Osteoarthritis Disease Progression Research Articles

Assessing the effects of body weight on subchondral bone formation with quantitative 18F-sodium fluoride PET.

The aim of this study was to quantify subchondral bone remodeling in the elbows, hands, knees, and feet using volumetric and metabolic parameters derived from 18F-sodium fluoride positron emission tomography (NaF-PET) and to assess the convergent validity of these parameters as an index of joint degeneration and preclinical osteoarthritis. A retrospective analysis was conducted in 34 subjects (32 males, 2 females) with metastatic bone disease who underwent full-body NaF-PET/CT scans. An adaptive contrast-oriented thresholding algorithm was applied to segment NaF-avid regions in the bilateral elbows, hands, knees, and feet of each subject, and metabolically active volume (MAV), maximum standardized uptake value (SUVmax), mean metabolic volumetric product (MVPmean), and partial volume-corrected MVPmean (cMVPmean) of the segmented regions were calculated. Global parameters for MAV, SUVmax, MVPmean, and cMVPmean were defined as the sum of the corresponding values in all the joints of a subject. Inter-rater reliability was determined with Lin's concordance correlation, and associations of global values with subject body weight and age were assessed with Pearson correlation and Spearman correlation analyses. Inter-rater reliability was observed to be the highest in SUVmax (ρc = 0.99), followed by MVPmean (ρc = 0.96), cMVPmean (ρc = 0.93), and MAV (ρc = 0.93). MAV, MVPmean, and cMVPmean were observed to significantly increase with weight (all p < 0.0001) determined by Pearson correlation. In addition, Spearman rank-order analysis demonstrated a significant correlation between SUVmax and weight in addition to MAV, MVPmean, and cMVPmean and weight (all p < 0.01). No significant association between age and any PET parameter was observed. These preliminary data demonstrate the feasibility and reliability of assessing bone turnover at the joints using quantitative NaF-PET. Our findings corroborate the fact that biomechanical factors including mechanical loading and weight-bearing are contributors to osteoarthritis disease progression.

Vitamin D3 protects articular cartilage by inhibiting the Wnt/β-catenin signaling pathway.

Low expression levels of 25-hydroxyvitamin D (vitamin D3) in the blood have been reported to be associated with the progression of osteoarthritis; however, the mechanisms by which this occurs remain unclear. The present study aimed to determine the effects of vitamin D3 on chondrocytes. MTT assays were used to determine whether vitamin D3 affects chondrocytes viability. Primary chondrocytes were treated with control culture medium, vitamin D3, tumor necrosis factor (TNF)-α, TNF-α + PNU-74654 [Wingless-related integration site (Wnt)/β-catenin signaling pathway inhibitor] or TNF-α + vitamin D3. Reverse transcription-quantitative PCR and western blotting were utilized to measure the gene and protein expression of collagen II, aggrecan, matrix metalloproteinase (MMP)-3 and MMP-13, A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4, ADAMTS-5, Wnt-3a and nuclear β-catenin. The results demonstrated that TNF-α reduced the expression levels of aggrecan and collagen II, and increased the expression levels of MMP-3, MMP-13, ADAMTS-4 and ADAMTS-5. Furthermore, vitamin D3 and PNU-74654 were observed to partially attenuate the effects induced by TNF-α. Moreover, similar findings were reported following co-treatment with vitamin D3 and TNF-α. Western blotting data revealed that TNF-α increased Wnt-3a and β-catenin protein levels in chondrocytes, while Vitamin D3 and PNU-74654 decreased the expression levels of Wnt-3a and nuclear β-catenin. In conclusion, the findings of the present study provided evidence to suggest that vitamin D3 may prevent articular cartilage degeneration and osteoarthritic disease progression by inhibiting the expression levels of MMP-3, MMP-13, ADAMTS-4 and ADAMTS-5 through suppressing the Wnt/β-catenin signaling pathway. These results suggested that vitamin D3 may be of therapeutic value for the prevention and treatment of osteoarthritis.

Differences in subchondral trabecular bone microstructure and finite element analysis-based biomechanical properties between osteoporosis and osteoarthritis.

SummaryBackground/ObjectiveThe microstructure of the subchondral trabecular bone, including the composition and distribution of plates and rods, has an important influence on the disease progression and mechanical properties of osteoarthritis (OA) and osteoporosis (OP). We aimed to determine whether differences in plates and rods influence the variations in the quantities and qualities of the subchondral trabecular bone between OA and OP.Materials and methodsThirty-eight femoral head samples [OA, n = 13; OP, n = 17; normal control (NC), n = 8] were collected from male patients undergoing total hip arthroplasty. They were scanned using microcomputed tomography, and subchondral trabecular structures were analysed using individual trabecular segmentation. Micro-finite element analysis (μFEA) was applied to assess the mechanical property of the trabecular bone. Cartilage changes were evaluated by using histological assessment. Analysis of variance was used to compare intergroup differences in structural and mechanical properties and cartilage degradation. Pearson analysis was used to evaluate the relationship between the trabecula microstructure and biomechanical properties.ResultsCompared with the OP and NC group, there was serious cartilage damage in the OA group. With respect to the microstructure results, the OA group had the highest plate and rod trabecular microstructures including number and junction density among the three groups. For the mechanical properties detected via μFEA, the OA group had higher stiffness and failure load than did the OP group. Pearson analysis revealed that compared with OP, OA had a higher number of microstructure parameters (e.g., rod bone volume fraction and rod trabecular number) that were positively correlated with its mechanical property.ConclusionsCompared with OP, the OA subchondral bone has both increased plate and rod microarchitecture and has more microstructures positively related with its mechanical property. These differences may help explain the variation in mechanical properties between these bone diseases.The translational potential of this articleOur findings suggested that changes in the plates and rods of the subchondral trabecular bone play a critical role in OA and OP progression and that the improvement of the subchondral trabecular bone may be a promising treatment approach.

Association between disease progression and depression onset in persons with radiographic knee osteoarthritis.

Osteoarthritis (OA) disease progression may lead to deteriorating psychosocial function, but it is unclear what aspects of disease severity are related to the onset of depression. This study assessed which components of OA disease progression cumulatively contribute to depression onset in persons with radiographic knee OA. Osteoarthritis Initiative participants (n = 1651) with radiographic disease (Kellgren-Lawrence grade ≥2) in one or both knees and below the screening threshold for probable depression [Center for Epidemiological Studies Depression (CES-D) scale <16] at baseline were included. Disease severity was measured from baseline to the third annual follow-up visit using joint space width, 20-meter gait speed, and the Western Ontario and McMaster Universities Osteoarthritis Index pain subscale, each categorized into quintiles. Depression onset (CES-D ≥ 16) was assessed annually at four follow-up visits. Marginal structural models that account for time-dependent confounding and attrition evaluated the association between each time-varying disease severity measure and depression onset. Each disease severity measure exhibited a non-linear relationship concerning the probability of depression onset, with the higher quintiles generally being associated with a larger risk. The highest quintile (relative to the lowest) of joint space width and gait speed were both significantly associated with depression onset. By contrast, none of the higher pain quintiles compared with the lowest were significantly associated with the onset of depression. Faster disease progression as measured by either worsening structural severity or decreasing physical performance corresponds to an increased risk of depression among individuals with radiographic knee OA.

Impact of total knee replacement on trajectories of structure and symptoms in knee osteoarthritis - data from osteoarthritis initiative

Purpose: Understanding patterns of symptomatic and structural progression has been a major research focus in knee osteoarthritis (OA). Latent class growth analysis is a statistical approach that aims to identify clusters of subjects with similar progression trajectories. This approach has been used recently in knee OA to uncover longitudinal trajectories of both structural (e.g., quantitative MRI, joint space width (JSW), bone shape) and symptom (e.g., WOMAC Pain) progression. In longitudinal studies, it is common for subjects to drop out before the scheduled end of follow-up. Previous studies have shown that subjects undergoing total knee replacement (TKR) progress more quickly in the years leading up to TKR than subjects not undergoing the procedure. By not accounting for dropout due to TKR in estimating disease trajectories, we may fail to identify a trajectory of rapid progressors. Our objective was to evaluate the impact of incorporating TKR on estimates of structure (JSW) and symptom (WOMAC Pain) trajectories in knee OA. Methods: We used data from the Osteoarthritis Initiative (OAI), a multicenter, longitudinal, observational study of knee OA. We selected knees with radiographic, symptomatic OA at baseline (KL 2+, WOMAC Pain greater than 0). Eligible subjects had at least one follow-up visit. To assess joint structure we used serial measures of fixed JSW at x=0.25 in the medial tibiofemoral compartment, measured annually from baseline to year 4, and at years 6 and 8. WOMAC Pain was used to assess symptoms (0 - 100, 100 worst), assessed annually through year 9. After selecting patients with baseline pain, we modeled trajectories starting at year 1 to avoid modeling regression to the mean. We used latent class growth analysis (LGCA) to identify distinct subgroups, separately for JSW and pain. While LCGA can handle missing data under the missing at random assumption, these models on their own do not accommodate informative dropout. Thus, we used an extension of the LCGA framework to jointly model longitudinal outcome and time to TKR using joint latent class mixed models. We used the BIC, posterior group membership probability, and sufficient sample size per group (n=50) to select the final models. Results: We used data from 1,578 subjects with radiographic, symptomatic knee OA at baseline. 157 (10%) of subjects underwent TKR, with median time from baseline to TKR 5.5 years. On average, subjects undergoing TKR increased in pain by 2.3 points per year (19 points over 8 years) while subjects not undergoing TKR increased by 0.21 points per year (1.7 points over 8 years). Subjects undergoing TKR decreased in JSW by 0.31mm per year (2.5mm over 8 years) while subjects not undergoing TKR decreased in JSW by 0.09mm per year (0.75mm over 8 years). We found three distinct JSW trajectories. In our final model the majority (84%) of the cohort was in a stable trajectory, 5.9% of the cohort was in a late progression trajectory, and 8.4% of the cohort was an early progression trajectory (Figure 1). While the number and shape of trajectories was largely unchanged when we moved from the initial JSW model to the final joint JSW and TKR model, 32% of TKRs were re-classified, most from the stable to a progressing trajectory. In our initial model of pain trajectories we found 4 distinct trajectories: stable low pain (70%), rapidly increasing pain (13%), rapidly decreasing pain (5%) and increasing high pain (12%) (Figure 2a). After incorporating TKR our model identified a fifth trajectory. The increasing high pain trajectory (year 1 WOMAC pain 40) was split into a moderate increasing pain trajectory (year 1 WOMAC pain 28) and a high pain trajectory (year 1 WOMAC pain 52) (Figure 2b). 68% of TKRs were re-classified, most from the stable to increasing pain trajectory, stable to moderate pain, or the high to moderate pain. In the final model, only 2% of TKRs are in the stable pain trajectory, compared to 42% in the initial model. Conclusions: In longitudinal studies restricting analysis to completers may lead to underestimation of disease progression. In analyses seeking to uncover latent subgroups this could result in subjects being misclassified or entire trajectories being missed. Investigators studying disease progression in OA should consider the potential impact of dropout due to TKR, particularly when a large proportion of subjects undergo the procedure.View Large Image Figure ViewerDownload Hi-res image Download (PPT)View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Location and timing of the first osteophyte after arthroscopic knee surgeries

Purpose: Preventing disease development and/or progression of osteoarthritis of the knee (KOA) has been sought from standpoint of not only social welfare but also social economy. Due to rapid progression of aging society the requirement is growing worldwide. Unfortunately effective method is still open to be explored and researchers are straggling to establish it. One possible first step is to achieve this will be to detect initial change of KOA as early as possible. Imaging biomarkers are thought to be suitable for this purpose due to its property to assess only corresponding joint without being affected by systemic changes.

Knee laxity after staircaseexercise predicts radiographic disease progression in knee osteoarthritis

Purpose: Osteoarthritis (OA) of the knee is one of the major causes of joint dysfunction and physically disabling conditions in the elderly. Joint laxity is considered one of the major factors involved in the progression as well as development of knee OA. Our group reported the increasing of knee joint laxity after stair up down exercise in knee OA patients. And we considered the knee joint laxity after exercise influences the progression of knee OA. The purpose of this study was to evaluate whether the knee joint laxity after staircase climbing produces the knee joint OA progression or not.

The relationship between synovial inflammation, structural pathology, and pain in post-traumatic osteoarthritis: differential effect of stem cell and hyaluronan treatment

BackgroundSynovitis is implicated in the severity and progression of pain and structural pathology of osteoarthritis (OA). Increases in inflammatory or immune cell subpopulations including macrophages and lymphocytes have been reported in OA synovium, but how the particular subpopulations influence symptomatic or structural OA disease progression is unclear. Two therapies, hyaluronan (HA) and mesenchymal stem cells (MSCs), have demonstrated efficacy in some clinical settings: HA acting as device to improve joint function and provide pain relief, while MSCs may have immunomodulatory and disease-modifying effects. We used these agents to investigate whether changes in pain sensitization or structural damage were linked to modulation of the synovial inflammatory response in post-traumatic OA.MethodsSkeletally mature C57BL6 male mice underwent medial-meniscal destabilisation (DMM) surgery followed by intra-articular injection of saline, a hyaluronan hexadecylamide derivative (Hymovis), bone marrow-derived stem cells (MSCs), or MSC + Hymovis. We quantified the progression of OA-related cartilage, subchondral bone and synovial histopathology, and associated pain sensitization (tactile allodynia). Synovial lymphocytes, monocyte/macrophages and their subpopulations were quantified by fluorescent-activated cell sorting (FACS), and the expression of key inflammatory mediators and catabolic enzyme genes quantified by real-time polymerase chain reaction (PCR).ResultsMSC but not Hymovis significantly reduced late-stage (12-week post-DMM) cartilage proteoglycan loss and structural damage. Allodynia was initially reduced by both treatments but significantly better at 8 and 12 weeks by Hymovis. Chondroprotection by MSCs was not associated with specific changes in synovial inflammatory cell populations but rather regulation of post-injury synovial Adamts4, Adamts5, Mmp3, and Mmp9 expression. Reduced acute post-injury allodynia with all treatments coincided with decreased synovial macrophage and T cell numbers, while longer-term effect on pain sensitization with Hymovis was associated with increased M2c macrophages.ConclusionsThis therapeutic study in mice demonstrated a poor correlation between cartilage, bone or synovium (histo)pathology, and pain sensitization. Changes in the specific synovial inflammatory cell subpopulations may be associated with chronic OA pain sensitization, and a novel target for symptomatic treatment.

Assessment of human cartilage regeneration in a patient with knee osteoarthritis using autologous adipose-tissue-derived stem cells and Platelet-rich plasma: a case study

Cartilage regenerative medicine has been met with much interest due to their ability to inhibit disease progression of osteoarthritis (OA). The use of adipose-derived stem cells has been suggested as a reliable method for OA treatment because of their potential to differentiate into a variety of cell lines and their potent capability to self-renewal and repair. The aim of this study is to assess adipose-derived stem cells in combination with PRP ability in treating a patient with knee OA. A 53-year- old man with osteoarthritis was selected for this treatment. Human abdominal subcutaneous adipose sample was obtained from a patient with knee OA. Stem cells were obtained from adipose tissue of abdominal origin by digesting lipoaspirate tissue with collagenase. ADSCs cultured in DMEM medium supplemented with 10% FBS. Also, ADSCs expanded and characterized by flow cytometry. These stem cells, along with platelet-rich plasma and calcium chloride, were injected into the right knee. Pre-treatment and post-treatment MRI scans, physical therapy, and pain score data were then analyzed. The MRI data for the patient demonstrated significant positive changes. Probable cartilage regeneration was sensible in the patient. Along with MRI evidence, the measured physical therapy outcomes, subjective pain, and functional status all improved. Autologous adipose-derived stem cell injection, in conjunction with platelet-rich plasma is a promising minimally invasive therapy for osteoarthritis of human knees. The present clinical case report demonstrated that a combination of percutaneous injection of autologous ADSCs and PRPmay be able to regenerate cartilage in human knee OA.

KARAOKE: Krill oil versus placebo in the treatment of knee osteoarthritis: protocol for a randomised controlled trial

BackgroundKnee osteoarthritis (OA) is a common and important cause of pain and disability, but interventions aimed at modifying structures visible on imaging have been disappointing. While OA affects the whole joint, synovitis and effusion have been recognised as having a role in the pathogenesis of OA. Krill oil reduces knee pain and systemic inflammation and could be used for targeting inflammatory mechanisms of OA.Methods/designWe will recruit 260 patients with clinical knee OA, significant knee pain and effusion-synovitis present on MRI in five Australian cities (Hobart, Melbourne, Sydney, Adelaide and Perth). These patients will be randomly allocated to the two arms of the study, receiving 2 g/day krill oil or inert placebo daily for 6 months. MRI of the study knee will be performed at screening and after 6 months. Knee symptoms, function and MRI structural abnormalities will be assessed using validated methods. Safety data will be recorded. Primary outcomes are absolute change in knee pain (assessed by visual analog score) and change in size of knee effusion-synovitis over 24 weeks. Secondary outcomes include improvement in knee pain over 4, 8, 12, 16 and 20 weeks. The primary analyses will be intention-to-treat analyses of primary and secondary outcomes. Per protocol analyses adjusting for missing data and for treatment compliance will be performed as the secondary analyses.DiscussionThis study will provide high-quality evidence to assess whether krill oil 2 g/day reduces pain and effusion-synovitis size in older adults with clinical knee OA and knee effusion-synovitis. If krill oil is effective and confirmed to be safe, we will provide compelling evidence that krill oil improves pain and function, changes disease trajectory and slows disease progression in OA. Given the lack of approved therapies for slowing disease progression in OA, and moderate cost of krill oil, these findings will be readily translated into clinical practice.Trial registrationAustralian New Zealand Clinical Trials Registry, ACTRN12616000726459. Registered on 02 June 2016.Universal Trial Number (UTN) U1111–1181-7087.

Short link N acts as a disease modifying osteoarthritis drug.

Osteoarthritis (OA) is a degenerative joint disease characterised by a progressive degradation of articular cartilage and underlaying bone and is associated with pain and disability. Currently, there is no medical treatment to reverse or even retard OA. Based on our previous reports, where we establish the repair potential of short Link N (sLN) in the intervertebral disc, a cartilage-like tissue, we hypothesise that sLN may hold similar promises in the repair of articular cartilage. This study aimed to determine if sLN, could prevent OA disease progression. Skeletally mature New Zealand white rabbits underwent unilateral anterior cruciate ligament transection (ACLT) of their left femorotibial joints to induce joint degeneration typical of OA. Beginning 3 weeks post-operatively, and every three weeks thereafter for 12 weeks, either saline (1 mL) or sLN (100 μg in 1 mL saline) was injected intraarticularly into the operated knee. Six additional rabbits underwent sham surgery but without ACLT or post-operative injections. The effects on gross joint morphology and cartilage histologic changes were evaluated. In the Saline group, prominent erosion of articular cartilage occurred in both femoral condyle compartments and the lateral compartment of the tibial plateau while, sLN treatment reduced the severity of the cartilage damage in these compartments of the knee showing erosion. Furthermore, statistically significant differences were detected between the joint OA score of the saline and sLN treated groups (p = 0.0118). Therefore, periodic intraarticular injection of sLN is a promising nonsurgical treatment for preventing or retarding OA progression, by reducing cartilage degradation.

Do non-steroidal anti-inflammatory drugs cause osteoarthritis progression, a systematic review and meta analysis

Do non-steroidal anti-inflammatory drugs cause osteoarthritis progression, a systematic review and meta analysis

The synovial fluid neuropeptide PACAP may act as a protective factor during disease progression of primary knee osteoarthritis and is increased following hyaluronic acid injection.

The correlation of serum and synovial fluid (SF) pituitary adenylate cyclase-activating polypeptide (PACAP) levels with disease progression of primary knee osteoarthritis (OA) was explored. Radiographic severity of OA was determined by Kellgren–Lawrence (K-L) grades. PACAP levels were measured by ELISA before treatment, and 4 and 8 wk following hyaluronic acid (HA) injection. Levels of IL-1β and MMP-3 were also detected. The numeric pain scale (NPS), revised Oxford Knee Score (OKS), and American Knee Society Score (AKSS) were employed to evaluate to symptomatic severity. Receiver-operating-characteristic (ROC) curve analysis was carried out to compare the diagnostic value of PACAP, IL-1β, and MMP-3 for the K-L grade. PACAP concentrations in SF but not serum were significantly lower in OA patients compared with controls. SF PACAP levels were negatively associated with K-L grades and higher NPS as well as worse AKSS and OKS. Further analysis demonstrated that PACAP concentration in SF was negatively correlated with expressions of IL-1β as well as MMP-3 and may act as a marker for radiographic progression along with MMP-3. Last, we found SF PACAP levels exhibited an incremental trend after HA injection. These findings confirmed the crucial role of PACAP deficiency in the development of primary knee OA.

Osteoarthritis disease progression in biomarker-based patient endotypes

Osteoarthritis disease progression in biomarker-based patient endotypes

Use of Vitamin D Supplements in Osteoarthritis: An Observational Study in a Tertiary Health Care Facility

Objective: The purpose of the study was to assess impact of vitamin D supplements on the disease progression and overall health of osteoarthritis (OA) patients.Methodology: A cohort study was carried out for 8 months (August 2017–March 2018) in the Orthopedics Department of Kasturba Hospital, Manipal, India, a tertiary care hospital. One hundred and forty-two patients who were diagnosed with OA (grades 1–3) with low serum 25(OH)D levels (severely deficient, deficient, or insufficient) were selected for the study. These patients were categorized into two cohorts: a control cohort (CC) and a study cohort (SC). CC members were patients (n = 71) who had not received vitamin D supplements, and SC members were patients (n = 71) who had received vitamin D supplements. Severity grading of OA, pain score, and health assessment were performed using the Kellgren–Laurence grading score, visual analogue scale (VAS), and WOMAC, respectively, at baseline and after 3 months of follow-up.Results: Subjects in the both CC and SC reported no statistically significant difference (similar in both group) in severity grade (p = 0.303), pain score (p = 0.099), parathyroid hormone (PTH) (p = 0.083), and health status (p = 0.76) at baseline. After 3 months of follow-up (post vitamin D supplementation), OA patients have shown statistically significant difference in severity grades, serum 25(OH)D status, PTH level (p < 0.001), and overall health status (p = 0.001) in the SC with respect to baseline. Likewise, percentage distribution of positive changes was significantly higher in severity grade, pain score, serum 25(OH)D level, overall health status (p < 0.001), and PTH (p = 0.040) of SC as compared to CC at follow-up.Conclusion: Vitamin D supplements have significantly improved serum 25(OH)D levels, PTH, severity grade, and pain score of OA patients. Most importantly, vitamin D supplements have shown improvement in the overall health of OA patients, emphasizing the place of vitamin D supplements in the management of OA.Clinical Trial Registry-India (CTRI) registration no: CTRI/2017/12/011031

Regional gene expression analysis of multiple tissues in an experimental animal model of post-traumatic osteoarthritis

To characterize local disease progression of the medial meniscus transection (MMT) model of post-traumatic osteoarthritis (OA) at the molecular level, in order to establish a baseline for therapeutic testing at the preclinical stage. Weight-matched male Lewis rats underwent MMT or sham surgery on the left limb with the right leg as contralateral control. At 1 and 3 weeks post-surgery, tissues were harvested from different areas of the articular cartilage (medial and lateral tibial plateaus, and medial osteophyte region) and synovium (medial and lateral), and analyzed separately. RNA was extracted and used for microarray (RT-PCR) analysis. Gene expression changes due to surgery were isolated to the medial side of the joint. Gene changes in chondrocyte phenotype of the medial tibial plateau cartilage preceded changes in tissue composition genes. Differences in inflammatory markers were only observed at the osteophyte region at 3 weeks post-surgery. There was surgical noise in the synovium at week 1, which dissipated at week 3. At this later timepoint, meniscal instability resulted in elevated expression of matrix degradation proteins and osteogenic markers in the synovium and cartilage. These results suggest feedback interactions between joint tissues during disease progression. Regional tissue expression differences found in MMT joints indicated similar pathophysiology to human OA, and provided novel insights about this degeneration model. The examination of gene expression at a localized level in multiple tissues provides a well-characterized baseline to evaluate mechanistic effects of potential therapeutic agents on OA disease progression in the MMT model.

Health Literacy and Osteoarthritis Self-Management

Background: Osteoarthritis is a disabling joint disease with no known cure that negatively effects life quality among high numbers of aging adults. Aim: To examine the concept of health literacy as a potentially overlooked, but highly salient, disease correlate among this older chronically disabled group. Method: A literature search using the key terms osteoarthritis and health literacy was conducted using the major data bases. Results: Although almost no work has focused on health literacy and osteoarthritis, the concept of health literacy is clearly linked to health status and health outcomes. Varying from marginal to high, health literacy is not always assessed or recognized as being clinically relevant, however, despite a large volume of related literature. Conclusion: Acknowledging the possible role of limited health literacy in the context of osteoarthritis disease progression, and applying carefully tailored directives for overcoming any related health literacy limitations may offer a novel approach for improving the outcomes for older people with this condition.

Synovial Fluid Fatty Acid Profiles Differ between Osteoarthritis and Healthy Patients.

ObjectiveFree fatty acids (FAs) may influence cartilage metabolism and osteoarthritis (OA) disease progression. It is not clearly studied which FAs are present in the synovial fluid of knee joints and whether there are differences in FA content between nonsymptomatic and OA knee joints. The aim of this study was to investigate the presence of different types of FAs in synovial fluid of both OA- and nonsymptomatic control joints, and to analyze differences between both groups.DesignA total of 23 synovial fluid samples were collected from patients with end-stage knee OA undergoing total knee replacement, with approval of the medical ethical committee. As controls, 6 synovial fluid samples were obtained from postmortem donors without any history of joint disease or arthritis. Measurement of free FA concentration was done by mass spectrometry for saturated FAs (SFA), monounsaturated FAs (MUFA), and omega-3 and omega-6 polyunsaturated FAs (n-3 PUFAs and n-6 PUFAs).ResultsOur measurements demonstrated the presence of SFAs, MUFAs, n-3 and n-6 PUFAs in synovial fluid of both nonsymptomatic and OA knee joints. The n-6/n-3 ratio was significantly lower in the OA group (P = 0.0005). Arachidonic acid (n-6 PUFA) concentrations were also lower in OA synovial fluid (P = 0.01), while tetracosadienoic acid (P = 0.0001) and nervonic acid (P = 0.001) (MUFAs) were higher in synovial fluid of patients with knee OA.ConclusionSynovial fluid contains a broad spectrum of free FAs. The FAs profile differs between OA and control subjects, including a tendency for less n-6 FAs in OA joints.

Functional folate receptor cell-associated inflammatory cytokines predict the progression of knee osteoarthritis

Purpose: In our prior study using 99mTc-EC20 (Etarfolatide) imaging, we observed folate receptor positive (FR+) cells in vivo in the synovium of the majority (76%) of knees of patients with osteoarthritis (OA). The quantity of these FR+ cells was associated with radiographic severity of knee joint space narrowing and osteophyte and knee pain. To identify the cells with functional folate receptors and their involvement in disease pathogenesis and progression in knee OA, we characterized the immune cell populations of OA synovium and synovial fluid by flow cytometry and evaluated the correlation of functional folate receptor positive phenotypes with cytokine production, knee OA severity and progression. Based on results from our pilot Etarfolatide study, we hypothesized that immune cells bearing functional folate receptors would be pro-inflammatory. Methods: For these analyses, we evaluated specimens from three different cohorts. Total Knee Replacement (TKR) Cohort: waste synovial tissue (SV) and matched synovial fluid (SF) obtained from knee OA patients at the time of total knee arthroplasty (n=18) at Duke University Hospital. Cell populations from SV and SF were phenotyped for cell surface markers and functional FR (FR+ detected by incubating cells with fluorescently labeled folate conjugate) using polychromatic flow cytometry. The EC20 Scan Cohort: SF from radiographic knee OA patients (Kellgren-Lawrence (KL) grade 1-4) (n=26 knees), Etarfolatide and computed tomography (CT) imaging. The Prediction of Osteoarthritis Progression (POP) Cohort: SF samples from radiographic knee OA patients (KL grade 1-3) with three-year follow-up and available SF (n=107 knees). Inflammatory cytokines were quantified in SF from all three cohorts and concentrations correlated with the immunophenotypic and imaging data. Results: Using polychromatic flow cytometry, FR+ macrophages and neutrophils were identified in both the SF and SV of the TKR cohort (Table 1). On a per cell basis, neutrophils took up significantly more folate conjugate than macrophages. Among the SF cytokines, transforming growth factor beta 1 (TGF-β1) and neutrophil elastase correlated with FR+ macrophages and FR+ neutrophils, respectively. The SF concentration of both of these cytokines were strongly correlated with the in vivo FR+ synovial phenotype by Etarfolatide uptake in the EC20 cohort (p < 0.0001). TGF-β1 and elastase were both strongly correlated with the osteophyte (OST) score (p < 0.05) in the EC20 (evaluated by CT) and POP (evaluated by radiograph) cohorts. Lastly, in the POP cohort, baseline TGF-β1 and elastase were associated with knee OA progression based on disease outcomes (no progression, radiographic features of OST, OST plus joint space narrowing (JSN) and total knee replacement (TKR) in sequence for linear trend analysis) (p<0.0001 and p=0.0014, respectively) (Fig 1A). Receiver operating characteristics (ROC) analysis of SF TGF-β1 (adjusting for age, BMI, gender, baseline OST and JSN) for the determination of any knee OA progression (either OST, JSN or TKR progression vs. non-progression) yielded an area under the curve (AUC) of 0.95 (95% CI [0.87, 0.98]) (Fig 1B). ROC analysis of elastase yielded an AUC of 0.90 (CI [0.80, 0.95]) (Fig 1B). Applying the Youden index as the cut-off value, for TGF-β1 the sensitivity was 97% (CI [89, 99]), the specificity 85% (CI [62, 97]), and the positive predictive value (PPV) 95% (CI [88, 98]). For elastase the sensitivity was 85% (CI [74, 0.92]), the specificity 86% (CI [65, 97]), and the PPV 95% (CI [86, 98]). Conclusions: We have identified activated macrophages and neutrophils as the functional folate receptor bearing cells in knee OA. The correlation of SF TGF-β1 and elastase with the EC20 imaging phenotype confirmed the pro-inflammatory nature of the FR+ cells in vivo. We further confirmed the pro-inflammatory nature of these cells based on the association of these cell markers with knee OA progression. Taken together, these results suggest that these cells could be potential therapeutic targets in OA. The promising AUC scores for these markers also suggest that SF TGF-β1 and elastase could be the novel biomarkers of risk of progression in knee OA.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Synovial Fluid Eotaxin-1 Levels May Reflect Disease Progression in Primary Knee Osteoarthritis Among Elderly Han Chinese: A Cross-Sectional Study.

The CC chemokine family member eotaxin-1, also named chemokine C-C motif ligand 11 (CCL11), has been detected in knee osteoarthritis (OA) and could induce breakdown of cartilage matrix. This study was performed to investigate the plasma and synovial fluid eotaxin-1 levels with the disease progression in elderly Han Chinese with primary knee OA. A total of 143 elderly primary knee OA patients and 135 healthy controls were enrolled in the study. The Western Ontario and McMaster Universities Arthritis Index (WOMAC) was performed to evaluate the clinical severity. The radiographic severity was assessed by Kellgren-Lawrence (K-L) grading. Plasma and synovial fluid (SF) eotaxin-1 levels were explored using enzyme-linked immunosorbent assay. The SF levels of matrix metalloproteinase-3 (MMP-3) and interleukin-6 (IL-6) were also examined. Elevated plasma eotaxin-1 levels were found in knee OA patients compared with healthy controls. Eotaxin-1 levels in SF of knee OA patients with K-L grade 4 were significantly elevated compared with those with K-L grades 2 and 3. Meanwhile, knee OA patients with K-L grade 3 had significantly increased SF levels of eotaxin-1 compared with those with K-L grade 2. Plasma eotaxin-1 levels in different K-L grading did not reach significant difference. Eotaxin-1 levels in SF of knee OA patients were significantly associated with disease severity evaluated by KL grading criteria. In addition, eotaxin-1 levels in SF were positively related to clinical severity illustrated by WOMAC as well as biochemical markers MMP-3 and IL-6. Eotaxin-1 levels in SF instead of plasma, were independently and positively related to the disease severity in elderly knee OA patients. The inhibition of eotaxin-1 and its related signaling pathways may serve as a novel therapeutic approach for OA progression.