and semi-quantitative radiographic patellofemoral (PF) OA characteristics. Using functional data analysis, distinctive sets of trajectories were identified for WOMAC, TF and PF characteristics, based on model fit and clinical interpretation. The probabilities of knee membership to each trajectory were used in hierarchical cluster analyses to derive knee OA phenotypes. The number and composition of potential phenotypes was selected again based on model fit (silhouette score) and clinical interpretation. Five trajectories representing different constant levels or changing WOMAC scores were identified. For TF and PF OA, eight and six trajectories respectively were identified based on (changes in) joint space narrowing, osteophytes and sclerosis. Combining the probabilities of knees belonging to these different trajectories resulted in six clusters ('phenotypes') of knees with different degrees of functional (WOMAC) and radiographic (PF) parameters; TF parameters were found not to significantly contribute to clustering. Including baseline characteristics as well resulted in eight clusters of knees, dominated by sex, menopausal status and WOMAC scores, with only limited contribution of PF features. Several stable and progressive trajectories of OA symptoms and radiographic features were identified, resulting in phenotypes with relatively independent symptomatic and radiographic features. Sex and menopausal status may be especially important when phenotyping knee OA patients, while radiographic features contributed less. Possible phenotypes were identified that, after validation, could aid personalized treatments and patients selection.

Effects of Leptin and Body Weight on Inflammation and Knee Osteoarthritis Phenotypes in Female Rats.

Leptin is a proinflammatory adipokine that contributes to obesity-associated osteoarthritis (OA), especially in women. However, the extent to which leptin causes knee OA separate from the effect of increased body weight is not clear. We hypothesized that leptin is necessary to induce knee OA in obese female rats but not sufficient to induce knee OA in lean rats lacking systemic metabolic inflammation. The effect of obesity without leptin signaling was modeled by comparing female lean Zucker rats to pair fed obese Zucker rats, which possess mutant fa alleles of the leptin receptor gene. The effect of leptin without obesity was modeled in female F344BN F1 hybrid rats by systemically administering recombinant rat leptin versus saline for 23 weeks via osmotic pumps. Primary OA outcomes included cartilage histopathology and subchondral bone micro-computed tomography. Secondary outcomes included targeted cartilage proteomics, serum inflammation, and synovial fluid inflammation following an acute intra-articular challenge with interleukin-1β (IL-1β). Compared to lean Zucker rats, obese Zucker rats developed more severe tibial osteophytes and focal cartilage lesions in the medial tibial plateau, with modest changes in proximal tibial epiphysis trabecular bone structure. In contrast, exogenous leptin treatment, which increased plasma leptin sixfold without altering body weight, caused mild generalized cartilage fibrillation and reduced Safranin O staining compared to vehicle-treated animals. Leptin also significantly increased subchondral and trabecular bone volume and bone mineral density in the proximal tibia. Cartilage metabolic and antioxidant enzyme protein levels were substantially elevated with leptin deficiency and minimally suppressed with leptin treatment. In contrast, leptin treatment induced greater changes in systemic and local inflammatory mediators compared to leptin receptor deficiency, including reduced serum IL-6 and increased synovial fluid IL-1β. In conclusion, rat models that separately elevate leptin or body weight develop distinct OA-associated phenotypes, revealing how obesity increases OA pathology through both leptin-dependent and independent pathways. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Metabolic and inflammatory profiles define phenotypes with clinical relevance in female knee osteoarthritis patients with joint effusion.

Osteoarthritis has been the subject of abundant research in the last years with limited translation to the clinical practice, probably due to the disease's high heterogeneity. In this study, we aimed to identify different phenotypes in knee osteoarthritis (KOA) patients with joint effusion based on their metabolic and inflammatory profiles. A non-supervised strategy based on statistical and machine learning methods was applied to 45 parameters measured on 168 female KOA patients with persistent joint effusion, consecutively recruited at our hospital after a monographic OA outpatient visit. Data comprised anthropometric and metabolic factors and a panel of systemic and local inflammatory markers. The resulting clusters were compared regarding their clinical, radiographic and ultrasound severity at baseline and their radiographic progression at two years. Our analyses identified four KOA inflammatory phenotypes (KOIP): a group characterized by metabolic syndrome, probably driven by body fat and obesity, and by high local and systemic inflammation (KOIP-1); a metabolically healthy phenotype with mild overall inflammation (KOIP-2); a non-metabolic phenotype with high inflammation levels (KOIP-3); and a metabolic phenotype with low inflammation and cardiovascular risk factors not associated with obesity (KOIP-4). Of interest, these groups exhibited differences regarding pain, functional disability and radiographic progression, pointing to a clinical relevance of the uncovered phenotypes. Our results support the existence of different KOA phenotypes with clinical relevance and differing pathways regarding their pathophysiology and disease evolution, which entails implications in patients' stratification, treatment tailoring and the search of novel and personalized therapies.

Efficacy and safety of GLucocorticoid injections into InfrapaTellar faT pad in patients with knee ostEoarthRitiS: protocol for the GLITTERS randomized controlled trial

BackgroundKnee osteoarthritis (OA) is a prevalent disabling disorder that involves changes in articular cartilage damage, subchondral bone remodeling, synovitis, and abnormal infrapatellar fat pad (IPFP). Due to the complicated etiology and numerous phenotypes of knee OA, limited improvement is achieved for treatments among knee OA patients with different phenotypes. Inflammatory OA phenotype is a typical knee OA phenotype, and individualized treatment targeting inflammation is a promising way to obtain an optimal therapeutic effect for people with inflammatory knee OA phenotype. Glucocorticoid is a traditional anti-inflammatory drug for knee OA, and intra-articular glucocorticoid injections are recommended clinically. However, emerging evidence has shown that repeated intra-articular glucocorticoid injections in the long term would induce cartilage loss. IPFP and its adjacent synovium are considered as the main source of inflammation in knee OA. This GLITTERS trial aims to investigate if a glucocorticoid injection into the IPFP is effective and safe over 12 weeks among knee OA patients with an inflammatory phenotype.MethodsGLITTERS is a multicenter, double-blinded, randomized, and placebo-controlled clinical trial among knee OA patients with both Hoffa-synovitis and effusion-synovitis. Sixty participants will be allocated randomly and equally to either the glucocorticoid group or the control group. Each group will receive an injection of glucocorticoid or saline into the IPFP with an intra-articular hyaluronic acid injection as a background treatment at baseline and be followed at 4, 8, and 12 weeks. The primary outcomes will be changes in knee pain on a visual analog scale and effusion-synovitis volume measured on magnetic resonance imaging (MRI). The secondary outcomes will be changes in the total score of Western Ontario and McMaster Universities Osteoarthritis Index score, MRI-detected Hoffa-synovitis score, quality of life, pain medication use, IPFP volume, and the incidence of adverse reactions. Data analyses based on the intention-to-treat principle will include mixed-effects regressions, Wilcoxon rank-sum tests, and chi-square tests (or Fisher’s exact test).DiscussionGLITTERS may provide high-quality evidence for the efficacy and safety of ultrasound-guided glucocorticoid injections into IPFP among people with inflammatory knee OA in a short term. The results of this trial are expected to provide a reliable reference for a longer-term risk–benefit profile of this treatment in the future.Trial registrationClinicalTrials.gov NCT05291650. Registered on 23 March 2022.

Стратификация декомпенсированной формы остеоартрита и современные возможности предоперационной терапии препаратом Хондрогард® на основе фено- и эндотипирования

Aim: to perform a retrospective analysis of the pattern of changes in the structural and functional characteristics of articular cartilage and biomarkers in the blood serum of patients with knee osteoarthritis (OA), Kellgren-Lawrence Grade 3, and Grade 2 joint dysfunction, taking into consideration the identified phenotypes and endotypes of knee OA during the parenteral treatment with highly purified chondroitin sulfate (CS, Chondroguard®). Patients and Methods: the authors performed a retrospective analysis of the results of the earlier stage of an open prospective controlled randomized study, which included 67 patients with knee OA. The patients were referred to total knee arthroplasty (TKA). All patients received NSAIDs in a standard daily dose. At the stage of open prospective randomized clinical study, the patients were split into the control group (CG, n=35) and the study group (SG, n=32). In addition to NSAIDs, the SG patients received a course of parenteral CS two months prior to TKA. Retrospectively, patients in the SG and CG were divided into subgroups according to three disease phenotypes: an inflammatory phenotype caused by synovitis (CG: n=13; SG: n=11); injury-related phenotype (joint injury in the medical history) (CG: n=10; SG: n=10), and endocrine phenotype (CG: n=12; SG: n=11). Based on the identified phenotypes, the biosamples of the subchondral bone, articular cartilage of the femur and tibia, and the articular capsule obtained during TKA surgery procedure were assessed. Also, the levels of hyaluronic acid, ultrasensitive CRP, TNF-α, IL-6, leptin, adipsin, PIIANP, CTX-1, osteocalcin, MMP-3 and -13, COMP, sclerostin, 25(OH)D3 were determined in the blood at the baseline (visit 0), release from the hospital (visit 1) and 3 months after TKA (visit 3). Results: the morphological analysis of joint tissues and the laboratory blood tests provided a basis for characterizing at the endotype level the following three clinical and pathogenetic knee OA phenotypes: inflammatory, posttraumatic and endocrine. In patients with distinct phenotypes of knee OA, differences were revealed in the intensification of adaptive structural modifications in all layers of the articular cartilage and the extent of inflammation restriction in the synovial membrane of the knee joint, as well as the degradation manifestations in the subchondral bone after a two-month preoperative treatment course with Chondroguard ®. A more pronounced and considerable decrease in the blood levels of all tested compounds along with a significant increase in the blood levels of osteocalcin and 25(OH)D 3 were reported in patients with all phenotypes of knee OA in SG as compared to the changes in the lab tests detected in patients with all phenotypes of knee OA in CG. Conclusion: the extent of CS anti-inflammatory, analgetic, metabolic and structure-modifying effects may depend on endotypes determined in patients with specific OA phenotypes. These findings may pave the way for personalized Chondroguard® therapy to be used in patients with OA of various locations, stages, and degrees of functional impairment by identifying their specific OA phenotypes and endotypes. KEYWORDS: osteoarthritis, phenotype, endotype, biomarkers, hyaline cartilage, synovial membrane, morphology, chondroitin sulfate, Chondroguard, arthroplasty. FOR CITATION: Minasov T.B., Lila A.M., Nazarenko A.G. et al. Stratification of decompensated osteoarthritis and modern options of the preoperative therapy using Chondroguard® based on pheno- and endotyping. Russian Medical Inquiry. 2023;7(3):124–136 (in Russ.). DOI: 10.32364/2587-6821-2023-7-3-124-136.

1,25-Dihydroxyvitamin D Deficiency Accelerates Aging-related Osteoarthritis via Downregulation of Sirt1 in Mice.

Emerging observational data suggest that vitamin D deficiency is associated with the onset and progression of knee osteoarthritis (OA). However, the relationship between vitamin D level and OA and the role of vitamin D supplementation in the prevention of knee OA are controversial. To address these issues, we analyzed the articular cartilage phenotype of 6- and 12-month-old wild-type and 1α(OH)ase-/- mice and found that 1,25(OH)2D deficiency accelerated the development of age-related spontaneous knee OA, including cartilage surface destruction, cartilage erosion, proteoglycan loss and cytopenia, increased OARSI score, collagen X and Mmp13 positive chondrocytes, and increased chondrocyte senescence with senescence-associated secretory phenotype (SASP). 1,25(OH)2D3 supplementation rescued all knee OA phenotypes of 1α(OH)ase-/- mice in vivo, and 1,25(OH)2D3 rescued IL-1β-induced chondrocyte OA phenotypes in vitro, including decreased chondrocyte proliferation and cartilage matrix protein synthesis, and increased oxidative stress and cell senescence. We also demonstrated that VDR was expressed in mouse articular chondrocytes, and that VDR knockout mice exhibited knee OA phenotypes. Furthermore, we demonstrated that the down-regulation of Sirt1 in articular chondrocytes of 1α(OH)ase-/- mice was corrected by supplementing 1,25(OH)2D3 or overexpression of Sirt1 in mesenchymal stem cells (MSCs) and 1,25(OH)2D3 up-regulated Sirt1 through VDR mediated transcription. Finally, we demonstrated that overexpression of Sirt1 in MSCs rescued knee OA phenotypes in 1α(OH)ase-/- mice. Thus, we conclude that 1,25(OH)2D3, via VDR-mediated gene transcription, plays a key role in preventing the onset of aging-related knee OA in mouse models by up-regulating Sirt1, an aging-related gene that promotes articular chondrocyte proliferation and extracellular matrix protein synthesis, and inhibits senescence and SASP.

Structural phenotypes of knee osteoarthritis: potential clinical and research relevance.

A joint contains many different tissues that can exhibit pathological changes, providing many potential targets for treatment. Researchers are increasingly suggesting that osteoarthritis (OA) comprises several phenotypes or subpopulations. Consequently, a treatment for OA that targets only one pathophysiologic abnormality is unlikely to be similarly efficacious in preventing or delaying the progression of all the different phenotypes of structural OA. Five structural phenotypes have been proposed, namely the inflammatory, meniscus-cartilage, subchondral bone, and atrophic and hypertrophic phenotypes. The inflammatory phenotype is characterized by marked synovitis and/or joint effusion, while the meniscus-cartilage phenotype exhibits severe meniscal and cartilage damage. Large bone marrow lesions characterize the subchondral bone phenotype. The hypertrophic and atrophic OA phenotype are defined based on the presence large osteophytes or absence of any osteophytes, respectively, in the presence of concomitant cartilage damage. Limitations of the concept of structural phenotyping are that they are not mutually exclusive and that more than one phenotype may be present. It must be acknowledged that a wide range of views exist on how best to operationalize the concept of structural OA phenotypes and that the concept of structural phenotypic characterization is still in its infancy. Structural phenotypic stratification, however, may result in more targeted trial populations with successful outcomes and practitioners need to be aware of the heterogeneity of the disease to personalize their treatment recommendations for an individual patient. Radiologists should be able to define a joint at risk for progression based on the predominant phenotype present at different disease stages.

Knee osteoarthritis phenotypes based on synovial fluid immune cells correlate with clinical outcome trajectories

Knee osteoarthritis (KOA) is a highly heterogeneous disease encompassing a wide range of clinical phenotypes. Phenotypes based on immune cells and protein pattern in synovial fluid (SF) and their relationship to clinical trajectories have not been described. To assess phenotypes based on immune cells and protein pattern of SF in KOA. SF-derived immune cells were investigated in 119 patients with KOA using flow cytometry. Immune-phenotypes (iPhen) were determined by multivariate patient similarity network analysis and related to clinical trajectory (3-6 months post-sampling) along with protein pattern and macrophage chemokine receptors. Four iPhen were detected based on the distribution of T-lymphocytes, monocyte-macrophage lineage cells and activated CD8+ T-lymphocytes. The 'activated' phenotype (n=17) had high T-lymphocytes but low monocyte-macrophage lineage cells and neutrophils, all highly activated, and showed improved symptoms in 70% patients. The 'lymphoid progressive' phenotype (n=31) had high neutrophils, low lymphocytes and monocyte-macrophage lineage cells, low activation and was associated with lower pain levels. The 'myeloid progressive' phenotype (n=35) had high NK and monocyte-macrophage lineage cells but low T-lymphocytes and activation. The 'aggressive' phenotype (n=36) had high lymphocytes, macrophages, NK cells and neutrophils and high activation, and only 39% of patients improved during follow-up. Low CXCR4 and CCR7 expression on macrophages and high CXCL10 in SF were linked to improved clinical trajectory. We identified four immune-phenotypes that were associated with different clinical trajectories in KOA patients. How these phenotypes can be targeted therapeutically deserves further investigation.

Biclustering reveals potential knee OA phenotypes in exploratory analyses: Data from the Osteoarthritis Initiative

To apply biclustering, a methodology originally developed for analysis of gene expression data, to simultaneously cluster observations and clinical features to explore candidate phenotypes of knee osteoarthritis (KOA) for the first time. Data from the baseline Osteoarthritis Initiative (OAI) visit were cleaned, transformed, and standardized as indicated (leaving 6461 knees with 86 features). Biclustering produced submatrices of the overall data matrix, representing similar observations across a subset of variables. Statistical validation was determined using the novel SigClust procedure. After identifying biclusters, relationships with key outcome measures were assessed, including progression of radiographic KOA, total knee arthroplasty, loss of joint space width, and worsening Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores, over 96 months of follow-up. The final analytic set included 6461 knees from 3330 individuals (mean age 61 years, mean body mass index 28 kg/m2, 57% women and 86% White). We identified 6 mutually exclusive biclusters characterized by different feature profiles at baseline, particularly related to symptoms and function. Biclusters represented overall better (#1), similar (#2, 3, 6), and poorer (#4, 5) prognosis compared to the overall cohort of knees, respectively. In general, knees in biclusters #4 and 5 had more structural progression (based on Kellgren-Lawrence grade, total knee arthroplasty, and loss of joint space width) but tended to have an improvement in WOMAC pain scores over time. In contrast, knees in bicluster #1 had less incident and progressive KOA, fewer total knee arthroplasties, less loss of joint space width, and stable pain scores compared with the overall cohort. We identified six biclusters within the baseline OAI dataset which have varying relationships with key outcomes in KOA. Such biclusters represent potential phenotypes within the larger cohort and may suggest subgroups at greater or lesser risk of progression over time.

MRI-BASED STRUCTURAL PHENOTYPES AND INCIDENCE OF RADIOGRAPHIC OSTEOARTHRITIS:DATA FROM OSTEOARTHRITIS INITIATIVE

Purpose: Recently, the Rapid OsteoArthritis MRI Eligibility Score (ROAMES), a tri-compartmental anatomic approach characterizing structural knee OA phenotypes based on underlying pathophysiologic changes, was proposed to simplify OA grading with MRI for screening for large-scale drug trials. We applied deep learning and survival analysis to investigate the association between time to incident radiographic osteoarthritis (OA) and ROAMES structural phenotypes.

EEG theta and beta bands as brain oscillations for different knee osteoarthritis phenotypes according to disease severity

This study aims to investigate the multivariate relationship between different sociodemographic, clinical, and neurophysiological variables with resting-state, high-definition, EEG spectral power in subjects with chronic knee osteoarthritis (OA) pain. This was a cross-sectional study. Sociodemographic and clinical data were collected from 66 knee OA subjects. To identify associated factors, we performed independent univariate and multivariate regression models by frequency bands (delta, theta, alpha, beta, low-beta, and high-beta) and by pre-defined regions (frontal, central, and parietal). From adjusted multivariate models, we found that: (1) increased frontocentral high-beta power and reduced central theta activity are positively correlated with pain intensity (β = 0.012, 95% CI 0.004–0.020; and β = − 0.008; 95% CI 0.014 to − 0.003; respectively); (2) delta and alpha oscillations have a direct relationship with higher cortical inhibition; (3) diffuse increased power at low frequencies (delta and theta) are associated with poor cognition, aging, and depressive symptoms; and (4) higher alpha and beta power over sensorimotor areas seem to be a maladaptive compensatory mechanism to poor motor function and severe joint degeneration. Subjects with higher pain intensity and higher OA severity (likely subjects with maladaptive compensatory mechanisms to severe OA) have higher frontocentral beta power and lower theta activity. On the other hand, subjects with less OA severity and less pain have higher theta oscillations power. These associations showed the potential role of brain oscillations as a marker of pain intensity and clinical phenotypes in chronic knee OA patients. Besides, they suggest a potential compensatory mechanism of these two brain oscillators according to OA severity.

Determination of Pain Phenotypes in Knee Osteoarthritis Using Latent Profile Analysis.

To identify clinical phenotypes of knee osteoarthritis (OA) using measures from the following domains: 1) multimorbidity; 2) psychological distress; 3) pain sensitivity; and 4) knee impairment or pathology. Data were collected from 152 people with knee OA and from 31 pain-free individuals. In participants with knee OA, latent profile analysis (LPA) was applied to the following measures: normalized knee extensor strength, Functional Comorbidity Index (FCI), Pain Catastrophizing Scale (PCS), and local (knee) pressure pain threshold. Comparisons were performed between empirically derived phenotypes from the LPA and healthy older adults on these measures. Comparisons were also made between pheonotypes on pain intensity, functional measures, use of health care, and history of knee injury. LPA resulted in a four-group solution. Compared with all other groups, group 1 (9% of the study population) had higher FCI scores. Group 2 (63%) had elevated pain sensitivity and quadriceps weakness relative to group 4 and healthy older adults. Group 3 (11%) had higher PCS scores than all other groups. Group 4 (17%) had greater leg strength, except relative to healthy older adults, and reduced pain sensitivity relative to all groups. Groups 1 and 3 demonstrated higher pain and worse function than other groups, and group 4 had higher rates of knee injury. Four phenotypes of knee OA were identified using psychological factors, comorbidity status, pain sensitivity, and leg strength. Follow-up analyses supported the replicability of this phenotype structure, but future research is needed to determine its usefulness in knee OA care.

Identification of knee osteoarthritis disability phenotypes regarding activity limitation: a cluster analysis

BackgroundStudies have reported the subtypes of individuals with knee osteoarthritis (OA) attempting to cluster this heterogonous condition. Activity limitations are commonly used to set goals in knee OA management and better identify subgroups based on level of disability in this patient population. Therefore, the objective of this study was to identify those activity limitations which could classify the disability phenotypes of knee OA. The phenotypes were also validated by comparing impairments and participation restrictions.MethodsParticipants comprised individuals with symptomatic knee OA. They were interviewed and undertook physical examination according to a standard evaluation forms based on the International Classification of Functioning, Disability and Health (ICF) model. Cluster analysis was used to determine those activity limitations which could best classify the phenotypes of knee OA. To validate the clustered variables, comparisons and regression analysis were performed for the impairments consisting of pain intensity, passive range of motion and muscle strength, and the participation restrictions included the difficulty level of acquiring goods and services and community life.ResultsIn all, 250 participants with symptomatic knee OA were enrolled in the study. Three activity limitations identified from data distribution and literature were used as the cluster variables, included the difficulty level of maintaining a standing position, timed stair climbing and 40-m self-paced walk test. The analysis showed four phenotypes of individuals with knee OA according to the levels of disability from no to severe level of disability. All parameters of impairment and participation restrictions significantly differed among phenotypes. Subgroups with greater disability experienced worse pain intensity, limited range of motion (ROM), muscle power and participation restriction levels. The variance accounted for of the subgroups were also greater than overall participants.ConclusionThe results of this study emphasized the heterogeneous natures of knee OA. Three activity limitations identified could classify the individuals with symptomatic knee OA to homogeneous subgroups from no to severe level of disability. The management plan, based on these homogeneous subgroups of knee OA, could be designated by considering the levels of impairments and participation restrictions.

Features of morphology of articular cartilage in patients with different phenotypes of knee osteoarthritis

Features of morphology of articular cartilage in patients with different phenotypes of knee osteoarthritis

Correlation network analysis shows divergent effects of a long-term, high-fat diet and exercise on early stage osteoarthritis phenotypes in mice

BackgroundObesity increases knee osteoarthritis (OA) risk through metabolic, inflammatory, and biomechanical factors, but how these systemic and local mediators interact to drive OA pathology is not well understood. We tested the effect of voluntary running exercise after chronic diet-induced obesity on knee OA-related cartilage and bone pathology in mice. We then used a correlation-based network analysis to identify systemic and local factors associated with early-stage knee OA phenotypes among the different diet and exercise groups. MethodsMale C57BL/6J mice were fed a defined control (10% kcal fat) or high fat (HF) (60% kcal fat) diet from 6 to 37 weeks of age. At 25 weeks, one-half of the mice from each diet group were housed in cages with running wheels for the remainder of the study. Histology, micro computed tomography, and magnetic resonance imaging were used to evaluate changes in joint tissue structure and OA pathology. These local variables were then compared to systemic metabolic (body mass, body fat, and glucose tolerance), inflammatory (serum adipokines and inflammatory mediators), and functional (mechanical tactile sensitivity and grip strength) outcomes using a correlation-based network analysis. Diet and exercise effects were evaluated by two-way analysis of variance. ResultsAn HF diet increased the infrapatellar fat pad size and posterior joint osteophytes, and wheel running primarily altered the subchondral cortical and trabecular bone. Neither HF diet nor exercise altered average knee cartilage OA scores compared to control groups. However, the coefficient of variation was ≥25% for many outcomes, and some mice in both diet groups developed moderate OA (≥33% maximum score). This supported using correlation-based network analyses to identify systemic and local factors associated with early-stage knee OA phenotypes. In wheel-running cohorts, an HF diet reduced the network size compared to the control diet group despite similar running distances, suggesting that diet-induced obesity dampens the effects of exercise on systemic and local OA-related factors. Each of the 4 diet and activity groups showed mostly unique networks of local and systemic factors correlated with early-stage knee OA. ConclusionDespite minimal group-level effects of chronic diet-induced obesity and voluntary wheel running on knee OA pathology under the current test durations, diet and exercise substantially altered the relationships among systemic and local variables associated with early-stage knee OA. These results suggest that distinct pre-OA phenotypes may exist prior to the development of disease.

A 2-year, European Multicentre Study to Describe, Validate, and Predict Phenotypes of Knee Osteoarthritis

A 2-year, European Multicentre Study to Describe, Validate, and Predict Phenotypes of Knee Osteoarthritis

Knee Osteoarthritis Molecular Subgroups Revealed by Pathogenic Joint Gene Expression

Background: Osteoarthritis (OA) is a complex and heterogeneous condition, and one of the most common degenerative joint diseases. A standardized OA classification based on molecular criteria has yet to be defined. We performed transcriptomic profiling to determine the different molecular signatures associated with knee OA phenotypes. Methods: Five centres clinical research with next-generation sequencing was carried out using 201 samples from patients with knee osteoarthritis. Transcriptomic analysis and unsupervised clustering methods were performed on 131 cartilage samples. To investigate tissue crosstalk of the whole knee microenvironment, transcriptomic analysis was performed in 60 synovia and 65 subchondral bone samples. Findings: We identified four OA subgroups with distinct biological signatures: 1) the glycosaminoglycan metabolic disorder subgroup highly expressed ACAN, lowly expressed VCAN, and was enriched with glycosaminoglycan metabolic functions; 2) the collagen metabolic disorder subgroup presented with osteophyte formation, highly expressed COL1A1 and COL6A1, and was enriched with collagen catabolic functions; 3) the sensory neurons activated subgroup highly expressed GRIK2 and GRM7, and was enriched with synapse assembly functions; and 4) the immunogenic subgroup presented with high inflammation and narrow joint space, highly expressed IL1AŸ and CD34, and was enriched with immune responses. We also explored immune cell composition and tissue crosstalk for three identified metabolic disorder subgroups. Interpretation: These findings challenge the classical diagnosis model based on medical imaging, revealing distinct molecular subgroups in knee OA patients, and opening the door to precision diagnosis and treatment of OA. Funding Statement: This work was financially supported by the National Key R&D Program of China (2017YFA0104902), the National Natural Science Foundation of China (81630065, 31830029, 81802195) grants and China Postdoctoral Science Foundation (2017M621913). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: Informed consent was obtained from all the participants. The study was approved by the local clinical ethics committees of Zhejiang University School of Medicine and the affiliated hospital of Wenzhou Medical University (2017KYLL11).

New insights into the natural course of knee osteoarthritis: early regulation of cytokines and growth factors, with emphasis on sex-dependent angiogenesis and tissue remodeling. A pilot study

This study was conducted to identify cytokine profiles associated with radiographic phenotypes of knee osteoarthritis (rKOA) with a focus on early stage of the disease. The pilot population study involved 60 middle-aged patients (mean age 50±7.3y.). Standardized weight-bearing anteroposterior and axial radiographs were used to assess rKOA severity in tibiofemoral (TFJ) of patellofemoral joint (PFJ) by grading system (grades 0-3). Luminex (xMAP®) technology was used to simultaneously assess 60 biomarkers (BMs). Several pathways of angiogenic (CXCL10/IP-10, FGF1/2, PDGF-AA/BB, ANG1, RANTES), tissue remodeling/fibrosis (MMP1/3, TIMP2/3/4, TGFβ), and fat tissue (leptin) BMs associated with rKOA severity already in very early phase (grade 1). We identified several sets of cytokines as key markers of early knee osteoarthritis (KOA) predicting radiographic features in logistic-regression models (AUC=0.80-0.97). Marked sex-specificity of rKOA course was detected: upregulation of angiogenesis dominated in females, whereas the activation of tissue remodeling was dominant in males. Several of these shifts, e.g., decrease of CXCL10/IP-10, took place only in grade 1 KOA and disappeared or reversed in later stages. OA of different knee-joint compartments has distinct profiles of cytokines. A broad list of BMs (TIMP2/3/4, MMP1/3, TGFβ1/2, vWF-A2, sE-selectin and leptin) associated with OA in the PFJ. Our results demonstrate that substantial and time-limited shifts in the angiogenic and TIMP/MMP systems occur in the early stage of KOA. Our study findings highlight the sex-, grade- and compartment-dependent shifts in above processes. The data may contribute to the individualized prevention of KOA in the future.

CR4056, a first-in-class imidazoline-2 receptor ligand analgesic, in pain from knee osteoarthritis phenotypes: a randomized, placebo-controlled, double-blind, phase iia clinical trial

CR4056, a first-in-class imidazoline-2 receptor ligand analgesic, in pain from knee osteoarthritis phenotypes: a randomized, placebo-controlled, double-blind, phase iia clinical trial

A machine learning approach to knee OA phenotyping

Purpose: Knee osteoarthritis (KOA) is a heterogeneous condition characterized by changes in a variety of joint tissues and driven by a number of different potential mechanisms. To date, most clinical trials of disease modifying drugs have treated all KOA as the same disease, based primarily on radiographic features, and have failed to improve outcomes. The purpose of this study was to explore machine learning approaches to phenotyping in KOA in order to better define the progressor phenotype that may be more responsive to a disease modifying intervention. Methods: We focused on identifying differences between those knees that progressed by both radiographic (loss of medial joint space width) and pain (using the WOMAC pain scale) criteria (“progressors”) and those that did not progress by either of these (“non-progressors”), as defined by the publicly available FNIH OA Biomarkers Consortium dataset of 600 individuals with 76 demographic, imaging (quantitative and semi-quantitative MRI), and biochemical variables. First, problematic variables and observations were removed, leaving 597 observations and 73 variables. The data were transformed to reduce skewness and standardized to address differences in scale. Direction-projection-permutation (DiProPerm) hypothesis testing was used to test equality of distributions (by z-score) in the Distance-Weighted Discrimination (DWD) direction as quantified by the mean difference, using 100 permutations. Loadings on the DWD direction demonstrate the relative contribution of each variable to the class differences (e.g., progressors compared with non-progressors). In addition, we explored k-means clustering to partition the observations into 2 subgroups (additional subgroups were not supported by various statistical indices). Given multiple comparisons, a z-score of at least 3 (P value∼0.001) was considered statistically significant. Results: When considering all observations and all variables simultaneously, the progressors and non-progressors clearly separated with a z-score of 10.10 (Table 1).Table 1Z-scores derived from the DiProPerm test for the difference between progressors and non-progressors.All variablesDemographicQuantitative MRISemi-Quant MRIBiochemicalDiProPerm z-scoresAll observations10.101.4711.6210.282.432 clusters16.191.496.515.722.0124.771.394.735.780.97z-scores >3 are statistically significant at P<0.001, in bold. Open table in a new tab z-scores >3 are statistically significant at P<0.001, in bold. No statistical improvement was seen with partitioning the observations into 2 clusters, although some of these clusters did have significant z-scores. We were also able to study the 4 groups of variable data separately, finding higher z-scores for the MRI variables (11.62 for quantitative and 10.28 for semi-quantitative), with lower scores for demographic and biochemical markers. Again, lesser z-scores were seen for the 2 clusters compared with using all observations. Finally, we were interested in the relative contributions of each variable to the overall difference between progressors and non-progressors (Fig. 1), where the DWD loadings were represented in a bar plot for the 40 variables with the greatest contribution. The greatest positive contribution was seen for WOMAC pain (which is part of the progression construct), lateral meniscal extrusion, and serum PIIANP; the largest negative contributions were from the number of subregions with bone marrow lesions, the number of locations with any osteophyte, and urine CTX-II. Conclusions: These innovative methods provide a way to assess numerous variables of different types and scalings simultaneously in relation to KOA progression as shown here, or for assessing any other outcome of interest. Such methodology could identify both known and novel KOA phenotypes, potentially improving patient selection for specific interventions and providing insight into pathophysiology in this heterogeneous condition.