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1.  [No title available] 
PMCID: PMC3923977  PMID: 24316288
2.  [No title available] 
PMCID: PMC3932784  PMID: 24361743
3.  [No title available] 
PMCID: PMC3933364  PMID: 24291351
4.  [No title available] 
PMCID: PMC3939799  PMID: 24333293
5.  [No title available] 
PMCID: PMC3946188  PMID: 24269633
6.  [No title available] 
PMCID: PMC3952937  PMID: 24361793
7.  [No title available] 
PMCID: PMC3967850  PMID: 24315792
8.  Identification of cartilage injury using quantitative multiphoton microscopy 
Objective
Cartilage injury can lead to post-traumatic osteoarthritis (PTOA). Immediate post-trauma cellular and structural changes are not widely understood. Furthermore, current cellular-resolution cartilage imaging techniques require sectioning of cartilage and/or use of dyes not suitable for patient imaging. In this study, we used multiphoton microscopy (MPM) data with FDA-approved sodium fluorescein to identify and evaluate the pattern of chondrocyte death after traumatic injury.
Method
Mature equine distal metacarpal or metatarsal osteochondral blocks were injured by 30 MPa compressive loading delivered over 1 sec. Injured and control sites were imaged unfixed and in situ 1 hour post-injury with sodium fluorescein using rasterized z-scanning. MPM data was quantified in MATLAB, reconstructed in 3-D, and projected in 2-D to determine the damage pattern.
Results
MPM images (600 per sample) were reconstructed and analyzed for cell death. The overall distribution of cell death appeared to cluster into circular (n=7) or elliptical (n=4) patterns (p=0.006). Dead cells were also prevalent near cracks in the matrix, with only 26.3% (SE=5.0%, p<0.0001) of chondrocytes near cracks being viable.
Conclusion
This study demonstrates the first application of MPM for evaluating cellular-scale cartilage injury in situ in live tissue, with clinical potential for detecting early cartilage damage. With this technique, we were able to uniquely observe two death patterns resulting from the same compressive loading, which may be related to local variability in matrix structure. These results also demonstrate proof-of-concept MPM diagnostic use in detecting subtle and early cartilage damage not detectable in any other way.
doi:10.1016/j.joca.2013.10.008
PMCID: PMC4117377  PMID: 24185113
Imaging; multiphoton microscopy; cartilage; post-traumatic osteoarthritis; injury
9.  Dysregulated FOXO transcription factors in articular cartilage in aging and osteoarthritis 
Objective
Aging is a major risk factor for osteoarthritis (OA). Forkhead-box class O (FoxO) transcription factors regulate mechanisms of cellular aging, including protein quality control, autophagy and defenses against oxidative stress. The objective of this study was to analyze FoxO transcription factors in normal, aging and OA cartilage.
Design
Knee joints from humans ages 23–90 and from mice at the age of 4–24 months and following surgically induced OA were analyzed for expression of FoxO proteins. Regulation of FoxO protein expression and activation was analyzed in cultured chondrocytes.
Results
Human cartilage expressed FOXO1 and FOXO3 but not FOXO4 proteins. FOXO1 and FOXO3 were more strongly expressed the superficial and mid zone as compared to the deep zone and were mainly localized in nuclei. During human joint aging, expression of FOXO1 and FOXO3 was markedly reduced in the superficial zone of cartilage regions exposed to maximal weight bearing. In OA cartilage, chondrocyte clusters showed strong FOXO phosphorylation and cytoplasmic localization. Similar patterns of FOXO expression in normal joints and changes in aging and OA were observed in mouse models. In cultured chondrocytes, IL-1β and TNF-α suppressed FOXO1, while TGF-β and PDGF increased FOXO1 and FOXO3 expression. FOXO1 and FOXO3 phosphorylation was increased by IL-1β, PDGF, bFGF, IGF-1, and the oxidant t-BHP.
Conclusions
Normal articular cartilage has a tissue specific signature of FoxO expression and activation and this is profoundly altered in aging and OA in humans and mice. Changes in FoxO expression and activation may be involved in cartilage aging and OA.
doi:10.1016/j.joca.2013.11.004
PMCID: PMC3932989  PMID: 24269635
FoxO; Cartilage; Osteoarthritis; Aging
10.  Longitudinal evaluation of T1ρ and T2 spatial distribution in osteoarthritic and healthy medial knee cartilage 
SUMMARY
Objective
To investigate longitudinal changes in laminar and spatial distribution of knee articular cartilage magnetic resonance imaging (MRI) T1ρ and T2 relaxation times, in individuals with and without medial compartment cartilage defects.
Design
All subjects (at baseline n = 88, >18 years old) underwent 3-Tesla knee MRI at baseline and annually thereafter for 3 years. The MR studies were evaluated for presence of cartilage defects (modified Whole-Organ Magnetic Resonance Imaging Scoring – mWORMS), and quantitative T1ρ and T2 relaxation time maps. Subjects were segregated into those with (mWORMS ≥2) and without (mWORMS ≤1) cartilage lesions at the medial tibia (MT) or medial femur (MF) at each time point. Laminar (bone and articular layer) and spatial (gray level co-occurrence matrix – GLCM) distribution of the T1ρ and T2 relaxation time maps were calculated. Linear regression models (cross-sectional) and Generalized Estimating Equations (GEEs) (longitudinal) were used.
Results
Global T1ρ, global T2 and articular layer T2 relaxation times at the MF, and global and articular layer T2 relaxation times at the MT, were higher in subjects with cartilage lesions compared to those without lesions. At the MT global T1ρ relaxation times were higher at each time point in subjects with lesions. MT T1ρ and T2 became progressively more heterogeneous than control compartments over the course of the study.
Conclusion
Spatial distribution of T1ρ and T2 relaxation time maps in medial knee OA using GLCM technique may be a sensitive indicator of cartilage deterioration, in addition to whole-compartment relaxation time data.
doi:10.1016/j.joca.2013.10.014
PMCID: PMC3934359  PMID: 24188868
GLCM; Texture; Quantitative MRI; Cartilage defects; Laminar
11.  Pre-radiographic osteoarthritic changes are highly prevalent in the medial patella and medial posterior femur in older persons: Framingham OA Study 
Objective
To determine which subregions of the knee joint have a high prevalence of pre-radiographic osteoarthritic changes, i.e. cartilage damage and osteophytes that can only be detected by MRI, in radiographically normal knees.
Methods
Institutional review board approval and written informed consent from all participants was obtained. Data was collected from a community cohort in Framingham, MA, involving people aged 50–79. Participants underwent weight-bearing posteroanterior and lateral knee radiography with the fixed-flexion protocol, and 1.5T MRI. Knees without radiographic osteoarthritis (Kellgren Lawrence grade 0 for the tibiofemoral joint and absence of any osteophytes or joint space narrowing in the patellofemoral joint) were included. The knee joint was divided into 14 subregions for cartilage and 16 subregions for osteophytes, and prevalence and severity of cartilage damage (grade 0–6) and osteophytes (grade 0–7) were semiquantitatively assessed using the Whole Organ Magnetic Resonance Imaging Score.
Results
The mean age of 696 participants was 62.3±8.4 years, and the mean body mass index was 27.9±5.1 kg/m2. Women comprised 55.2% of the study sample (384/696). Prevalence of cartilage damage (grade ≥2) was 47.7% (332/696) in the medial patellar and 29.9% (208/696) in patellar lateral subregions, and 24.0% (167/696) in femoral medial anterior and 26.5% (184/696) in femoral medial central subregions. Prevalence of osteophytes (grade ≥2) was highest at 60.8% (423/696) in the medial femoral posterior subregion, followed by 34.0% (237/696) in patellar lateral and 24.6% (171/696) in patellar medial subregions. For all other subregions, prevalence of these lesions was lower than the aforementioned percentages.
Conclusion
MRI-detected cartilage damage and osteophytes are highly prevalent in the medial patellofemoral and medial posterior tibiofemoral joints in radiographically normal knees in persons aged 50–79.
doi:10.1016/j.joca.2013.10.007
PMCID: PMC3947221  PMID: 24185108
12.  Oral and topical boswellic acid attenuates mouse osteoarthritis 
Objective
Boswellic acid is a plant-derived molecule with putative anti-inflammatory effects. This study was performed to determine whether oral or topical administration of boswellic acid can attenuate joint damage in a mouse model of osteoarthritis (OA).
Methods
Levels of boswellic acid were measured in the blood and synovium of mice treated with oral or topical boswellic acid. OA was generated by surgical destabilization of the medial meniscus (DMM). Therapy with oral or topical boswellic acid was initiated one day after surgery and continued for 12 weeks, when knees were harvested and scored histologically for degree of cartilage loss, osteophyte formation, and synovitis. Microdissected OA synovium was stimulated with IL-1β or lipopolysaccharide (LPS) in the presence or absence of boswellic acid and cytokine production by quantitative polymerase chain reaction (PCR) or multiplex enzyme linked immunoabsorbant assay (ELISA).
Results
Topical treatment resulted in synovial concentrations of boswellic acid 2–6-fold higher than that measured in plasma. Cartilage loss was significantly reduced in mice treated with oral or topical boswellic acid compared with vehicle control (P < 0.01 for both oral and topical therapies). Likewise, treatment with either oral boswellic acid or boswellic acid ointment reduced of synovitis (P = 0.006 and 0.025, respectively) and osteophyte formation (P = 0.009 and 0.030, respectively). In vitro, boswellic acid was able to inhibit IL-1β and TLR4 mediated induction of several inflammatory mediators from OA synovial explant tissue.
Conclusions
Significant synovial concentration and therapeutic efficacy can be achieved with topical boswellic acid treatment. These findings suggest that boswellic acid has potential as a disease-modifying agent in OA.
doi:10.1016/j.joca.2013.10.012
PMCID: PMC3992997  PMID: 24185109
Osteoarthritis; Disease modifying anti-osteoarthritis drugs; Topical therapy summary
13.  Lateral and Medial Joint Space Narrowing Predict Subsequent Cartilage Loss in the Narrowed, but not in the Non-narrowed Femorotibial Compartment - Data from the Osteoarthritis Initiative 
Objective
To determine the predictive value of unicompartimental joint space narrowing (JSN) for MRI-based cartilage thickness loss in the narrowed and the non-narrowed femorotibial compartment.
Methods
922 knees from 922 Osteoarthritis Initiative participants (62.2±9.0 years, , 61% females) with radiographic osteoarthritis (158 without JSN [noJSN], 175 with lateral JSN [latJSN], 589 with medial JSN [medJSN]) were analyzed using 3T MRI. One-year cartilage thickness change was determined in the lateral (LFTC) and medial femorotibial compartment (MFTC), and in femorotibial subregions. The probability of subsequent cartilage loss was calculated using predefined thresholds. The predictive value of JSN for the probability and magnitude of cartilage loss was compared between latJSN, medJSN and noJSN knees using Fisher's exact and Mann-Whitney-U tests.
Results
The probability of cartilage loss was greater in the narrowed compartment of latJSN /medJSN knees (34.9%/32.4%) than in noJSN knees (13.3%/12.7%, p≤6.4×10−6) and so was the magnitude of cartilage thickness change (p≤8.2×10−6). No significant differences were observed between the narrowed compartments of latJSN vs. medJSN knees (probability: p=0.58, magnitude: p=0.19) or between the non-narrowed compartment of latJSN/medJSN vs. noJSN knees (probability: p≥0.35, magnitude: p=≥0.23). These results were confirmed by the location-independent ordered value analyses of femorotibial subregions.
Conclusion
The predictive value of latJSN for lateral compartment cartilage loss was comparable to that of medJSN for medial compartment cartilage loss, whereas cartilage loss in the non-narrowed compartment was similar to that in noJSN knees. These findings provide important clues to predicting progression of knee OA, and in tailoring inclusion criteria for clinical trials.
doi:10.1016/j.joca.2013.10.011
PMCID: PMC4054605  PMID: 24185111
Magnetic resonance imaging; Knee osteoarthritis; lateral joint space narrowing; cartilage loss; cartilage thickness
14.  [No title available] 
PMCID: PMC4291455  PMID: 25450852
15.  Nerve growth factor: an update on the science and therapy 
SUMMARY
Objective
Nerve growth factor (NGF) is a key regulator of nociceptive pain and thus appears to be an interesting target molecule for an innovative class of analgesic medication. We set out to review the principles of neurogenic inflammation and results of anti-NGF regimens in animal studies as well as clinical trials with patients with back pain and osteoarthritis (OA).
Design
We searched using Google Scholar Search and Pubmed as well as through conference reports for articles and abstracts related to NGF and clinical trials using anti-NGF regimens. We report on efficacy findings and adverse events (AEs) related to these agents in this review.
Results
We identified five full articles and eight abstract reports relating to anti-NGF agents studied for use in back pain and in OA.
Conclusions
Anti-NGF agents either alone or in combination with non-steroidal anti-inflammatory agents (NSAIDs) were more efficacious for the treatment of pain in a number of trials of knee and hip pain compared to NSAIDs alone. However, adverse effects that included rapidly progressive OA and joint replacement were more common in patients treated with anti-NGF and NSAIDs than either treatment alone. Anti-NGF treatment related neurologic symptoms including paresthesias, and potentially other types of adverse effects were usually transient but warrant additional investigation.
doi:10.1016/j.joca.2013.06.004
PMCID: PMC4252012  PMID: 23973134
Neurogenic inflammation; Nerve growth factor; Receptor antagonists; Osteoarthitis
16.  The association of parity with osteoarthritis and knee replacement in the Multicenter Osteoarthritis Study 
Objective
We evaluated the association of parity to both risk of knee replacement (KR) and knee osteoarthritis (OA).
Design
The NIH-funded Multicenter Osteoarthritis Study (MOST) is a longitudinal observational study of persons age 50 to 79 years with either symptomatic knee OA or at elevated risk of disease. Baseline and 30-month knee radiographic OA (ROA) was defined as Kellgren/Lawrence (K/L) grade≥2 or KR. Women were grouped based by number of births: 0; 1 (reference group); 2; 3; 4; and 5 or more. We examined the relation of parity to the incidence over 30 months of ROA and KR using a Poisson regression model. Generalized estimating equations were used to control for correlation between two knees within a subject. We adjusted for age, BMI, race, education, occupation, baseline estrogen use, clinical site, injury, and for KR analyses WOMAC pain and use of pain medication.
Results
Among 1618 women who reported parity information, mean age was 62.6 years, mean BMI 30.7 kg/m2, mean WOMAC pain subscale score 3.7 at baseline. There were 115 KRs and 134 cases of incident knee ROA over 30 months. The relative risk of incident KR was 2.7 times as high (95% CI: 1.0, 7.3) and relative risk of incident knee ROA was 2.6 times as high (95% CI: 1.2, 5.3) among women with 5–12 children compared with those with one birth.
Conclusion
Parity in women at risk for OA is associated with both incident ROA and KR, particularly for those with more than 4 children.
doi:10.1016/j.joca.2013.08.025
PMCID: PMC3855897  PMID: 24029601
parity; knee; osteoarthritis; joint replacement
17.  Moderate Dynamic Compression Inhibits Pro-Catabolic Response of Cartilage to Mechanical Injury, TNF-α and IL-6, but Accentuates Degradation Above a Strain Threshold 
Objective
Traumatic joint injury can initiate early cartilage degeneration in the presence of elevated inflammatory cytokines (e.g., TNF-α and IL-6). The positive/negative effects of post-injury dynamic loading on cartilage degradation and repair in vivo is not well-understood. This study examined the effects of dynamic strain on immature bovine cartilage in vitro challenged with TNF-α + IL-6 and its soluble receptor (sIL-6R) with/without initial mechanical injury.
Methods
Groups of mechanically injured or non-injured explants were cultured in TNF-α + IL-6/sIL-6R for 8 days. Intermittent dynamic compression was applied concurrently at 10%, 20%, or 30% strain amplitude. Outcome measures included sGAG loss (DMMB), aggrecan biosynthesis (35S-incorporation), aggrecanase activity (Western blot), chondrocyte viability (fluorescence staining) and apoptosis (nuclear blebbing via light microscopy), and gene expression (qPCR).
Results
In bovine explants, cytokine-alone and injury-plus-cytokine treatments markedly increased sGAG loss and aggrecanase activity, and induced chondrocyte apoptosis. These effects were abolished by moderate 10% and 20% strains. However, 30% strain-amplitude greatly increased apoptosis and had no inhibitory effect on aggrecanase activity. TNF+IL-6/sIL-6R downregulated matrix gene expression and upregulated expression of inflammatory genes, effects that were rescued by moderate dynamic strains but not by 30% strain.
Conclusions
Moderate dynamic compression inhibits the pro-catabolic response of cartilage to mechanical injury and cytokine challenge, but there is a threshold strain-amplitude above which loading becomes detrimental to cartilage. Our findings support the concept of appropriate loading for post-injury rehabilitation.
doi:10.1016/j.joca.2013.08.021
PMCID: PMC3855909  PMID: 24007885
Dynamic Compression; Cartilage; Injury; Cytokines; Apoptosis; Rehabilitation post-injury
18.  Micromechanical Mapping of Early Osteoarthritic Changes in the Pericellular Matrix of Human Articular Cartilage 
Objective
Osteoarthritis (OA) is a degenerative joint disease characterized by the progressive loss of articular cartilage. While macroscale degradation of the cartilage extracellular matrix (ECM) has been extensively studied, microscale changes in the chondrocyte pericellular matrix (PCM) and immediate microenvironment with OA are not fully understood. The objective of this study was to quantify osteoarthritic changes in the micromechanical properties of the ECM and PCM of human articular cartilage in situ using atomic force microscopy (AFM).
Method
AFM elastic mapping was performed on cryosections of human cartilage harvested from both condyles of macroscopically normal and osteoarthritic knee joints. This method was used to test the hypotheses that both ECM and PCM regions exhibit a loss of mechanical properties with OA and that the size of the PCM is enlarged in OA cartilage as compared to normal tissue.
Results
Significant decreases were observed in both ECM and PCM moduli of 45% and 30%, respectively, on the medial condyle of OA knee joints as compared to cartilage from macroscopically normal joints. Enlargement of the PCM, as measured biomechanically, was also observed in medial condyle OA cartilage, reflecting the underlying distribution of type VI collagen in the region. No significant differences were observed in elastic moduli or their spatial distribution on the lateral condyle between normal and OA joints.
Conclusion
Our findings provide new evidence of significant site-specific degenerative changes in the chondrocyte micromechanical environment with OA.
doi:10.1016/j.joca.2013.08.026
PMCID: PMC3856176  PMID: 24025318
Atomic force microscopy; chondron; type VI collagen; scanning probe microscopy; proteoglycan
19.  Loss of Extracellular Matrix from Articular Cartilage is Mediated by the Synovium and Ligament after Anterior Cruciate Ligament Injury 
Objective
Post-traumatic osteoarthritis (PTOA) occurs after anterior cruciate ligament (ACL) injury. PTOA may be initiated by early expression of proteolytic enzymes capable of causing degradation of the articular cartilage at time of injury. This study investigated the production of three of these key proteases in multiple joint tissues after ACL injury and subsequent markers of cartilage turnover.
Design
ACL transection was performed in adolescent minipigs. Collagenase (MMP-1 and MMP-13) and aggrecanase (ADAMTS-4) gene expression changes were quantified in the articular cartilage, synovium, injured ligament, and the provisional scaffold at days 1, 5, 9, and 14 post-injury. Markers of collagen degradation (C2C), synthesis (CPII) and aggrecan synthesis (CS846) were quantified in the serum and synovial fluid. Histologic assessment of the cartilage integrity (OARSI scoring) was also performed.
Results
MMP-1 gene expression was upregulated in the articular cartilage, synovium and ligament after ACL injury. MMP-13 expression was suppressed in the articular cartilage, but upregulated 100fold in the synovium and ligament. ADAMTS-4 was upregulated in the synovium and ligament but not in the articular cartilage. The concentration of collagen degradation fragments (C2C) in the synovial joint fluid nearly doubled in the first five days after injury.
Conclusion
We conclude that upregulation of genes coding for proteins capable of degrading cartilage ECM is seen within the first few days after ACL injury, and this response is seen not only in chondrocytes, but also in cells in the synovium, ligament and provisional scaffold.
doi:10.1016/j.joca.2013.09.003
PMCID: PMC3917322  PMID: 24036379
Cartilage; metalloproteinases; aggrecanase; ACL; joint tissues
20.  Pain trajectory groups in persons with, or at high risk of, knee osteoarthritis: findings from the Knee Clinical Assessment Study and the Osteoarthritis Initiative 
Osteoarthritis and Cartilage  2014;22(12):2041-2050.
Summary
Objective
The authors aimed to characterize distinct trajectories of knee pain in adults who had, or were at high risk of, knee osteoarthritis using data from two population-based cohorts.
Method
Latent class growth analysis was applied to measures of knee pain severity on activity obtained at 18-month intervals for up to 6 years between 2002 and 2009 from symptomatic participants aged over 50 years in the Knee Clinical Assessment Study (CAS-K) in the United Kingdom. The optimum latent class growth model from CAS-K was then tested for reproducibility in a matched sample of participants from the Osteoarthritis Initiative (OAI) in the United States.
Results
A 5-class linear model produced interpretable trajectories in CAS-K with reasonable goodness of fit and which were labelled “Mild, non-progressive” (N = 201, 35%), “Progressive” (N = 162, 28%), “Moderate” (N = 124, 22%) “Improving” (N = 68, 12%), and “Severe, non-improving” (N = 15, 3%). We were able to reproduce “Mild, non-progressive”, “Moderate”, and “Severe, non-improving” classes in the matched sample of participants from the OAI, however, absence of a “Progressive” class and instability of the “Improving” classes in the OAI was observed.
Conclusions
Our findings strengthen the grounds for moving beyond a simple stereotype of osteoarthritis as “slowly progressive”. Mild, non-progressive or improving symptom trajectories, although difficult to reproduce, can nevertheless represent a genuinely favourable prognosis for a sizeable minority.
doi:10.1016/j.joca.2014.09.026
PMCID: PMC4256061  PMID: 25305072
Knee; Pain; Latent class growth analysis; Longitudinal; Osteoarthritis; Trajectories; ABIC, sample-size adjusted Bayesian information criterion; AIC, Akaike information criterion; BIC, Bayesian information criterion; B-LRT, Bootstrap likelihood ratio test; CAS-K, knee clinical assessment study; OAI, osteoarthritis initiative; VLMR-LRT, Viong-Lo-Mendall-Rubin likelihood ratio test; WOMAC, Western Ontario & McMaster Universities Osteoarthritis Index
21.  Interleukin 6 Mediates Select Effects of Notch in Chondrocytes 
Objective
Notch receptors determine cell fate by regulating transcription, an event mediated by the Notch intracellular domain (NICD), which is generated by proteolysis brought about by Notch-ligand interactions. Since Notch activation or exposure to interleukin (Il)6 have similar effects in chondrocytes, we explored whether Il6 contributes to the mechanisms of Notch action in these cells.
Method
NICD was overexpressed in primary chondrocytes from RosaNotch mice, where the Rosa26 promoter precedes a loxP-flanked STOP cassette followed by the NICD coding sequence. Cells were infected with adenoviral vectors expressing Cre to induce NICD or green fluorescent protein as control. Gene expression was determined by quantitative reverse-transcription polymerase chain reaction. Il6 protein concentration in the culture media was determined by enzyme-linked immunosorbent assay. To test the mechanisms of Notch action on Il6 expression, cells were transfected with a fragment of the Il6 promoter or control vector pGL3, or transcriptionally arrested with 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole. Il6 was inhibited with a neutralizing antibody, whereas a normal immunoglobulin G was used as control.
Results
NICD induced Il6 mRNA and protein, and transactivated the Il6 promoter without affecting Il6 mRNA stability. Il6 neutralization had no impact on gene expression under basal conditions, and did not modify the effects of NICD on sex determining region-Y-related high mobility group-box gene 9, collagen type II α1 and collagen type X α1 expression. Conversely, Il6 neutralization opposed aggrecan (Acan) suppression and prevented matrix metalloprotease (Mmp)13 induction by NICD.
Conclusion
Il6 mediates suppression of Acan and induction of Mmp13 expression by Notch in chondrocytes.
doi:10.1016/j.joca.2013.08.010
PMCID: PMC3795792  PMID: 23954701
Notch; Mmp13; Il6; Col10a1; Acan; chondrocytes
22.  HIGH PREVALENCE OF CONTRALATERAL ANKLE ABNORMALITIES IN ASSOCIATION WITH KNEE OSTEOARTHRITIS AND MALALIGNMENT 
Objective
To evaluate ankle joint abnormalities in a knee osteoarthritis (OA) cohort.
Methods
Participants (n=159) with symptomatic and radiographic OA in at least one knee underwent technetium-99m methylene diphosphonate bone scan (scored 0–3) of the ankles and forefeet. Knee radiographs were graded for OA features of joint space narrowing (JSN) and osteophyte (OST). Ankle symptoms and history of ankle injury were assessed by self-report. Knee alignment was measured from a long-limb radiograph. Ankle radiographs were obtained on those who returned for follow-up (n=138) and were graded for ankle tibiotalar JSN and OST.
Design
Ankle scintigraphic abnormalities were frequent (31% of individuals, one-third bilateral). Ankle symptoms were reported by 23% of individuals and history of ankle injury by 24%. Controlling for gender, age, BMI, and contralateral predictor, ankle scintigraphic abnormalities were associated with: ipsilateral ankle symptoms (P=0.005); contralateral knee JSN (P=0.001), knee OST (P=0.006) and knee malalignment (P=0.08); and history of ankle injury or surgery of either ankle (P<0.0001). At follow-up, scintigraphic abnormalities of the ankle were strongly associated with presence of tibiotalar radiographic OA (P<0.0001).
Conclusions
Although considered rare, we observed a high prevalence of radiographic features of ankle OA in this knee OA cohort. History of overt ankle injury did not appear to account for the majority of ankle abnormalities. These results are consistent with a probable kinematic association of knee OA pathology and contralateral ankle abnormalities and suggest that interventions targeting mechanical factors may be needed to prevent ankle OA in the setting of knee OA.
doi:10.1016/j.joca.2013.07.008
PMCID: PMC3795812  PMID: 23867580
osteoarthritis; ankle; knee; scintigraphy; alignment
23.  Association of Cartilage Defects, and other MR Findings with Pain and Function in Individuals with Mild-Moderate Radiographic Hip Osteoarthritis and Controls 
Objective
To evaluate the relationship of hip radiographic osteoarthritis (ROA) and MR findings of cartilage lesions, labral tears, bone marrow edema like lesions (BMEL) and subchondral cysts with self-reported and physical function.
Design
Eighty five subjects were classified as controls (n= 55, KL 0, 1) or having mild-moderate ROA (n = 30, KL 2, 3). T2-weighted MR images at 3-Tesla were graded for presence of cartilage lesions, labral tears, BMELs and subchondral cysts. Posterior wall sign, cross-over sign, center-edge angle and alpha angle were also recorded. Function was assessed using Hip Osteoarthritis Outcome Score (HOOS), Timed-Up and Go (TUG) test and Y-Balance Test (YBT). Analysis compared function between subjects with and without ROA and those with and without femoral or acetabular cartilage lesions, adjusted for age. Non-parametric correlations were used to assess the relationship between radiographic scores, MR scores and function.
Results
Subjects with acetabular cartilage lesions had worse HOOS (Difference = 5–10%, P = 0.036–0.004), but not TUG or YBT, scores. Acetabular cartilage lesions, BMELs and subchondral cysts were associated with worse HOOS scores (ρ= 0.23–0.37, P = 0.041–0.001). Differences in function between subjects with and without ROA or femoral cartilage lesions were not significant. Other radiologic findings were not associated with function.
Conclusions
Acetabular cartilage defects, but not femoral cartilage defects or ROA, were associated with greater self-reported pain and disability. BMELs and subchondral cysts were related to greater hip related self-reported pain and disability. None of the radiographic or MR features were related to physical function.
doi:10.1016/j.joca.2013.08.009
PMCID: PMC3804140  PMID: 23948977
BMEL; subchondral cyst; Kellgren-Lawrence; Balance; Y-Balance Test; Labral tears
24.  Articular Osteochondrosis: A Comparison of Naturally-Occurring Human and Animal Disease 
Background
Osteochondrosis (OC) is a common developmental orthopedic disease affecting both humans and animals. Despite increasing recognition of this disease among children and adolescents, its pathogenesis is incompletely understood because clinical signs are often not apparent until lesions have progressed to end-stage, and examination of cadaveric early lesions is not feasible. In contrast, both naturally-occurring and surgically-induced animal models of disease have been extensively studied, most notably in horses and swine, species in which OC is recognized to have profound health and economic implications. The potential for a translational model of human OC has not been recognized in the existing human literature.
Objective
The purpose of this review is to highlight the similarities in signalment, predilection sites and clinical presentation of naturally-occurring OC in humans and animals and to propose a common pathogenesis for this condition across species.
Study Design
Review
Methods
The published human and veterinary literature for the various manifestations of OC was reviewed. Peer-reviewed original scientific articles and species-specific review articles accessible in PubMed (US National Library of Medicine) were eligible for inclusion.
Results
A broad range of similarities exists between OC affecting humans and animals, including predilection sites, clinical presentation, radiographic/MRI changes, and histological appearance of the end stage lesion, suggesting a shared pathogenesis across species.
Conclusion
This proposed shared pathogenesis for OC between species implies that naturally-occurring and surgically-induced models of OC in animals may be useful in determining risk factors and for testing new diagnostic and therapeutic interventions that can be used in humans.
doi:10.1016/j.joca.2013.08.011
PMCID: PMC3815567  PMID: 23954774
osteochondrosis; osteochondritis dissecans; articular-epiphyseal cartilage complex; endochondral ossification; translational model; pathogenesis
25.  Varus Thrust and Knee Frontal Plane Dynamic Motion in Persons with Knee Osteoarthritis 
Objective
Varus thrust visualized during walking is associated with a greater medial knee and an increased risk of medial knee osteoarthritis (OA) progression. Little is known about varus thrust presence determined by visual observation relates to quantitative gait kinematic We hypothesized that varus thrust presence is associated with greater knee frontal plane dynamic movement during the stance phase of gait.
Methods
Participants had knee OA in at least one knee. Trained examiners assessed participants for varus thrust presence during ambulation. Frontal plane knee motion during ambulation captured using external passive reflective markers and an 8-camera motion analysis system. To examine the cross-sectional relationship between varus thrust and frontal plane knee motion, used multivariable regression models with the quantitative motion measures as dependent variables and varus thrust (present/absent) as predictor; models were adjusted for age, gender, BMI, gait speed, and knee static alignment.
Results
236 persons [mean BMI: 28.5 kg/m2 (SD 5.5), mean age: 64.9 years (SD 10.4), 75.8% women] contributing 440 knees comprised the study sample. 82 knees (18.6%) had definite varus thrust. Knees with varus thrust had greater peak varus angle and greater peak varus angular velocity during stance than knees without varus thrust (mean differences 0.90° and 6.65°/sec, respectively). These patterns remained significant after adjusting for age, gender, BMI, gait speed, and knee static alignment.
Conclusion
Visualized varus thrust during walking was associated with a greater peak knee varus angular velocity and a greater peak knee varus angle during stance phase of gait.
doi:10.1016/j.joca.2013.08.007
PMCID: PMC4014355  PMID: 23948980
Knee osteoarthritis; Instability; Varus thrust; Gait analysis

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