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1.  Examining Sex Differences in Knee Pain: The Multicenter Osteoarthritis Study 
Objective
To determine whether women experience greater knee pain severity than men at equivalent levels of radiographic knee osteoarthritis (OA).
Design and Methods
A cross-sectional analysis of 2712 individuals (60% women) without knee replacement or a recent steroid injection. Sex differences in pain severity at each KL grade were assessed by knee using VAS scale and WOMAC with and without adjustment for age, analgesic use, BMI, clinic site, comorbid conditions, depression score, education, race, and widespread pain (WSP) using generalized estimating equations. Effect sizes (Cohen’s d) were also calculated. Analyses were repeated in those with and without patellofemoral OA (PFOA).
Results
Women reported higher VAS pain at all KL grades in unadjusted analyses (d=0.21–0.31, p<0.0001–0.0038) and in analyses adjusted for all covariates except WSP (d=0.16–0.22, p<0.0001–0.0472). Pain severity differences further decreased with adjustment for WSP (d=0.10–0.18) and were significant for KL grade ≤2 (p=0.0015) and 2 (p=0.0200). Presence compared with absence of WSP was associated with significantly greater knee pain at all KL grades (d=0.32–0.52, p<0.0001–0.0008). In knees with PFOA, VAS pain severity sex differences were greater at each KL grade (d=0.45–0.62, p=0.0006–0.0030) and remained significant for all KL grades in adjusted analyses (d=0.31–0.57, p=0.0013–0.0361). Results using WOMAC were similar.
Conclusions
Women reported greater knee pain than men regardless of KL grade, though effect sizes were generally small. These differences increased in the presence of PFOA. The strong contribution of WSP to sex differences in knee pain suggests that central sensitivity plays a role in these differences.
doi:10.1016/j.joca.2014.06.030
PMCID: PMC4180745  PMID: 24999111
sex differences; knee pain; knee osteoarthritis
2.  Summary of the OA Biomarkers Workshop 2010 - Genetics and Genomics: New Targets in OA 
Summary
On November 4th and 5th 2010 a group of more than 100 international investigators gathered in Atlanta for the 2nd Osteoarthritis (OA) Biomarkers Global Initiative workshop titled “Genetics and Genomics: New Targets in OA”. The 1st workshop took place in April 2009 and focused on in vitro (soluble) biomarkers whilst the 3rd and final workshop will take place in 2012 and will focus on imaging biomarkers. The Osteoarthritis Research Society International (OARSI) has organized the workshops. In addition to OARSI, the National Institute of Arthritis, Musculoskeletal and Skin Diseases, the Arthritis Foundation, Amgen, Genzyme, the American Orthopaedic Society for Sports Medicine and Pfizer sponsored the 2nd meeting. It was clear from this meeting that experiments in the genetics, epigenetics and genomics of OA, are yielding valuable insights into the etiology of this heterogeneous disease but that much still needs to be learnt. Combining genetic insights with conventional biomarkers and imaging modalities may provide scientists with the enhanced tools to understand this complex disease. With those tools in hand, clinicians and industry can develop protocols to ultimately improve patient care.
doi:10.1016/j.joca.2011.06.002
PMCID: PMC4500043  PMID: 21723402
3.  Comparison of vertebral and intervertebral disc lesions in aging humans and rhesus monkeys 
Objective
To compare gross and histologic patterns of age-related degeneration within the intervertebral disc and adjacent vertebra between rhesus monkeys and humans.
Materials and methods
We examined age-related patterns of disc degeneration from mid-sagittal sections of the intervertebral disc and adjacent vertebral bodies among six rhesus monkey thoracolumbar and seven human lumbar spines. Gross morphology and histopathology were assessed via the Thompson grading scheme and other degenerative features of the disc and adjacent bone.
Results
Thompson grades ranged from 3 through 5 for rhesus monkey discs (T9-L1) and 2 through 5 for the human discs (T12-S1). In both rhesus monkey and human discs, presence of distinct lesions were positively associated with Thompson grade of the overall segment. Degenerative patterns differed for radial tears, which were more prevalent with advanced disc degeneration in humans only. Additionally, compared to the more uniform anteroposterior disc degeneration patterns of humans, rhesus monkeys showed more severe osteophytosis and degeneration on the anterior border of the vertebral column.
Conclusions
Rhesus monkey spines evaluated in the present study appear to develop age-related patterns of disc degeneration similar to humans. One exception is the absence of an association between radial tears and disc degeneration, which could reflect species-specific differences in posture and spinal curvature. Considering rhesus monkeys demonstrate similar patterns of disc degeneration, and age at a faster rate than humans, these findings suggest longitudinal studies of rhesus monkeys may be a valuable model for better understanding the progression of human age-related spinal osteoarthritis and disc degeneration.
doi:10.1016/j.joca.2014.04.027
PMCID: PMC4105267  PMID: 24821664
spinal osteoarthritis; intervertebral disc degeneration; histopathology; rhesus monkey
4.  Influences of Alignment and Obesity on Knee Joint Loading in Osteoarthritic Gait 
Objective
To determine the influences of frontal plane knee alignment and obesity on knee joint loads in older, overweight and obese adults with knee osteoarthritis.
Methods
Cross-sectional investigation of alignment and obesity on knee joint loads using community dwelling older adults (age ≥ 55 yrs.; 27 kg·m−2 ≥ BMI ≤ 41 kg·m−2; 69% female) with radiographic knee osteoarthritis that were a subset of participants (157 out of 454) enrolled in the Intensive Diet and Exercise for Arthritis (IDEA) clinical trial.
Results
A higher BMI was associated with greater (p = 0.0006) peak knee compressive forces [overweight, 2411 N (2182, 2639), class 1 obesity, 2772 N (2602, 2943), class 2+ obesity, 2993 N (2796, 3190)] and greater (p = 0.004) shear forces [overweight, 369 N (322, 415), class 1 obesity, 418 N (384, 453), class 2+ obesity, 472 N (432, 513)], independent of alignment, and varus alignment was associated (p < 0.0001) with greater peak external knee adduction moments, independent of BMI [valgus, 18.7 Nm (15.1, 22.4), neutral, 27.7 Nm (24.0, 31.4), varus, 37.0 Nm (34.4, 39.7)].
Conclusion
BMI and alignment were associated with different joint loading measures; alignment was more closely associated with the asymmetry or imbalance of loads across the medial and lateral knee compartments as reflected by the frontal plane external adduction moment, while BMI was associated with the magnitude of total tibio-femoral force. These data may be useful in selecting treatment options for knee osteoarthritis patients (e.g., diet to reduce compressive loads or bracing to change alignment).
doi:10.1016/j.joca.2014.05.013
PMCID: PMC4108726  PMID: 24857973
5.  Prodromal symptoms in knee osteoarthritis: a nested case–control study using data from the Osteoarthritis Initiative 
Osteoarthritis and Cartilage  2015;23(7):1083-1089.
Summary
Objective
In order to gain a better understanding of the timing of emergent symptoms of osteoarthritis, we sought to investigate the existence, duration and nature of a prodromal symptomatic phase preceding incident radiographic knee osteoarthritis (ROA).
Design
Data were from the incidence cohort of the Osteoarthritis Initiative (OAI) public use datasets. Imposing a nested case–control design, ten control knees were selected for each case of incident tibiofemoral ROA between 2004 and 2010 from participants aged 45–79 years. Candidate prodromal symptoms were Western Ontario & McMaster Universities Osteoarthritis Index (WOMAC) and Knee injury and Osteoarthritis Outcome Score (KOOS) subscale scores and individual items, available up to 4 years prior to the time of incident ROA. Multi-level models were used to estimate the length of the prodromal phases.
Results
The prodromal phase for subscale scores ranged from 29 months (KOOS Other Symptoms) to 37 months (WOMAC Pain). Pain and difficulty on activities associated with higher dynamic knee loading were associated with longer prodromal phases (e.g., pain on twisting/pivoting (39 months, 95% confidence interval: 13, 64) vs pain on standing (25 months: 7, 42)).
Conclusions
Our analysis found that incident ROA is preceded by prodromal symptoms lasting at least 2–3 years. This has potential implications for understanding phasic development and progression of osteoarthritis and for early recognition and management.
doi:10.1016/j.joca.2014.12.026
PMCID: PMC4491193  PMID: 25843364
Knee osteoarthritis; Symptoms; Epidemiology; Case–control; Prodrome
6.  Lysophosphatidic Acid Mediates Fibrosis In Injured Joints By Regulating Collagen Type I Biosynthesis 
Objective
Articular cartilage is a highly specialized tissue which forms the surfaces in synovial joints. Full-thickness cartilage defects caused by trauma or microfracture surgery heal via the formation of fibrotic tissue characterized by a high content of collagen I (COL I) and subsequent poor mechanical properties. The goal of this study is to investigate the molecular mechanisms underlying fibrosis after joint injury.
Design
Rat knee joint models are used to mimic cartilage defects after acute injury. Immunohistochemistry was performed to detect proteins related to fibrosis. Human fetal chondroyges and bone marrow stromal cells (BMSCs) were used to study the influence of lipid lysophosphatidic acid (LPA) on Collagen I (COL I) synthesis. Quantitative PCR, ELISA and immunohistochemistry were performed to evaluate the productions of COL I. Chemical inhibitors were used to block LPA signaling both in vitro and in vivo.
Results
After full-thickness cartilage injury in rat knee joints, stromal cells migrating to the injury expressed high levels of the LPA-producing enzyme autotaxin (ATX); intact articular cartilage in rat and humans expressed negligible levels of ATX despite expressing the LPA receptors LPAR1 and LPAR2. LPA-induced increases in COL I production by chondrocytes and BMSCs was mediated via the MAP kinase (MAPK) and PI3 Kinase (PI3K) signaling pathways. Inhibition of the ATX/LPA axis significantly reduced COL I-enriched fibrocartilage synthesis in full-thickness cartilage defects in rats in favor of the collagen II-enriched normal state.
Conclusion
Taken together, these results identify an attractive target for intervention in reducing the progression of post-traumatic osteoarthritis.
doi:10.1016/j.joca.2014.11.012
PMCID: PMC4465392  PMID: 25464168
autotaxin; lysophosphatidic acid; chondrocytes; cartilage injury; collagen type I; fibrosis
7.  The independent and combined effects of intensive weight loss and exercise training on bone mineral density in overweight and obese, older adults with osteoarthritis 
Objective
To determine the effects of dietary-induced weight loss (D) and weight loss plus exercise (D+E) compared to exercise alone (E) on bone mineral density (BMD) in older adults with knee osteoarthritis (OA).
Design
Data come from 284 older (66.0±6.2 years), overweight/obese (BMI 33.4±3.7 kg/m2), adults with knee OA enrolled in the Intensive Diet and Exercise for Arthritis (IDEA) study. Participants were randomized to 18 months of walking and strength training (E; n=95), dietary-induced weight loss targeting 10% of baseline weight (D; n=88) or a combination of the two (D+E; n=101). Body weight and composition (DXA), regional BMD, were obtained at baseline and 18 months.
Results
E, D, and D+E groups lost 1.3±4.5 kg, 9.1±8.6 kg and 10.4±8.0 kg, respectively (p<0.01). Significant treatment effects were observed for BMD in both hip and femoral neck regions, with the D and D+E groups showing similar relative losses compared to E (both p<0.01). Despite reduced BMD, fewer overall participants had T-scores indicative of osteoporosis after intervention (9 at 18 months vs. 10 at baseline). Within the D and D+E groups, changes in hip and femoral neck, but not spine, BMD correlated positively with changes in body weight (r=0.21 and 0.54 respectively, both p=<0.01).
Conclusions
Weight loss via an intensive dietary intervention, with or without exercise, results in bone loss at the hip and femoral neck in overweight and obese, older adults with OA. Although the exercise intervention did not attenuate weight loss associated reductions in BMD, classification of osteoporosis and osteopenia remained unchanged.
doi:10.1016/j.joca.2014.04.002
PMCID: PMC4051847  PMID: 24742955
bone density; obesity; weight loss; exercise; osteoarthritis
8.  Cigarette smoking and risk of total knee replacement for severe osteoarthritis among Chinese in Singapore - The Singapore Chinese Health Study 
Purpose
Data on the effects of cigarette smoking with osteoarthritis (OA) are inconsistent and no study has examined the effect of smoking cessation. We examined smoking status, duration, dosage and cessation in association with risk of total knee replacement (TKR) for severe knee OA among elderly Chinese in Singapore.
Methods
We used data from the Singapore Chinese Health Study, a population-based prospective cohort of 63,257 Chinese men and women aged 45 to 74 years during enrolment between 1993 and 1998. Detailed information on smoking, current diet and lifestyle factors were obtained through in-person interviews. As of 31 December 2011, 1,973 incident TKR cases for severe knee OA had been identified via linkage with nationwide hospital discharge database. We used Cox regression methods to examine smoking in relation to TKR risk with adjustment for age, gender, education, body mass index, comorbidities and physical activity level.
Results
Compared to never smokers, current smokers had a 51% decrease in risk of TKR [Hazards ratio (HR) =0.49; 95% confidence interval (CI) =0.40-0.60]. Among current smokers, there was a very strong dose-dependent association between increasing duration and dosage of smoking with decreasing risk of TKR (p for trend<0.0001). Among former smokers, there was a dose-dependent response between decrease in duration of smoking cessation and reduction in TKR risk (p for trend=0.034).
Conclusion
Our findings strongly implicate smoking as a protective factor for total knee replacement indicated for severe knee OA. This concurs with experimental data that nicotine promotes proliferation and collagen synthesis in chondrocytes.
doi:10.1016/j.joca.2014.03.013
PMCID: PMC4051850  PMID: 24680935
Knee osteoarthritis; smoking; Chinese; cohort study
9.  Energy Recovery in Individuals with Knee Osteoarthritis 
Objective
Pathological gaits have been shown to limit transfer between potential (PE) and kinetic (KE) energy during walking, which can increase locomotor costs. The purpose of this study was to examine whether energy exchange would be limited in people with knee osteoarthritis (OA).
Methods
Ground reaction forces during walking were collected from 93 subjects with symptomatic knee OA (self-selected and fast speeds) and 13 healthy controls (self-selected speed) and used to calculate their center of mass (COM) movements, PE and KE relationships, and energy recovery during a stride. Correlations and linear regressions examined the impact of energy fluctuation phase and amplitude, walking velocity, body mass, self-reported pain, and radiographic severity on recovery. Paired t-tests were run to compare energy recovery between cohorts.
Results
Symptomatic knee OA subjects displayed lower energetic recovery during self-selected walking speeds than healthy controls (p=0.0018). PE and KE phase relationships explained the majority (66%) of variance in recovery. Recovery had a complex relationship with velocity and its change across speeds was significantly influenced by the self-selected walking speed of each subject. Neither radiographic OA scores nor subject self-reported measures demonstrated any relationship with energy recovery.
Conclusions
Knee OA reduces effective exchange of PE and KE, potentially increasing the muscular work required to control movements of the COM. Gait retraining may return subjects to more normal patterns of energy exchange and allow them to reduce fatigue.
doi:10.1016/j.joca.2014.04.004
PMCID: PMC4435530  PMID: 24752039
Knee osteoarthritis; Energy recovery; Mechanical work; Locomotor costs
10.  Intermittent applied mechanical loading induces subchondral bone thickening that may be intensified locally by contiguous articular cartilage lesions 
Osteoarthritis and Cartilage  2015;23(6):940-948.
Summary
Objectives
Changes in subchondral bone (SCB) and cross-talk with articular cartilage (AC) have been linked to osteoarthritis (OA). Using micro-computed tomography (micro-CT) this study: (1) examines changes in SCB architecture in a non-invasive loading mouse model in which focal AC lesions are induced selectively in the lateral femur, and (2) determines any modifications in the contralateral knee, linked to changes in gait, which might complicate use of this limb as an internal control.
Methods
Right knee joints of CBA mice were loaded: once with 2weeks of habitual use (n = 7), for 2weeks (n = 8) or for 5weeks (n = 5). Both left (contralateral) and right (loaded) knees were micro-CT scanned and the SCB and trabecular bone analysed. Gait analysis was also performed.
Results
These analyses showed a significant increase in SCB thickness in the lateral compartments in joints loaded for 5weeks, which was most marked in the lateral femur; the contralateral non-loaded knee also showed transient SCB thickening (loaded once and repetitively). Epiphyseal trabecular bone BV/TV and trabecular thickness were also increased in the lateral compartments after 5 weeks of loading, and in all joint compartments in the contralateral knee. Gait analysis showed that applied loading only affected gait in the contralateral himd-limb in all groups of mice from the second week after the first loading episode.
Conclusions
These data indicate a spatial link between SCB thickening and AC lesions following mechanical trauma, and the clear limitations associated with the use of contralateral joints as controls in such OA models, and perhaps in OA diagnosis.
doi:10.1016/j.joca.2015.01.012
PMCID: PMC4459965  PMID: 25655679
Mechanical loading; Joint; Articular cartilage; Subchondral bone and osteoarthritis
11.  Dissecting the contribution of knee joint NGF to spinal nociceptive sensitization in a model of OA pain in the rat 
Osteoarthritis and Cartilage  2015;23(6):906-913.
Summary
Objective
Although analgesic approaches targeting nerve growth factor (NGF) for the treatment of osteoarthritis (OA) pain remain of clinical interest, neurophysiological mechanisms by which NGF contribute to OA pain remain unclear. We investigated the impact of local elevation of knee joint NGF on knee joint, vs remote (hindpaw), evoked responses of spinal neurones in a rodent model of OA pain.
Design
In vivo spinal electrophysiology was carried out in anaesthetised rats with established pain behaviour and joint pathology following intra-articular injection of monosodium iodoacetate (MIA), vs injection of saline. Neuronal responses to knee joint extension and flexion, mechanical punctate stimulation of the peripheral receptive fields over the knee and at a remote site (ipsilateral hind paw) were studied before, and following, intra-articular injection of NGF (10 μg/50 μl) or saline.
Results
MIA-injected rats exhibited significant local (knee joint) and remote (lowered hindpaw withdrawal thresholds) changes in pain behaviour, and joint pathology. Intra-articular injection of NGF significantly (P < 0.05) increased knee extension-evoked firing of spinal neurones and the size of the peripheral receptive fields of spinal neurones (100% increase) over the knee joint in MIA rats, compared to controls. Intra-articular NGF injection did not significantly alter responses of spinal neurones following noxious stimulation of the ipsilateral hind paw in MIA-injected rats.
Conclusion
The facilitatory effects of intra-articular injection of NGF on spinal neurones receiving input from the knee joint provide a mechanistic basis for NGF mediated augmentation of OA knee pain, however additional mechanisms may contribute to the spread of pain to remote sites.
doi:10.1016/j.joca.2015.01.010
PMCID: PMC4459966  PMID: 25623624
Pain; Osteoarthritis; Spinal; Monosodium iodoacetate
12.  Trajectories and Risk Profiles of Pain in Persons with Radiographic, Symptomatic Knee Osteoarthritis: Data from the Osteoarthritis Initiative 
Background
Little is known about the temporal evolution of pain severity in persons with knee OA. We sought to describe the pain trajectory over 6 years in a cohort of subjects with radiographic, symptomatic knee OA.
Methods
We used data from the Osteoarthritis Initiative (OAI), a multi-center, longitudinal study of subjects with diagnosed radiographic evidence of knee OA. Pain was assessed at baseline and annually for 6 years. Our analysis cohort included subjects with symptomatic knee OA at baseline, defined as baseline Kellgren-Lawrence (KL) score ≥2 with WOMAC pain score >0. We used group-based trajectory modeling to identify distinct patterns of pain progression over 6-year follow-up. Factors examined included sex, race, education, comorbidities, age, body mass index (BMI), alignment, KL grade, and depression.
Results
We used data from 1,753 OAI participants with symptomatic knee OA. Mean baseline WOMAC pain score was 26.5 (0–100,100 = worst) with standard deviation 19. Group-based trajectory modeling identified 5 distinct pain trajectories; baseline pain scores for each ranged from 15 to 62. None of the trajectories exhibited substantial worsening. One fifth of subjects in the two trajectories with the greatest pain underwent total knee replacement over follow-up. Higher KL grade, obesity, depression, medical comorbidities, female sex, non-white race, lower education, and younger age were associated with trajectories characterized by greater pain.
Conclusion
We found that knee pain changes little, on average, over six years in most subjects. These observations suggest knee OA is characterized by persistent rather than inexorably worsening symptoms.
doi:10.1016/j.joca.2014.03.009
PMCID: PMC4028704  PMID: 24662734
osteoarthritis; pain; trajectories; group-based trajectory modeling; cohort study
13.  Three-dimensional hip cartilage quality assessment of morphology and dGEMRIC by planar maps and automated segmentation 
Objective
The quantitative interpretation of hip cartilage MRI has been limited by the difficulty of identifying and delineating the cartilage in a 3D dataset, thereby reducing its routine usage. In this paper a solution is suggested by unfolding the cartilage to planar 2D maps on which both morphology and biochemical degeneration patterns can be investigated across the entire hip joint.
Design
Morphological TrueFISP and biochemical dGEMRIC hip images were acquired isotropically for 15 symptomatic subjects with mild or no radiographic osteoarthritis. A multi-template based label fusion technique was used to automatically segment the cartilage tissue, followed by a geometric projection algorithm to generate the planar maps. The segmentation performance was investigated through a leave-one-out study, for two different fusion methods and as a function of the number of utilized templates.
Results
For each of the generated planar maps, various patterns could be seen, indicating areas of healthy and degenerated cartilage. Dice coefficients for cartilage segmentation varied from 0.76 with four templates to 0.82 with 14 templates. Regional analysis suggests even higher segmentation performance in the superior half of the cartilage.
Conclusions
The proposed technique is the first of its kind to provide planar maps that enable straightforward quantitative assessment of hip cartilage morphology and dGEMRIC values. This technique may have important clinical applications for patient selection for hip preservation surgery, as well as for epidemiological studies of cartilage degeneration patterns. It is also shown that 10-15 templates are sufficient for accurate segmentation in this application.
doi:10.1016/j.joca.2014.08.012
PMCID: PMC4404159  PMID: 25278060
Osteoarthritis; hip; dGEMRIC; MRI; segmentation; label fusion
14.  Tibial coverage, meniscus position, size and damage in knees discordant for joint space narrowing – data from the Osteoarthritis Initiative 
SUMMARY
Introduction
Meniscal extrusion is thought to be associated with less meniscus coverage of the tibial surface, but the association of radiographic disease stage with quantitative measures of tibial plateau coverage is unknown. We therefore compared quantitative and semi-quantitative measures of meniscus position and morphology in individuals with bilateral painful knees discordant on medial joint space narrowing (mJSN).
Methods
A sample of 60 participants from the first half (2,678 cases) of the Osteoarthritis Initiative cohort fulfilled the inclusion criteria: bilateral frequent pain, Osteoarthritis Research Society International (OARSI) mJSN grades 1–3 in one, no-JSN in the contra-lateral (CL), and no lateral JSN in either knee (43 unilateral mJSN1; 17 mJSN2/3; 22 men, 38 women, body mass index (BMI) 31.3 ± 3.9 kg/m2). Segmentation and three-dimensional quantitative analysis of the tibial plateau and meniscus, and semi-quantitative evaluation of meniscus damage (magnetic resonance imaging (MRI) osteoarthritis knee score – MOAKS) was performed using coronal 3T MR images (MPR DESSwe and intermediate-weighted turbo spin echo (IW-TSE) images). CL knees were compared using paired t-tests (between-knee, within-person design).
Results
Medial tibial plateau coverage was 36 ± 9% in mJSN1 vs 45 ± 8% in CL no-JSN knees, and was 31 ± 9% in mJSN2/3 vs 46 ± 6% in no-JSN knees (both P < 0.001). mJSN knees showed greater meniscus extrusion and damage (MOAKS), but no significant difference in meniscus volume. No significant differences in lateral tibial coverage, lateral meniscus morphology or position were observed.
Conclusions
Knees with medial JSN showed substantially less medial tibial plateau coverage by the meniscus. We suggest that the less meniscal coverage, i.e., less mechanical protection may be a reason for greater rates of cartilage loss observed in JSN knees.
doi:10.1016/j.joca.2012.11.015
PMCID: PMC4398339  PMID: 23220556
Meniscus; Joint space narrowing; Radiographic osteoarthritis; Magnetic resonance imaging; Tibial coverage
15.  Can cartilage loss be detected in knee osteoarthritis (OA) patients with 3–6 months' observation using advanced image analysis of 3 T MRI? 
SUMMARY
Purpose
Prior investigations of magnetic resonance imaging (MRI) biomarkers of cartilage loss in knee osteoarthritis (OA) suggest that trials of interventions which affect this biomarker with adequate statistical power would require large clinical studies of 1–2 years duration. We hypothesized that smaller, shorter duration. “Proof of Concept” (PoC) studies might be achievable by: (1) selecting a population at high risk of rapid medial tibio-femoral (TF) progression, in conjunction with; (2) high-field MRI (3 T), and; (3) using advanced image analysis. The primary outcome was the cartilage thickness in the central medial femur.
Methods
Multi-centre, non-randomized, observational cohort study at four sites in the US. Eligible participants were females with knee pain, a body mass index (BMI) ≥25 kg/m2, symptomatic radiographic evidence of medial TF OA, and varus mal-alignment The 29 participants had a mean age of 62 years, mean BMI of 36 kg/m2, with eight index knees graded as Kellgren–Lawrence (K&L)=2 and 21 as K&L = 3. Eligible participants had four MRI scans of one knee: two MRIs (1 week apart) were acquired as a baseline with follow-up MRI at 3 and 6 months. A trained operator, blind to time-point but not subject, manually segmented the cartilage from the Dual Echo Steady State water excitation MR images. Anatomically corresponding regions of interest were identified on each image by using a three-dimensional statistical shape model of the endosteal bone surface, and the cartilage thickness (with areas denuded of cartilage included as having zero thickness – ThCtAB) within each region was calculated. The percentage change from baseline at 3 and 6 months was assessed using a log-scale analysis of variance (ANOVA) model including baseline as a covariate. The primary outcome was the change in cartilage thickness within the aspect of central medial femoral condyle exposed within the meniscal window (w) during articulation, neglecting cartilage edges [nuclear (n)] (nwcMF ThCtAB), with changes in other regions considered as secondary endpoints.
Results
Anatomical mal-alignment ranged from −1.9° to 6.3°, with mean 0.9°. With one exception, no changes in ThCtAB were detected at the 5% level for any of the regions of interest on the TF joint at 3 or 6 months of follow-up. The change in the primary variable (nwcMF ThCtAB) from (mean) baseline at 3 months from the log-scale ANOVA model was −2.1% [95% confidence interval (CI) (−4.4%, +02%)]. The change over 6 months was 0.0% [95% CI (−2.7%, +2.8%)]. The 95% CI for the change from baseline did not include zero for the cartilage thickness within the meniscal window of the lateral tibia (wLT ThCtAB) at 6 month follow-up (−1.5%, 95% CI [−2.9, −0.2]), but was not significant at the 5% level after correction for multiple comparisons.
Conclusions
The small inconsistent compartment changes, and the relatively high variabilities in cartilage thickness changes seen over time in this study, provide no additional confidence for a 3- or 6-month PoC study using a patient population selected on the basis of risk for rapid progression with the MRI acquisition and analyses employed.
doi:10.1016/j.joca.2010.02.010
PMCID: PMC4398342  PMID: 20219688
Osteoarthritis; Magnetic resonance imaging; Cartilage thickness
16.  The impact of knee instability with and without buckling on balance confidence, fear of falling and physical function: the Multicenter Osteoarthritis Study 
SUMMARY
Objective
Knee buckling, in which a knee gives way during weight-bearing, is common in people with knee pain and knee osteoarthritis (OA), but little is known about the prevalence of sensations of knee instability, slipping or shifting in which the knee does not actually buckle, or of the psychosocial and physical consequences of these symptoms.
Design
We asked participants in the Multicenter Osteoarthritis Study (MOST) separately about episodes of knee buckling and sensations of knee instability without buckling in the past 3 months, and assessed fear of falling, poor balance confidence (Activities-specific Balance Confidence (ABC) Scale ≤ 67/100), activity limitation due to concern about buckling, and poor physical function (Western Ontario and McMaster Universities Arthritis Index (WOMAC) physical function ≥ 28/68). We used Poisson regression to estimate prevalence ratios (PRs) for cross-sectional associations of buckling and sensations of instability without buckling with these outcomes, adjusting for confounders.
Results
Of 2120 participants (60% female, 40% ≥ 65 years, mean Body mass index (BMI): 31 kg/m258), 18% reported buckling, 27% had sensations of knee instability without buckling, and 9% reported both symptoms. Buckling and sensations of instability without buckling were each significantly associated with fear of falling, poor balance confidence, activity limitations, and poor WOMAC physical function. Subjects who reported both buckling and instability without buckling and those with at least two buckling episodes (15%) had the strongest association with poor outcomes.
Conclusions
Knee buckling and especially sensations of knee instability without buckling were common and each was significantly associated with fear of falling, poor balance confidence, activity limitations, and poor physical function.
doi:10.1016/j.joca.2014.01.008
PMCID: PMC4059670  PMID: 24508777
Osteoarthritis; Epidemiology; Outcome measures; Falls
17.  Targeted mutation of NOV/CCN3 in mice disrupts joint homeostasis and causes osteoarthritis-like disease 
Osteoarthritis and Cartilage  2015;23(4):607-615.
Summary
Objective
The matricellular protein NOV/CCN3, is implicated in osteoarthritis (OA) and targeted mutation of NOV in mice (Novdel3) leads to joint abnormalities. This investigation tested whether NOV is required for joint homeostasis and if its disruption causes joint degeneration.
Method
NOV expression in the adult mouse joint was characterized by immunohistochemistry. A detailed comparison of the joints of Novdel3−/− and Novdel3+/+ (wild-type) males and females at 2, 6 and 12 months of age was determined by X-ray, histology and immunohistochemistry.
Results
NOV protein was found in specific cells in articular cartilage, meniscus, synovium and ligament attachment sites in adult knees. Novdel3−/− males exhibited severe OA-like pathology at 12 months (OARSI score 5.0 ± 0.5, P < 0.001), affecting all tissues of the joint: erosion of the articular cartilage, meniscal enlargement, osteophytic outgrowths, ligament degeneration and expansion of fibrocartilage. Subchondral sclerosis and changes in extracellular matrix composition consistent with OA, were also seen. The density of articular cartilage cells in Novdel3+/+ knee joints is maintained at a constant level from 2 to 12 months of age whereas this is not the case in Novdel3−/− mice. Compared with age and sex-matched Novdel3+/+ mice, a significant increase in articular cartilage density was seen in Novdel3−/− males at 2 months, whereas a significant decrease was seen at 6 and 12 months in both Novdel3−/− males and females.
Conclusion
NOV is required for the maintenance of articular cartilage and for joint homeostasis, with disruption of NOV in ageing Novdel3−/− male mice causing OA-like disease.
doi:10.1016/j.joca.2014.12.012
PMCID: PMC4373756  PMID: 25541297
NOV/CCN3; Joint homeostasis; Osteoarthritis; Targeted mouse mutant
18.  Transcriptional analysis of micro-dissected articular cartilage in post-traumatic murine osteoarthritis 
Osteoarthritis and Cartilage  2015;23(4):616-628.
Summary
Objective
Identify gene changes in articular cartilage of the medial tibial plateau (MTP) at 2, 4 and 8 weeks after destabilisation of the medial meniscus (DMM) in mice. Compare our data with previously published datasets to ascertain dysregulated pathways and genes in osteoarthritis (OA).
Design
RNA was extracted from the ipsilateral and contralateral MTP cartilage, amplified, labelled and hybridized on Illumina WGv2 microarrays. Results were confirmed by real-time polymerase chain reaction (PCR) for selected genes.
Results
Transcriptional analysis and network reconstruction revealed changes in extracellular matrix and cytoskeletal genes induced by DMM. TGFβ signalling pathway and complement and coagulation cascade genes were regulated at 2 weeks. Fibronectin (Fn1) is a hub in a reconstructed network at 2 weeks. Regulated genes decrease over time. By 8 weeks fibromodulin (Fmod) and tenascin N (Tnn) are the only dysregulated genes present in the DMM operated knees. Comparison with human and rodent published gene sets identified genes overlapping between our array and eight other studies.
Conclusions
Cartilage contributes a minute percentage to the RNA extracted from the whole joint (<0.2%), yet is sensitive to changes in gene expression post-DMM. The post-DMM transcriptional reprogramming wanes over time dissipating by 8 weeks. Common pathways between published gene sets include focal adhesion, regulation of actin cytoskeleton and TGFβ. Common genes include Jagged 1 (Jag1), Tetraspanin 2 (Tspan2), neuroblastoma, suppression of tumourigenicity 1 (Nbl1) and N-myc downstream regulated gene 2 (Ndrg2). The concomitant genes and pathways we identify may warrant further investigation as biomarkers or modulators of OA.
doi:10.1016/j.joca.2014.12.014
PMCID: PMC4373757  PMID: 25545425
Osteoarthritis; Destabilisation of the medial meniscus (DMM); Microarray; Tenascin; Fibromodulin; Fibronectin
19.  OARSI–OMERACT initiative: defining thresholds for symptomatic severity and structural changes in disease modifying osteoarthritis drug (DMOAD) clinical trials 
SUMMARY
Objective
Total joint replacement has been proposed as an endpoint in disease modifying osteoarthritis drug (DMOAD) randomized clinical trials (RCTs); however, disparities have generated concerns regarding this outcome. A combined Osteoarthritis Research Society International (OARSI)/Outcome Measures in Rheumatology (OMERACT) initiative was launched in 2004 to develop a composite index [‘virtual total joint replacement’ (VJR)] as a surrogate outcome for osteoarthritis (OA) progression in DMOAD RCTs. Our objective was to evaluate the prevalence of patients fulfilling different thresholds of sustained pain, reduced function, and X-ray change in existing DMOAD RCTs.
Design
Post hoc analysis of summary data from the placebo arm of eight DMOAD RCTs.
Results
Eight OA RCTs representing 1379 patients were included. Pain was assessed by WOMAC and/or VAS and function by WOMAC and/or Lequesne. Among six knee and two hip studies, 248 (22%) and 132 (51%) patients respectively had X-ray progression [decrease joint space width (JSW) ≥0.5 mm]. The prevalence of patients fulfilling clinical and radiographic criteria was highest (n = 163, 12%) in the least stringent scenario (pain + function ≥80 at ≥2 visits); with few patients (n = 129, 2%) in the most stringent scenario (pain + function ≥80 at ≥4 visits). Using these prevalence data, a sample size of 352–2144 per group would be needed to demonstrate a 50% difference between groups.
Conclusions
The prevalence of patients with sustained symptomatic OA of at least a moderate degree with X-ray progression is low. Even using lenient criteria to define VJR, large patient numbers would be required to detect differences between groups in DMOAD RCTs. Investigation of the optimal cutoff threshold and combination of symptoms and radiographic change should be pursued.
doi:10.1016/j.joca.2011.11.013
PMCID: PMC4375956  PMID: 22178465
Osteoarthritis; Outcomes; Randomized clinical trials
20.  Low rate of total hip replacement as reflected by a low prevalence of hip osteoarthritis in South Korea 
Summary
Objective
We attempted to estimate the rate of total hip replacement (THR) using a national database and the prevalence of hip osteoarthritis (OA) from the reading of intravenous pyelograms (IVPs) in a Korean population.
Materials
Reimbursement records from all hospitals in South Korea were extracted from the Health Insurance Review Agency (HIRA) database. Records with both the procedure code corresponding to THR and containing the diagnosis code for hip OA were selected. We estimated the age- and sex-specific rates of THR from 2002 to 2006. Hip joints from 580 subjects older than 70 years old who underwent an IVP were assessed for the presence of OA.
Results
The rate of THR increased with age, reaching a peak over the age of 65–69 years, with the age-standardized risk ratios in women vs men of approximately 1.5. Although the rate of THR increased over the 5-year study period, it was significantly lower than that of total knee replacement (TKR) in Korean population (THR vs TKR 1:15.9). The prevalence of hip OA in the IVP cohort was 1.2% (1.7% for men and 0.7% for women).
Conclusion
The rate of THR was significantly lower than that of TKR in Korean population. Hip OA prevalence among the IVP subjects was 1.2%. Further studies on factors that account for the low prevalence of hip OA among Asians need to be conducted.
doi:10.1016/j.joca.2008.04.024
PMCID: PMC4373077  PMID: 18558502
Hip; Osteoarthritis; Arthroplasty; Replacement; Prevalence
21.  Imaging of cartilage and bone: promises and pitfalls in clinical trials of osteoarthritis 
summary
Imaging in clinical trials is used to evaluate subject eligibility, and/or efficacy of intervention, supporting decision making in drug development by ascertaining treatment effects on joint structure. This review focusses on imaging of bone and cartilage in clinical trials of (knee) osteoarthritis. We narratively review the full-text literature on imaging of bone and cartilage, adding primary experience in the implementation of imaging methods in clinical trials. Aims and constraints of applying imaging in clinical trials are outlined. The specific uses of semi-quantitative and quantitative imaging biomarkers of bone and cartilage in osteoarthritis trials are summarized, focusing on radiography and magnetic resonance imaging (MRI). Studies having compared both imaging methodologies directly and those having established a relationship between imaging biomarkers and clinical outcomes are highlighted. To make this review of practical use, recommendations are provided as to which imaging protocols are ideal for capturing specific aspects of bone and cartilage tissue, and pitfalls in their usage are highlighted. Further, the longitudinal sensitivity to change, of different imaging methods is reported for various patient strata. From these power calculations can be accomplished, provided the strength of the treatment effect is known. In conclusion, current imaging methodologies provide powerful tools for scoring and measuring morphological and compositional aspects of most articular tissues, capturing longitudinal change with reasonable to excellent sensitivity. When employed properly, imaging has tremendous potential for ascertaining treatment effects on various joint structures, potentially over shorter time scales than required for demonstrating effects on clinical outcomes.
doi:10.1016/j.joca.2014.06.023
PMCID: PMC4351816  PMID: 25278061
Clinical trial; Imaging; Cartilage; Bone; Recommendations
22.  BMP-2 induces ATF4 phosphorylation in chondrocytes through a COX-2/PGE2 dependent signaling pathway 
Objective
BMP-2 is approved for fracture non-union and spine fusion. We aimed to further dissect its downstream signaling events in chondrocytes with the ultimate goal to develop novel therapeutics that can mimic BMP-2 effect but have less complications.
Methods
BMP-2 effect on COX-2 expression was examined using RT-PCR and Western blot analysis. Genetic approach was used to identify the signaling pathway mediating the BMP-2 effect. Similarly, the pathway transducing the PGE2 effect on ATF4 was investigated. Immunoprecipitation was performed to assess the complex formation after PGE2 binding.
Results
BMP-2 increased COX-2 expression in primary mouse costosternal chondrocytes (PMCSC). The results from the C9 Tet-off system demonstrated that endogenous BMP-2 also upregulated COX-2 expression. Genetic approaches using PMCSC from ALK2fx/fx, ALK3fx/fx, ALK6−/−, and Smad1fx/fx mice established that BMP-2 regulated COX-2 through activation of ALK3-Smad1 signaling. PGE-2 EIA showed that BMP-2 increased PGE2 production in PMCSC. ATF4 is a transcription factor that regulates bone formation. While PGE2 did not have significant effect on ATF4 expression, it induced ATF4 phosphorylation. In addition to stimulating COX-2 expression, BMP-2 also induced phosphorylation of ATF4. Using COX-2 deficient chondrocytes, we demonstrated that the BMP-2 effect on ATF4 was COX-2-dependent. Tibial fracture samples from COX-2−/− mice showed reduced phospho-ATF4 immunoreactivity compared to WT ones. PGE2 mediated ATF4 phosphorylation involved signaling primarily through the EP2 and EP4 receptors and PGE2 induced an EP4-ERK1/2-RSK2 complex formation.
Conclusions
BMP-2 regulates COX-2 expression through ALK3-Smad1 signaling, and PGE2 induces ATF4 phosphorylation via EP4-ERK1/2-RSK2 axis.
doi:10.1016/j.joca.2013.12.020
PMCID: PMC3947583  PMID: 24418675
23.  Pharmacologic regimens for knee osteoarthritis prevention: Can they be cost-effective? 
Objective
We sought to determine the target populations and drug efficacy, toxicity, cost, and initiation age thresholds under which a pharmacologic regimen for knee osteoarthritis (OA) prevention could be cost-effective.
Design
We used the Osteoarthritis Policy (OAPol) Model, a validated state-transition simulation model of knee OA, to evaluate the cost-effectiveness of using disease modifying OA drugs (DMOADs) as prophylaxis for the disease. We assessed four cohorts at varying risk for developing OA: (1) no risk factors, (2) obese, (3) history of knee injury, and (4) high-risk (obese with history of knee injury). The base case DMOAD was initiated at age 50 with 40% efficacy in the first year, 5% failure per subsequent year, 0.22% major toxicity, and annual cost of $1,000. Outcomes included costs, quality-adjusted life expectancy, and incremental cost-effectiveness ratios (ICERs). Key parameters were varied in sensitivity analyses.
Results
For the high-risk cohort, base case prophylaxis increased quality-adjusted life-years (QALY) by 0.04 and lifetime costs by $4,600, and produced an ICER of $118,000 per QALY gained. ICERs >$150,000/QALY were observed when comparing the base case DMOAD to the standard of care in the knee injury only cohort; for the obese only and no risk factors cohorts, the base case DMOAD was less cost-effective than the standard of care. Regimens priced at $3,000 per year and higher demonstrated ICERs above cost-effectiveness thresholds consistent with current US standards.
Conclusions
The cost-effectiveness of DMOADs for OA prevention for persons at high risk for incident OA may be comparable to other accepted preventive therapies.
doi:10.1016/j.joca.2014.01.005
PMCID: PMC4006219  PMID: 24487044
disease-modifying osteoarthritis drugs; knee osteoarthritis; prophylaxis; cost-effectiveness
24.  Integrin α1β1 differentially regulates cytokine-mediated responses in chondrocytes 
Objective
To elucidate the role of integrin α1β1 in chondrocyte responses to inflammatory interleukin-1α (IL-1) and anabolic transforming growth factor-β1 (TGF-β1) in the knee.
Methods
Intracellular calcium transient responses to IL-1 and TGF-β1 were measured in wild type and integrin α1-null chondrocytes using real time ex vivo confocal microscopy and immunohistochemistry was performed to analyze TGF-β1-mediated activation of Smad2/3 in tibial and femoral chondrocytes.
Results
Loss of integrin α1β1 reduces intracellular calcium transient response to IL-1, while it enhances chondrocyte responses to TGF-β1 as measured by intracellular calcium transients and activation of downstream Smad2/3.
Conclusions
Integrin α1β1 plays a vital role in mediating chondrocyte responses to two contrasting factors that are critical players in the onset and progression of osteoarthritis - inflammatory IL-1 and anabolic TGF-β. Further investigation into the molecular mechanisms by which integrin α1β1 mediates these responses will be an important next step in understanding the influence of increased expression of integrin α1β1 during the early stages of osteoarthritis on disease progression.
doi:10.1016/j.joca.2013.12.019
PMCID: PMC4028170  PMID: 24418674
integrin α1β1; TGF-β; IL-1; chondrocyte; intracellular calcium transient; Smad2/3
25.  Age-related differences in sagittal-plane knee function at heel-strike of walking are increased in osteoarthritic patients 
Objective.
To compare age-related patterns of gait with patterns associated with knee osteoarthritis (OA), the following hypotheses were tested: H1) The sagittal-plane knee function during walking is different between younger and older asymptomatic subjects; H2) The age-related differences in H1 are increased in patients with knee OA.
Design.
Walking trials were collected for 110 participants (1.70 ± 0.09 m, 80 ± 14 kg). There were 29 younger asymptomatic subjects (29 ± 4 years) and 81 older participants (59 ± 9 years), that included 27 asymptomatic subjects and 28 and 26 patients with moderate and severe medial knee OA. Discrete variables characterizing sagittal-plane knee function were compared among the four groups using ANOVAs.
Results.
During the heel-strike portion of the gait the cycle at preferred walking speed, the knee was less extended and the shank less inclined in the three older groups compared to the younger asymptomatic group. There were similar differences between the severe OA group and the older asymptomatic and moderate OA groups. Both OA groups also had the femur less posterior relative to the tibia and smaller extension moment than the younger group. During terminal stance, the severe OA group had the knee less extended and smaller knee extension moment than the younger asymptomatic and older moderate OA groups.
Conclusions.
The differences in knee function, particularly those during heel-strike which were associated with both age and disease severity, could form a basis for looking at mechanical risk factors for initiation and progression of knee OA on a prospective basis.
doi:10.1016/j.joca.2013.12.014
PMCID: PMC4211113  PMID: 24445065
Aging; gait analysis; kinematics; kinetics; osteoarthritis

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