Increased Osteoarthritis Severity Research Articles

Spatial assessment of femoral neck bone density and microstructure in hip osteoarthritis

Osteoarthritis (OA) is known to involve profound changes in bone density and microstructure near to, and even distal to, the joint. Critically, however, a full, spatial picture of these abnormalities has not been well documented in a quantitative fashion in hip OA. Here, micro-computed tomography (44.8 μm/voxel) and data-driven computational anatomy were used to generate 3-D maps of the distribution of bone density and microstructure in human femoral neck samples with early (6F/4M, mean age = 51.3 years), moderate (14F/8M, mean age = 60 years), and severe (16F/6M, mean age = 63.3 years) radiographic OA. With increasing severity of radiographic OA, there was decreased cortical bone mineral density (BMD) (p=0.003), increased cortical thickness (p=0.001), increased cortical porosity (p=0.0028), and increased cortical cross-sectional area (p=0.0012, due to an increase in periosteal radius (p=0.018)), with no differences detected in the total femoral neck or trabecular compartment measures. No OA-related region-specific differences were detected through Statistical Parametric Mapping, but there were trends towards decreased tissue mineral density (TMD) in the inferior femoral neck with increasing OA severity (0.050 <p ≤ 0.091), possibly due to osteophytes. Overall, the lack of differences in cortical TMD among radiographic OA groups indicated that the decrease in cortical BMD with increasing OA severity was largely due to the increased cortical porosity rather than decreased tissue mineralization. As porosity is inversely associated with stiffness and strength in cortical bone, increased porosity may offset the effect that increased cortical cross-sectional area would be expected to have on reducing stresses within the femoral neck. The use of high-resolution imaging and quantitative spatial assessment in this study provide insight into the heterogeneous and multi-faceted changes in density and microstructure in hip OA, which have implications for OA progression and fracture risk.

Skeletal muscle mitochondrial respiration in a model of age-related osteoarthritis is impaired after dietary rapamycin.

A decline in skeletal muscle mitochondrial function is associated with the loss of skeletal muscle size and function during knee osteoarthritis (OA). We have recently reported that 12-weeks of dietary rapamycin (Rap, 14ppm), with or without metformin (Met, 1000ppm), increased plasma glucose and OA severity in male Dunkin Hartley (DH) guinea pigs, a model of naturally occurring, age-related OA. The purpose of the current study was to determine if increased OA severity after dietary Rap and Rap+Met was accompanied by impaired skeletal muscle mitochondrial function. Mitochondrial respiration and hydrogen peroxide (H2O2) emissions were evaluated in permeabilized muscle fibers via high-resolution respirometry and fluorometry using either a saturating bolus or titration of ADP. Rap and Rap+Met decreased complex I (CI)-linked respiration and tended to increase ADP sensitivity, consistent with previous findings in patients with end-stage OA. The decrease in CI-linked respiration was accompanied with lower CI protein abundance. Rap and Rap+Met did not change mitochondrial H2O2 emissions. There were no differences between mitochondrial function in Rap versus Rap+Met suggesting that Rap was likely driving the change in mitochondrial function. This is the first inquiry into how lifespan extending treatments Rap and Rap+Met can influence skeletal muscle mitochondria in a model of age-related OA. Collectively, our data suggest that Rap with or without Met inhibits CI-linked capacity and increases ADP sensitivity in DH guinea pigs that have greater OA severity.

Sexual dimorphic impact of adult-onset somatopause on life span and age-induced osteoarthritis.

Osteoarthritis (OA), the most prevalent joint disease, is a major cause of disability worldwide. Growth hormone (GH) has been suggested to play significant roles in maintaining articular chondrocyte function and ultimately articular cartilage (AC) homeostasis. In humans, the age‐associated decline in GH levels was hypothesized to play a role in the etiology of OA. We studied the impact of adult‐onset isolated GH deficiency (AOiGHD) on the life span and skeletal integrity including the AC, in 23‐ to 30‐month‐old male and female mice on C57/BL6 genetic background. Reductions in GH during adulthood were associated with extended life span and reductions in body temperature in female mice only. However, end‐of‐life pathology revealed high levels of lymphomas in both sexes, independent of GH status. Skeletal characterization revealed increases in OA severity in AOiGHD mice, evidenced by AC degradation in both femur and tibia, and significantly increased osteophyte formation in AOiGHD females. AOiGHD males showed significant increases in the thickness of the synovial lining cell layer that was associated with increased markers of inflammation (IL‐6, iNOS). Furthermore, male AOiGHD showed significant increases in matrix metalloproteinase‐13 (MMP‐13), p16, and β‐galactosidase immunoreactivity in the AC as compared to controls, indicating increased cell senescence. In conclusion, while the life span of AOiGHD females increased, their health span was compromised by high‐grade lymphomas and the development of severe OA. In contrast, AOiGHD males, which did not show extended life span, showed an overall low grade of lymphomas but exhibited significantly decreased health span, evidenced by increased OA severity.

The effect of knee joint effusion on gait mechanics and muscle activations in individuals with moderate knee osteoarthritis

Purpose: Knee osteoarthritis (OA) is the most common joint disease and is often characterized by pain, stiffness, swelling and limited tolerance to weight-bearing activities. It has been shown to be associated with biological inflammatory processes in the synovium, synovitis, and mechanical insults that lead to the deterioration of the joint structures. Synovitis is usually characterized by knee joint swelling and the mechanical knee joint environment during a loading stimulus can be studied in vivo using state-of-the-art gait analyses. The study objective is to compare knee mechanics and muscle activation patterns during gait in individuals with knee OA who have and do not have knee joint swelling. Methods: 45 patients diagnosed with moderate medial compartment knee OA were recruited. Knee swelling was measured at three locations (mid, medial, lateral) of the supra-patellar recess (SRD) using ultrasound imaging. A maximum depth, regardless of the location was determined. Effusion presence was defined as a SRD depth >4 mm. Knee joint motion was calculated from skin markers and net external moments calculated through inverse dynamics during walking on a dual-belt instrumented treadmill at self-selected speed. Electromyography (EMG) from vastus medialis (VM) and lateralis (VL), medial (MH) and lateral hamstrings (LH), medial (MG) and lateral gastrocnemius (LG) was recorded using standardized procedures. Two-sample unpaired t-tests were used to test for significant differences in sagittal plane knee joint angles, sagittal and frontal external moments, pain, Knee Osteoarthritis Outcome Scores, age, body mass index, stride characteristics, and knee extensor and flexor strength. Principal component analysis (PCA) was performed on the EMG waveforms to capture amplitude and temporal based features. Principal Pattern (PP)-scores were calculated from principal patterns that together explained >90% of the waveform variability. Two-way mixed-model Analysis of Variance models were performed on the PP-scores to identify muscle, group and interaction effects. Bonferroni corrected pairwise post-hoc comparisons were made. A P-value of 0.05 was used to determine statistical significance. Results: Of the 45 participants, 25 had effusion (SRD > 4mm). No significant differences were found between groups in subject demographic and anthropometrics, questionnaire outcomes, and knee strength (P > 0.05). Both groups had a similar radiographic grade distribution. No biomechanical differences existed between both groups, however the effusion group had greater overall amplitudes of VM and VL (PP1-scores) and greater early stance activation of the gastrocnemius muscles (PP2-scores). No other group differences or group by muscle interactions existed. Conclusions: These results, as shown in Figure 1, indicate that specific amplitude knee joint muscle activation patterns are altered in the presence of knee effusion during gait in individuals with knee OA. Greater stance phase amplitudes in the quadriceps and gastrocnemius muscles are consistent with responses aimed at providing neuromuscular knee joint support and increasing early stance active stiffness, respectively, in order to preserve knee function when effusion is present. These muscular adaptations have been previously reported with increased OA severity suggesting a possible link between gait mechanics and knee swelling as knee OA progresses. The 4 mm SRD threshold has previously been linked to a higher risk of knee OA progression, supporting findings of this study. Future studies can investigate different cut-off values for the detection of effusion sonographically to establish whether biomechanical subgroups may exist.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Altered erector spinae activity and trunk motion occurs with moderate and severe unilateral hip OA.

People with hip osteoarthritis (OA) demonstrate altered movement patterns in the hip joint, as well as the pelvis and spine. While kinematic changes have been described in the literature, little is known about the associated erector spinae (ES) activity. Increased or prolonged ES activity may contribute to the low back pain often associated with hip OA. Using a cross-sectional cohort study, 3D trunk motions and ES surface electromyography were recorded on 19 individuals with severe OA (SOA), 20 with moderate hip OA (MOA), and 19 asymptomatic (ASYM) individuals during treadmill walking, using standardized collection and processing procedures. Principal component analysis was used to derive electromyographic amplitude and temporal waveform features. Three-dimensional thoracic motion in a global system, and thoraco-lumbar motion was calculated. Various statistical analyses determined between group differences (α = 0.05). In the sagittal plane, thoracic motion was greater in the SOA group (p < 0.001), whereas the ASYM group used less thoraco-lumbar motion than either OA group (p ≤ 0.002). Greater frontal plane angular excursion during early stance was found in the thoracic region in the SOA group (p ≤ 0.001) . With increasing OA severity, bilateral ES activity increased during the swing phase of gait (p < 0.001), whereas during stance, the SOA ipsilateral ES activity was higher than other groups (p < 0.001). Statement of clinical significance: with moderate and severe OA, sagittal, and frontal trunk motion increases during gait. ES activity during the entire gait cycle is more sustained with increased disease severity, which may aide our understanding of low back pain associated with hip OA. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1826-1832, 2018.

RADIOGRAPHIC HIP OSTEOARTHRITIS IS PREVALENT, AND IS RELATED TO CAM DEFORMITY 12-24 MONTHS POST-HIP ARTHROSCOPY

The prevalence of radiographic hip osteoarthritis (OA), and its relationship with outcomes after hip arthroscopy is unclear. The aims of this study were to: (i) describe the prevalence of OA and cam deformity 12-24 months post hip arthroscopy; (ii) to determine the association between radiographic OA and cam deformity, surgical and clinical findings and symptoms; and (iii) describe the differences between legs for radiological and clinical findings. Cross sectional study. Seventy patients, mean age 36.7(range 18-59) years, 12-24 months post-arthroscopy. Outcomes were collected prospectively via clinical and radiographic examination. (i)Prevalence of OA and cam deformity measured on and anteroposterior pelvic radiographs; (ii)Hip disability and Osteoarthritis Outcome Score (HOOS) and International Hip Outcome Tool (iHOT-33) patient-reported outcomes (PROs); (iii)hip internal and external rotation range of motion (ROM). Associations between OA and surgical findings, PROs and clinical findings were determined using generalized estimated equations, between operated and non-operated sides. The prevalence of OA was 37%. The likelihood of OA 12-24 months after surgery was positively associated with alpha angle size 12-24 months post-hip arthroscopy surgery (p=0.010). There were no differences between operated and non-operated legs in radiographic or clinical findings. Radiographic OA is prevalent in a population which has undergone hip arthroscopy. Increased OA severity is associated with a higher alpha angle 12-24 months post-surgery. Cross-sectional study Level IV.

Dysregulation of both miR-140-3p and miR-140-5p in synovial fluid correlate with osteoarthritis severity.

ObjectivesThis study looked to analyse the expression levels of microRNA-140-3p and microRNA-140-5p in synovial fluid, and their correlations to the severity of disease regarding knee osteoarthritis (OA).MethodsKnee joint synovial fluid samples were collected from 45 patients with OA of the knee (15 mild, 15 moderate and 15 severe), ten healthy volunteers, ten patients with gouty arthritis, and ten with rheumatoid arthritis. The Kellgren–Lawrence grading (KLG) was used to assess the radiological severity of knee OA, and the patients were stratified into mild (KLG < 2), moderate (KLG = 2), and severe (KLG > 2). The expression of miR-140-3p and miR-140-5p of individual samples was measured by SYBR Green quantitative polymerase chain reaction (PCR) analysis. The expression of miR-140-3p and miR-140-5p was normalised to U6 internal control using the 2-△△CT method. All data were processed using SPSS software.ResultsExpression of both miR-140-3p and miR-140-5p was downregulated in OA synovial fluid, showing a statistical difference between the OA and non-OA group, and increased OA severity was associated with a decreased expression of miR-140-3p or miR-140-5p. The Spearman rank correlation analysis suggested that the expression of miR-140-3p or miR-140-5p was negatively correlated with OA severity. In addition, the expression of miR-140-5p was 7.4 times higher than that of miR-140-3p across all groups.ConclusionThe dysregulation of miR-140-3p and miR-140-5p in synovial fluid and their correlations with the disease severity of OA may provide an important experimental basis for OA classification, and the miR-140-3p/miR-140-5p are of great potential as biomarkers in the diagnosis and clinical management of patients with OA.Cite this article: C-M. Yin, W-C-W. Suen, S. Lin, X-M. Wu, G. Li, X-H. Pan. Dysregulation of both miR-140-3p and miR-140-5p in synovial fluid correlate with osteoarthritis severity. Bone Joint Res 2017;6:612–618. DOI: 10.1302/2046-3758.611.BJR-2017-0090.R1.

Metabolic Dysregulation Accelerates Progression in Early Degenerative Rat Knee Joints Driven by Local Inflammatory Changes

Purpose: Obesity is a well-known and important risk factor for osteoarthritis (OA). Moreover, obesity is highly associated with the metabolic syndrome (MetS), which is defined as the simultaneous occurrence of the following factors: obesity, insulin resistance, abnormal blood lipid levels and hypertension. Growing evidence indicates that both OA and MetS are low-grade inflammatory conditions with elevation in systemic inflammatory markers. Nonetheless, it is unclear whether MetS low-grade inflammation induces OA, or contributes to the disease. The aim of this study was to determine the contribution of metabolic alterations, induced by a High-Fat Diet (HFD), on the onset or progression of OA in a rat model of local cartilage damage. Methods: Forty Wistar rats (12 weeks old, male; Charles-River, Sulzfeld, Germany), were randomly divided over two groups: twenty rats were fed a HFD (60% of the kcal contained fat: D12492i, Research Diets Inc., New Brunswick, USA) while the other animals received a standard diet. After 12 weeks, local articular cartilage damage was induced on the femoral condyles, in one knee joint according to the groove model in 14 rats of each diet group. Remaining animals served as a control group in each arm. At week 24, serum was collected, subchondral bone was assessed by μCT scan (Quantum FX, PerkinElmar, USA) to identify diet and/or surgery related changes. In addition, OA severity was evaluated by rat OARSI histopathology score and in parallel macrophage activity with CD68 immunostaining from histological sections was assessed. Results: HFD feeding resulted in metabolic dysregulation as indicated by significantly increased weight (2,6 g/day vs. 1,9 g/day; p<0.001), fasting insulin (4.2 ± 1.7 mU/L vs. 2.8 ± 1.6 mU/L; p=0.003) and total cholesterol (152 ± 30 mg/dL vs. 116 ± 32 mg/dL; p=0.003) compared to the standard fed rats. HFD feeding alone resulted in very mild cartilage degeneration (2 ± 1.1 vs 0.58 ± .7; p=0.06) and synovial inflammation (1.0 ± 0.6 vs 0.3 ± 0.5; p=0.075) both subscores of the rat OARSI histopathology score without changes on the subchondral bone parameters. However, when HFD feeding is combined with the surgical model of applied local cartilage damage, OA severity is statistically significant increased compared to the local cartilage damage group on a standard diet (6.2 ± 2.1 vs 3.4 ± 1.4; p=0.001). Synovial membrane inflammation (1.3 ± 0.9vs 0.5 ± 0.5; p=0.011; Figure 1A+D) and multiple large osteophyte formation, demonstrated by histology (0.9 ± 1 vs 0.2 ± 0.4; p=0.04; Figure 1B) and quantified on μCT (328 ± 349 μm³ vs 7 ± 14 μm³; p<0.001; see Figure 1C+E), contributes most to this increased OA severity. OA related subchondral bone changes were observed on the tibia compartment by μCT, independent for the diet. Immunohistochemical CD68 expression as observed on both the synovial membrane as well as in the subchondral bone as shown in Figure 2 can explain the increase in selected inflammatory parameters when groove surgery is combined with a HFD. Conclusions: This study shows that a high-fat diet induces metabolic alterations and increases the inflammatory state of the joint. This by itself does not result in severe osteoarthritis. However, when adding a HFD to a mild cartilage damage model of OA, joint degeneration is significantly increased 12 weeks post-surgery. This progression of joint degeneration appears to be driven mainly by the inflammatory response as demonstrated by an increased CD68 expression in both the subchondral bone and synovium membrane and enhanced synovitis and osteophytosis. Hence, our findings indicate that systemic metabolic and subsequent inflammatory factors need an additional trigger to contribute to the progression of the OA.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Adiponectin in patients with knee osteoarthritis

Background Investigations suggest that adipokines may play an important role in pathogenesis and cartilage damage in osteoarthritis (OA). Whether adiponectin (ADN) has proinflammatory or anti-inflammatory actions in OA remain controversial. Aim The aim of this study was to measure the serum level of ADN in patients with knee osteoarthritis (KOA) and to evaluate the relationship between its level and clinical and radiological picture of OA. Patients and methods The study included 56 patients with primary symptomatic KOA and 30 matched controls. Parameters of obesity and serum ADN, leptin (LEP), and matrix metalloproteinase (MMP)-3 were measured in all participants. Clinical features of KOA severity and activity were evaluated in the patients. Extent of knee joint damage due to OA was evaluated by means of plain radiograph and MRI. The volume of the infrapatellar fat pad was measured using MRI. Results KOA patients had high serum ADN, LEP, and MMP-3 compared with controls and they were higher in female KOA patients than in male KOA patients. Serum ADN, LEP, and MMP-3 were significantly correlated with parameters of obesity and with each other. The serum ADN level was significantly correlated with tenderness, visual analogue scale pain, OA activity, OA severity, and also with Western Ontario and McMaster Universities Osteoarthritis Index score. Serum LEP level was significantly correlated with OA severity. Serum level of MMP-3 was significantly correlated with the tenderness score. Higher ADN serum levels were associated with increased Kellgren–Lawrence grade, increased Noyes MRI grade, increased OA severity MRI grade, and increased meniscal degeneration MRI grade. Serum levels of ADN, LEP, and MMP-3 were significantly correlated with the Hoffa fat pad volume. Conclusion ADN serum level was associated with radiological evidence of OA severity and was correlated with serum LEP and MMP-3 levels. These findings strongly suggest that ADN is involved in the pathogenesis of joint inflammation and cartilage destruction in OA and may be a target for disease-modifying drug development.

Analysis of single nucleotide polymorphisms within ADAM12 and risk of knee osteoarthritis in a Chinese Han population.

Objective. Osteoarthritis (OA) is a complex arthritic condition in which the genetic factor plays a major role. One of the candidate genes of is the ADAM12 gene, but no consistency has been reached till now. This study aims to investigate the potential role of four single nucleotide polymorphisms (SNPs) of the ADAM12 gene in susceptibility to knee OA and its progression in Chinese Han population. Methods. The rs1278279, rs3740199, rs1044122, and rs1871054 polymorphisms were genotyped and compared in a population based cohort consisting of 164 OA subjects and 200 age- and gender-matched controls. Results. The SNP rs1871054 was found with increased risk of OA susceptibility in comparing the genotype frequencies between the case and control groups no matter for which model of comparison (allele level, dominant model, recessive model, and extreme genotype model). Additionally, the SNP rs1871054 was found associated with increased OA severity according to the K/L grade. Conclusion. In summary, we have identified that the rs1871054 variant within the ADAM12 gene is a risk factor for increased osteoarthritis susceptibility and severity.

Dietary fatty acid content regulates wound repair and the pathogenesis of osteoarthritis following joint injury

ObjectiveThe mechanisms linking obesity and osteoarthritis (OA) are not fully understood and have been generally attributed to increased weight, rather than metabolic or inflammatory factors. Here, we examined the influence...

Patterns of Femoral Cartilage Thickness are Different in Asymptomatic and Osteoarthritic Knees and Can be Used to Detect Disease-Related Differences Between Samples

Measures of mean cartilage thickness over predefined regions in the femoral plate using magnetic resonance imaging have provided important insights into the characteristics of knee osteoarthritis (OA), however, this quantification method suffers from the limited ability to detect OA-related differences between knees and loses potentially important information regarding spatial variations in cartilage thickness. The objectives of this study were to develop a new method for analyzing patterns of femoral cartilage thickness and to test the following hypotheses: (1) asymptomatic knees have similar thickness patterns, (2) thickness patterns differ with knee OA, and (3) thickness patterns are more sensitive than mean thicknesses to differences between OA conditions. Bi-orthogonal thickness patterns were extracted from thickness maps of segmented magnetic resonance images in the medial, lateral, and trochlea compartments. Fifty asymptomatic knees were used to develop the method and establish reference asymptomatic patterns. Another subgroup of 20 asymptomatic knees and three subgroups of 20 OA knees each with a Kellgren/Lawrence grade (KLG) of 1, 2, and 3, respectively, were selected for hypotheses testing. The thickness patterns were similar between asymptomatic knees (coefficient of multiple determination between 0.8 and 0.9). The thickness pattern alterations, i.e., the differences between the thickness patterns of an individual knee and reference asymptomatic thickness patterns, increased with increasing OA severity (Kendall correlation between 0.23 and 0.47) and KLG 2 and 3 knees had significantly larger thickness pattern alterations than asymptomatic knees in the three compartments. On average, the number of significant differences detected between the four subgroups was 4.5 times greater with thickness pattern alterations than mean thicknesses. The increase was particularly marked in the medial compartment, where the number of significant differences between subgroups was 10 times greater with thickness pattern alterations than mean thickness measurements. Asymptomatic knees had characteristic regional thickness patterns and these patterns were different in medial OA knees. Assessing the thickness patterns, which account for the spatial variations in cartilage thickness and capture both cartilage thinning and swelling, could enhance the capacity to detect OA-related differences between knees.

Deciphering the role of 75kDa SirT1 fragment in osteoarthritis

s / Osteoarthritis and Cartilage 21 (2013) S9–S62 S49 Fig. Molecular networks generated from the genes differentially expressed by age. The molecular networks generated from genes differentially expressed in meniscus by age (top: up-regulated genes; bottom: down-regulated genes) using GRANITE. The colors are based on the database from which the network is extracted. ellipse 1⁄4 protein; square 1⁄4 transcription factor 79 DECIPHERING THE ROLE OF 75KDA SIRT1 FRAGMENT IN OSTEOARTHRITIS M. Dvir-Ginzberg y, H. Oppenheimer y, H. Meir y, O. Gabay z, K. Zaal z, C. Sanchez x, A. Haze k, L. Kandel k, M. Leibergall k. yHebrew Univ. of Jerusalem, Jerusalem, Israel; zNIAMS, NIH, MD, USA; xHebrew Univ. of Jerusalem, University of Liege, Liege, Belgium; kHebrew Univ. of JerusalemHadassah Med. Center, Jerusalem, Israel Objective: SirT1 is a nuclear NAD-dependent deacetylase associated with cellmetabolismand survival. In joints, recent evidence shows that it regulates cartilage homeostasis and is involved in the inflammatory phase of osteoarthritis (OA). It is widely held that the inflammatory cytokines tumor necrosis factor alpha (TNFa), and interleukin 1b (IL-1b) may elicit chondrocyte death associated with the deterioration of articular cartilage (AC) in OA. Exposing human chondrocytes to both cytokines leads to cathepsin B-mediated cleavage of the nuclear full-length SirT1 (FLSirT1; 110kDa) to generate a stable but enzymatically inactive 75kDa fragment of SirT1 (75SirT1). Here we aim to elucidate the biological andbiochemical role of 75kDa SirT1 fragment in-vivo and in-vitro Methods: Using immunoblot analyses we aimed to detect cathepsin B, FLSirT1 and/or 75SirT1 in OA and normal human chondrocytes. Confocal imaging of SirT1 was used tomonitor its subcellular trafficking following TNFa stimulation of human chondrocytes. Coimmunofluorescent staining for cathepsin B, mitochondrial cytochrome oxidase subunit IV and lysosome-associated membrane protein 1 together with SirT1was performed. Human chondrocytes were tested for apoptosis by fluorescence-activated cell sorter analysis and immunoblotting for caspases 3 and 8. Human chondrocyte mitochondrial extracts were obtained and analyzed for 75SirT1-cytochrome C association. In-vivo assays of heterozygous haploinsufficient (SirT1+/-) and wildtype (WT; SirT1+/+) 129/J mice aged 1 or 9 months were systematically compared for musculoskeletal features, scored for osteoarthritis (OA) severity, and monitored for chondrocyte apoptosis in articular cartilage. Protein extracts from articular chondrocytes were isolated and immunoblotted for SirT1 and active caspase 3. Results: Confocal imaging, immunoprecipitation assays and immunoblot analyses following TNFa challenge of human chondrocytes exhibited that 75SirT1 was generated and exported to the cytoplasm wherein it colocalized with the mitochondrial membrane and associates with cytochrome C. Additionally, levels of cathepsin B and 75SirT1 were elevated in OA versus normal chondrocytes. Subjecting human chondrocytes to TNFa and a cathepsin B inhibitor (ALLN), enhanced levels of apoptotic cell and cleaved caspase 3. Immunoblot assays comparing medial tibial plateau articular cartilage (MTP-AC) of heterozygous haploinsufficient (SirT1+/-) and wild-type (WT; SirT1+/+) 129/J mice revealed reduced levels of FLSirT1 in both strains at 9 months compared to their 1 month equivalent. WT 9-monthold strains presented the 75SirT1 fragments in immunoblot assays, whereas age-matched SirT1+/-mice possessed undetected 75SirT1 levels. Interestingly, 9 month-old SirT1+/mice exhibited increased OA severity andaugmented levels of apoptosis comparedwithage-matchedWTmice. Conclusion: Despite 75SirT1 being enzymatically impaired our results show that it is relatively stable and participates in promoting chondrocyte survival following exposure to proinflammatory cytokines or during articular cartilage maturation. 80 ASYMPTOMATIC INDIVIDUALS WITH RADIOGRAPHIC EVIDENCE OF KNEE OSTEOARTHRITIS WALK WITH DIFFERENT KNEE MECHANICS PATTERNS THAN SYMPTOMATIC INDIVIDUALS WITH THE SAME RADIOGRAPHIC EVIDENCE J.L. Astephen Wilson, G. Hatfield, W.D. Stanish, C.L. HubleyKozey. Dalhousie Univ., Halifax, NS, Canada

Secreted 14-3-3ε: discovery by proteomics of a novel biomarker and/or therapeutical target in osteoarthritis

Secreted 14-3-3ε: discovery by proteomics of a novel biomarker and/or therapeutical target in osteoarthritis

Characterization of cell metabolic changes in osteoarthritic labrum cells

Characterization of cell metabolic changes in osteoarthritic labrum cells

Spontaneous osteoarthritis in Str/ort mice is unlikely due to greater vulnerability to mechanical trauma

Relative contributions of genetic and mechanical factors to osteoarthritis (OA) remain ill-defined. We have used a joint loading model found to produce focal articular cartilage (AC) lesions, to address whether genetic susceptibility to OA in Str/ort mice is related to AC vulnerability to mechanical trauma and whether joint loading influences spontaneous OA development. We also develop finite element (FE) models to examine whether AC thickness may explain any differential vulnerability to load-induced lesions. Right knees of 8-week-old Str/ort mice were loaded, AC integrity scored and thickness compared to CBA mice. Mechanical forces engendered in this model and the impact of AC thickness were simulated in C57Bl/6 mice using quasi-static FE modelling. Unlike joints in non-OA prone CBA mice, Str/ort knees did not exhibit lateral femur (LF) lesions in response to applied loading; but exhibited thicker AC. FE modeling showed increased contact pressure and shear on the lateral femoral surface in loaded joints, and these diminished in joints containing thicker AC. Histological analysis of natural lesions in the tibia of Str/ort joints revealed that applied loading increased OA severity, proteoglycan loss and collagen type II degradation. Genetic OA susceptibility in Str/ort mice is not apparently related to greater AC vulnerability to trauma, but joint loading modifies severity of natural OA lesions in the medial tibia. FE modelling suggests that thicker AC in Str/ort mice diminishes tissue stresses and protects against load-induced AC lesions in the LF but that this is unrelated to their genetic susceptibility to OA.

Relationship between patient-reported disease severity and other clinical outcomes in osteoarthritis: a European perspective

Objective:To determine how patient-rated osteoarthritis (OA) severity correlates with other patient-reported and clinical outcomes in the European clinical setting.Methods:We used the Adelphi Arthritis VII (2008) Disease Specific Program (DSP). OA severity was patient-rated using the question ‘How bad would you say your arthritis is now?’ with responses of ‘mild,’ ‘moderate,’ and ‘severe.’ Patient-reported outcomes included a 0–100 mm pain visual analogue scale (VAS); questions on daily functioning; Work Productivity and Activity Impairment (WPAI) scale; and EuroQoL (EQ-5D). Regression models and chi-square analyses evaluated relationships between self-rated OA severity and other outcomes.Results:Patient-reported data were available from 1739 individuals (63.1% female, mean age 64.4 [standard deviation 11.9] years) from France, Germany, Italy, Spain, and the UK. With increasing OA severity; mild (24.5%), moderate (56.3%), severe (19.2%), statistically significant differences (p < 0.05) were observed with higher pain VAS scores (28.3, 49.9, 69.2, respectively), reduced function, and greater overall work impairment due to OA (24.3%, 38.5%, 68.6%, respectively). Significant associations of patient-reported OA severity with function and health status were indicated, including the EQ-5D health state index; 0.77 (mild), 0.62 (moderate), 0.30 (severe) (p < 0.0001). Physicians tended to overestimate patients who rated their OA as mild, and underrate patients who rated their OA as severe.Conclusions:In five European countries, patient-rated OA severity was associated with other patient-reported outcomes, and may be of benefit in the clinical setting when choosing treatment options aimed at improving pain, function and productivity, providing an accurate and tangible assessment of patient’s perceptions of their disease.

Relationship between patient-reported disease severity in osteoarthritis and self-reported pain, function and work productivity

IntroductionUnderstanding the relationship between patient-reported osteoarthritis (OA) severity and other patient-reported outcomes in the real-world clinical setting can provide a basis for appropriate patient management. The objective of this study was to determine how patient-reported OA severity correlates with patient-reported outcomes including pain, function and productivity.MethodsWe used the Adelphi Disease Specific Programme (DSP) for OA, a database aggregated from large, multinational, observational studies for specific chronic diseases. Data were obtained based on a 0 to 100 mm pain visual analogue scale (VAS) and a series of questions including functioning (that is, activities of daily living) and work productivity. OA severity was rated by the patients based on the question "How bad would you say your arthritis is now?" with potential responses of "mild," "moderate," and "severe." Regression models and chi-square analyses were used to evaluate the relationships between self-reported OA severity and other outcomes.ResultsOf 998 subjects in the OA DSP U.S. database, 714 (72.5%) agreed to participate. This sample was predominantly female (61.7%) with a mean age of 63.8 ± 12.9 years. Increased OA severity was associated with an older population (P < 0.05). With increasing OA severity (mild, moderate, severe), statistically significant differences (P < 0.05) were observed in increased pain VAS scores (23.5, 50.2, 70.8, respectively), lower functioning outcomes, and a higher percent of overall work impairment due to OA (17%, 37%, 48%, respectively). The increased work impairment at greater severity levels also resulted in higher costs related to lost work productivity, with annual costs due to lost productivity estimated at $6,096, $13,2510, and $17,214 per patient for self-reported mild, moderate, and severe OA, respectively (P < 0.05 for pairwise comparisons).ConclusionsIn the clinical practice setting, patient-reported OA severity was associated with other key patient-reported outcomes and thus may provide an accurate and tangible assessment of patients' perceptions of their disease. Identifying OA patients by their perceived severity level may be of benefit to patients and health-care providers when choosing treatment options aimed at reducing pain, and improving function and productivity.