Osteoarthritis and Cartilage

Osteoarthritis histopathology grading criteria – a never ending story?

Thomas Aigner — 2012-03-19

Mankin and colleagues have written one of the most extraordinary papers ever published more than 20000 times cited since its publication in 1971. This not because of the doubtless scientific merits of this paper or its main author, but because this paper presented a simple, to some extent biologically intuitive grading system of osteoarthritic cartilage changes, which has not had any competitive alternative since 40years. However, this grading system never received textbook status: thus, everybody felt it necessary to keep citing it because people kept modifying and criticizing it. The new paper by Pauli and colleagues published in this volume of Osteoarthritis and Cartilage continues in this tradition, so Mankin et al. 1971 will presumably remain the evergreen of osteoarthritis research in at least the near future. In this new paper, the Mankin score is compared to a scoring system recently proposed by Pritzker and colleagues, which was suggested to be more reliable and appropriate than Mankin’s system.

UTE T2∗ mapping detects sub-clinical meniscus degeneration

E.J. McWalter, G.E. Gold — 2012-04-05

The meniscus is increasingly being recognized as an important tissue in knee osteoarthritis (OA). We know that individuals who have undergone meniscectomy are at least 2.6 times more likely to develop knee OA within 22years and that, by the time end-stage lateral knee OA is reached, complete maceration or resection of the meniscus has occurred in approximately 50% of cases. However, relatively little is known about early stage meniscal degeneration, before tears, extrusion, myxoid degeneration, maceration or resection occurs because, until recently, the tools necessary to directly image the meniscus have not been available.

Repeated measurements, bilateral observations and pseudoreplicates, why does it matter?

J. Ranstam — 2012-04-05

Summary: A common requirement of statistical methods, critical to the interpretation of the data, is that the analyzed observations are independent. This is not always the case in experiments and clinical studies, a mistake which can be expected to lead to erroneous study results. The phenomenon is explained, its consequences described, and suggestions to avoid the problems presented.

Comparison of cartilage histopathology assessment systems on human knee joints at all stages of osteoarthritis development

2012-03-19

Abstract: Objective: To compare the MANKIN and OARSI cartilage histopathology assessment systems using human articular cartilage from a large number of donors across the adult age spectrum representing all levels of cartilage degradation.Design: Human knees (n=125 from 65 donors; age range 23–92) were obtained from tissue banks. All cartilage surfaces were macroscopically graded. Osteochondral slabs representing the entire central regions of both femoral condyles, tibial plateaus, and the patella were processed for histology and Safranin O – Fast Green staining. Slides representing normal, aged, and osteoarthritis (OA) tissue were scanned and electronic images were scored online by five observers. Statistical analysis was performed for inter- and intra-observer variability, reproducibility and reliability.Results: The inter-observer variability among five observers for the MANKIN system showed a similar good Intra-class correlation coefficient (ICC>0.81) as for the OARSI system (ICC>0.78). Repeat scoring by three of the five readers showed very good agreement (ICC>0.94). Both systems showed a high reproducibility among four of the five readers as indicated by the Spearman’s rho value. For the MANKIN system, the surface represented by lesion depth was the parameter where all readers showed an excellent agreement. Other parameters such as cellularity, Safranin O staining intensity and tidemark had greater inter-reader disagreement.Conclusion: Both scoring systems were reliable but appeared too complex and time consuming for assessment of lesion severity, the major parameter determined in standardized scoring systems. To rapidly and reproducibly assess severity of cartilage degradation, we propose to develop a simplified system for lesion volume.

UTE-T2∗ mapping detects sub-clinical meniscus injury after anterior cruciate ligament tear

A. Williams, Y. Qian, S. Golla, C.R. Chu — 2012-02-23

Summary: Objective: Meniscus tear is a known risk factor for osteoarthritis (OA). Quantitative assessment of meniscus degeneration, prior to surface break-down, is important to identification of early disease potentially amenable to therapeutic interventions. This work examines the diagnostic potential of ultrashort echo time-enhanced T2∗ (UTE-T2∗) mapping to detect human meniscus degeneration in vitro and in vivo in subjects at risk of developing OA.Design: UTE-T2∗ maps of 16 human cadaver menisci were compared to histological evaluations of meniscal structural integrity and clinical magnetic resonance imaging (MRI) assessment by a musculoskeletal radiologist. In vivo UTE-T2∗ maps were compared in 10 asymptomatic subjects and 25 ACL-injured patients with and without concomitant meniscal tear.Results: In vitro, UTE-T2∗ values tended to be lower in histologically and clinically normal meniscus tissue and higher in torn or degenerate tissue. UTE-T2∗ map heterogeneity reflected collagen disorganization. In vivo, asymptomatic meniscus UTE-T2∗ values were repeatable within 9% (root-mean-square average coefficient of variation). Posteromedial meniscus UTE-T2∗ values in ACL-injured subjects with clinically diagnosed medial meniscus tear (n=10) were 87% higher than asymptomatics (n=10, P<0.001). Posteromedial menisci UTE-T2∗ values of ACL-injured subjects without concomitant medial meniscal tear (n=15) were 33% higher than asymptomatics (P=0.001). Posterolateral menisci UTE-T2∗ values also varied significantly with degree of joint pathology (P=0.001).Conclusion: Significant elevations of UTE-T2∗ values in the menisci of ACL-injured subjects without clinical evidence of subsurface meniscal abnormality suggest that UTE-T2∗ mapping is sensitive to sub-clinical meniscus degeneration. Further study is needed to determine whether elevated subsurface meniscus UTE-T2∗ values predict progression of meniscal degeneration and development of OA.

Weight loss is effective for symptomatic relief in obese subjects with knee osteoarthritis independently of joint damage severity assessed by high-field MRI and radiography

2012-03-27

Summary: Objective: With an increasing prevalence of older and obese citizens, the problems of knee osteoarthritis (KOA) will escalate. Weight loss is recommended for obese KOA patients and in a majority of cases this leads to symptomatic relief. We hypothesized that pre-treatment structural status of the knee joint, assessed by radiographs, 1.5 T magnetic resonance imaging (MRI) and knee-joint alignment, may influence the symptomatic changes following a significant weight reduction.Design: Patients were recruited from a Department of Rheumatology. Eligibility criteria were age above 50 years, body mass index ≥30 kg/m2, primary KOA diagnosed according to the American College of Rheumatology (ACR) criteria and having verified structural damage. Patients underwent a 16 weeks dietary programme with formula products and counselling. MRI and radiographs of the most symptomatic knee were obtained at baseline and assessed for structural damage using the Boston-Leeds Osteoarthritis of the Knee Score, minimum joint space width and Kellgren–Lawrence score. Imaging variables, muscle strength and degree of alignment, were examined as predictors of changes in Knee Osteoarthritis Outcome Score (KOOS) and Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) - Osteoarthritis Research Society International (OARSI) Responder Criterion.Results: Structural damage at baseline assessed by imaging, muscle strength or knee-joint alignment showed no statistically significant association to changes in KOOS pain and function in daily living (r ≤ 0.13; P > 0.05) or the OMERACT-OARSI Responder Criterion (OR 0.48–1.68; P-values ≥ 0.13).Conclusions: Presence of joint damage did not preclude symptomatic relief following a clinically relevant weight loss in older obese patients with KOA. Neither muscle strength nor knee-joint alignment was associated with the degree of symptomatic relief.

The course of limitations in activities over 5 years in patients with knee and hip osteoarthritis with moderate functional limitations: risk factors for future functional decline

M.F. Pisters, C. Veenhof, G.M. van Dijk, M.W. Heymans, J.W.R. Twisk, J. Dekker — 2012-04-12

Summary: Objective: To describe the course of limitations in activities over 5 years follow-up and identify predictors of future limitations in activities in elderly patients with osteoarthritis (OA) of the hip or knee with moderate functional limitations.Method: A longitudinal cohort study with 5 years follow-up was conducted. Patients (n = 288) were recruited at rehabilitation centers and hospitals. The main outcome measures were self-reported and performance-based limitations in activities. Prognostic factors were demographic and clinical data, body functions, comorbidity, cognitive functioning, avoidance of activity and social support. Measurements were conducted at baseline, 1, 2, 3 and 5 years follow-up.Results: Both in patients with knee and hip OA, the course of limitations in activities remained fairly stable over a period of 5 years. Avoidance of activity, increased pain, more comorbidity, a higher age, a longer disease duration, a reduced muscle strength and range of joint motion at baseline predicted more future limitations in activities in patients with knee OA. In patients with hip OA, avoidance of activity, increased pain, more comorbidity, a higher age, a higher educational level and a reduced range of motion at baseline predicted more future limitations in activities.Conclusions: The course of limitations in activities remains fairly stable over a period of 5 years in elderly patients with hip or knee OA. However, at individual level there is considerable variation. Predictors of more future limitations in activities include avoidance of activity, increased pain, higher morbidity count, reduced range of motion, and a higher age.

Delineating the impact of obesity and its relationship on recovery after total joint arthroplasties

C.A. Jones, V. Cox, G.S. Jhangri, M.E. Suarez-Almazor — 2012-04-05

Summary: Objective: The primary aim of this study was to determine the impact of obesity in predicting short and long-term pain relief and functional recovery in total joint arthroplasty (TJA) either as an independent risk factor or a factor mediated by two chronic conditions associated with obesity-cardiac disease and diabetes mellitus.Method: A prospective observational study of 520 patients with primary joint arthroplasties. Pain and functional outcomes were evaluated with the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index within a month of surgery and then 6months and 3years post-operatively. Obesity, cardiac disease and diabetes mellitus were examined as potential risk factors for poor recovery. Patients were classified into four groups based on body mass index (BMI): (normal<25.0 kg/m2; overweight 25.0–29.9 kg/m2; obese Class 1 30.0–34.9 kg/m2; severe obese Class 2&3 35.0 ≥ kg/m2). Linear mixed models for each joint type (hip and knee arthroplasty) were developed to examine the pattern of recovery and the effect of obesity.Results: Ninety-nine (19%) patients were severely obese, 127 (24%) had cardiac disease and 58 (11%) had diabetes mellitus. Baseline pain and functional scores were similar regardless of BMI classification. Severe obesity was a significant risk factor for worse pain and functional recovery at 6months but no longer at 3years following total hip and knee arthroplasty. Cardiac disease predicted a slower recovery after hip arthroplasty. No significant interactions existed between obesity and cardiac disease or diabetes mellitus.Discussion: Severe obesity is an independent risk factor for slow recovery over 3years for both hip and knee arthroplasties.

The lifetime risk of total hip and knee arthroplasty: results from the UK general practice research database

2012-04-05

Summary: Objective: To estimate the lifetime risk of undergoing primary total hip (THR) or knee (TKR) replacement in the UK.Method: A Population-based cohort study of 25,845 patients who had undergone a THR and 23,260 patients who had undergone a TKR between 1991 and 2006, using data from the UK General Practice Research Database.Results: The estimated mortality-adjusted lifetime risk of THR at age 50 for the year 2005 was 11.6% (95% CI: 11.1, 12.1) for women and 7.1% (95% CI: 6.7, 7.5) for men. For TKR the risks were 10.8% (95% CI: 10.3, 11.3) for women and 8.1% (95% CI: 7.6, 8.5) for men. Between 1991 and 2006, the lifetime risk of THR at age 50 rose from 4.0% (95% CI: 3.5, 4.4) to 11.1% (95% CI: 10.6, 11.6) for women and for men from 2.2% (95% CI: 1.8, 2.5) to 6.6% (95% CI: 6.2, 7.0). Over the same period, for TKR the risk for women increased from 2.9% (95% CI: 2.6, 3.3) to 10.6% (95% CI: 10.1, 11.1) and for men from 1.8% (95% CI: 1.5, 2.2) to 7.7% (95% CI: 7.3, 8.2).Conclusion: The lifetime risk of undergoing THR or TKR is estimated to be substantially less than the risk of developing symptomatic hip or knee osteoarthritis. For the knee, the difference between these risk estimates is particularly wide. The reasons for the size of these differences are not clear, and further work is needed to quantify the extent of latent demand for these cost-effective and established interventions among the population with symptomatic osteoarthritis of the hip or knee.

Prevalence and predictors of health care use in patients with early hip or knee osteoarthritis: two-year follow-up data from the CHECK cohort

2012-04-16

Summary: Objective: To describe health care utilization (HCU) and predict analgesic use and health professional (HP) contact at baseline and 2 years in individuals with early symptomatic hip and/or knee osteoarthritis (OA).Design: Baseline and two-year data on HCU of the 1002 participants from the multi-centre Cohort Hip & Cohort Knee study were used. Six forms of health care services were described: analgesic use, supplement use, contact with a General Practitioner (GP), contact with a HP, contact in secondary care, and alternative medicine use. Multivariable logistic regression was performed in order to identify predisposing, enabling and disease-related variables that predict analgesic use and HP contact at 2 years; treatment modalities of first choice in early OA.Results: For the hip (n=170), the knee (n=414) and the hip and knee (n=418) group analgesic use (38%, 29% and 47%, respectively), contact with a GP (32%, 38% and 36%, respectively) and contact with a HP (26%, 18% and 20%, respectively), were reported most often at baseline. Contact with a GP significantly decreased, supplement use increased (to about one third), and other treatment modalities remained stable at 2 years. In all three groups, analgesic use at baseline was the strongest predictor for analgesic use at 2 years, whereas contact with a HP at baseline was the strongest predictor of contact with a HP after 2 years. Belonging to a first generation minority was a predisposing risk factor [Odds Ratio (95%-CI), 8.72 (1.55–48.97)] for analgesic use in the hip and knee group.Conclusions: In early OA, familiarity with HCU and other predisposing factors are, apart from disease-related factors strongly associated with HCU at 2 years. Further research is necessary to examine whether our findings reflect sub-optimal management of early OA in terms of efficacy and equity.

Side differences of thigh muscle cross-sectional areas and maximal isometric muscle force in bilateral knees with the same radiographic disease stage, but unilateral frequent pain – data from the osteoarthritis initiative

2012-04-03

Summary: Objective: To determine whether anatomical thigh muscle cross-sectional areas (MCSAs) and strength differ between osteoarthritis (OA) knees with frequent pain compared with contra-lateral knees without pain, and to examine the correlation between MCSAs and strength in painful vs painless knees.Methods: Forty-eight subjects (31 women; 17 men; age 45–78years) were drawn from 4,796 Osteoarthritis Initiative (OAI) participants, in whom both knees displayed the same radiographic stage (KLG2 or 3), one with frequent pain (most days of the month within the past 12months) and the contra-lateral one without pain. Axial MR images were used to determine MCSAs of extensors, flexors and adductors at 35% femoral length (distal to proximal) and in two adjacent 5 mm images. Maximal isometric extensor and flexor forces were used as provided from the OAI database.Results: Painful knees showed 5.2% lower extensor MCSAs (P = 0.00003; paired t-test), and 7.8% lower maximal extensor muscle forces (P = 0.003) than contra-lateral painless knees. There were no significant differences in flexor forces, or flexor and adductor MCSAs (P>0.39). Correlations between force and MCSAs were similar in painful and painless OA knees (0.44 < r < 0.66).Conclusions: Knees with frequent pain demonstrate lower MCSAs and force of the quadriceps (but not of other thigh muscles) compared with contra-lateral knees without knee pain with the same radiographic stage. Frequent pain does not appear to affect the correlations between MCSAs and strength in OA knees. The findings suggest that quadriceps strengthening exercise may be useful in treating symptomatic knee OA.

Responsiveness of the OARSI–OMERACT osteoarthritis pain and function measures

M. Bond, A. Davis, S. Lohmander, G. Hawker — 2012-04-11

Summary: Objective: To assess the responsiveness of the Intermittent and Constant Osteoarthritis Pain (ICOAP) measure, Hip Disability and Osteoarthritis Outcome Score Physical Function Short Form (HOOS–PS), and the Knee Disability and Osteoarthritis Outcome Score Physical Function Short Form (KOOS–PS) in a pharmacological trial.Methods: Data were obtained from a randomized double-blind trial comparing naproxcinod with naproxen and ibuprofen in individuals with hip or knee osteoarthritis (OA) (NCT00662896). Participants completed the ICOAP, HOOS–PS/KOOS–PS, and Western Ontario and McMaster Universities OA Index (WOMAC) Likert version 3.0 before and 13 weeks after treatment. In hip and knee OA participants separately, the mean pre-post treatment change in scores, effect size (ES) and standardized response mean (SRM) were determined for each measure by treatment arm, and for all arms combined.Results: Of 349 trial participants, 156 with knee OA and 48 with hip OA completed all measures at both time-points and were included (mean age 61 years; two-thirds female). Although there was both within treatment and between treatment variability in response, among knee OA participants, ICOAP intermittent, constant, and total scores and KOOS–PS scores showed, on average, moderate effects, with ESs ranging from 0.46 to 0.54 and SRMs from 0.49 to 0.56. Similar changes were seen for the WOMAC pain and function subscales (0.58 and 0.58, respectively). In those with hip OA, no significant improvement in symptoms was seen for any measure.Conclusion: Responsiveness to pharmaceutical intervention was demonstrated for ICOAP and KOOS–PS among participants with knee OA. Absence of treatment response precluded assessment of responsiveness in hip OA.

Evaluation of separate quantitative radiographic features adds to the prediction of incident radiographic osteoarthritis in individuals with recent onset of knee pain: 5-year follow-up in the CHECK cohort

2012-03-23

Summary: Objective: Detailed radiographic evaluation might enable the identification of osteoarthritis (OA) earlier in the disease. This study evaluated whether and which separate quantitative features on knee radiographs of individuals with recent onset knee pain are associated with incidence of radiographic OA and persistence and/or progression of clinical OA during 5-year follow-up.Method: From the Cohort Hip & Cohort Knee study participants with knee pain at baseline were evaluated. Radiographic OA development was defined as Kellgren & Lawrence (K&L) grade ≥II at 5-year follow-up. Clinical OA was defined as persistent knee pain and as progression of Westen Ontario & McMaster Universities Osteoarthritis index (WOMAC) pain and function score during follow-up. At baseline radiographic damage was determined by quantitative measurement of separate features using Knee Images Digital Analysis, and by K&L-grading.Results: Measuring osteophyte area [odds ratio (OR) = 7.0] and minimum joint space width (OR = 0.7), in addition to demographic and clinical characteristics, improved the prediction of radiographic OA 5 years later [area under curve receiver operating characteristic = 0.74 vs 0.64 without radiographic features]. When the predictive score (based on multivariate regression coefficients) was larger than the cut-off for optimal specificity, the chance of incident radiographic OA was 54% instead of the prior probability of 19%. Evaluating separate quantitative features performed slightly better than K&L-grading (AUC = 0.70). Radiographic characteristics hardly added to prediction of clinical OA.Conclusion: In individuals with onset knee pain, radiographic characteristics added to the prediction of radiographic OA development 5 years later. Quantitative radiographic evaluation in individuals with suspected OA is worthwhile when determining treatment strategies and designing clinical trials.

Coll2-1, Coll2-1NO2 and myeloperoxidase serum levels in erosive and non-erosive osteoarthritis of the hands

2012-04-05

Summary: Objective: Erosive osteoarthritis of the hand (EHOA) is thought to be an aggressive variant of hand osteoarthritis (HOA) characterised by prominent local inflammation and radiographic aspects of bone erosions in interphalangeal (IP) joints. However, rare studies have until now investigated the value of biomarkers in these patients. Thus, we determined Coll2-1, a marker of type II collagen denaturation, its nitrated form (Coll2-1NO2) and myeloperoxidase (MPO) levels in serum of patients with EHOA vs non-EHOA and subsequently evaluated their relationships with disease indices of severity and activity.Methods: Coll2-1, Coll2-1NO2 and MPO were measured using specific immunoassays in 82 patients, 57 with EHOA, all females, median age 59 (41–74yrs) and 20 with non-EHOA, all females, median age 55 (43–73yrs), fulfilling the American College of Rheumatology (ACR) criteria for hand OA. EHOA was characterized by the presence of at least one central bone erosion on radiograph in the IP joints. Patients were also evaluated for disease duration, number of affected (swollen and painful or tender) joints, radiographic score (RS) by Kallman scale and high sensitivity C-reactive protein (hsCRP).Results: Serum levels of MPO were higher in EHOA (230.0±152.1ng/ml) than in non-EHOA (160.2±111.5ng/ml, P=0.037). Coll2-1NO2 levels trended towards an elevation in EHOA compared non-EHOA (0.40±0.86 vs 0.22±0.14nmol/l, P=0.06), while Coll2-1 levels were not different. Correlations were found for disease duration and both MPO (R2=0.48, P=0.001) and Coll2-1NO2 (R2=0.73, P=0.01) after the splitting of the population in subgroups according to a cut off value above the 50th percentile. A correlation was found between hsCRP and MPO (R2=0.57, P=0.01).Conclusions: This study clearly demonstrates an elevation of some serum biomarkers in EHOA, in comparison with non-EHOA. In particular, MPO, hsCRP and the ratio Coll2-1NO2/Coll2-1 discriminated the two subsets of hand osteoarthritis (HOA), and a trend was also observed for Coll2-1NO2. These data suggest that these biomarkers could be helpful for the diagnosis of EHOA.

Cartilage and bone changes during development of post-traumatic osteoarthritis in selected LGXSM recombinant inbred mice

S. Hashimoto, M.F. Rai, K.L. Janiszak, J.M. Cheverud, L.J. Sandell — 2012-03-22

Summary: Introduction: Little evidence is available on the natural course of osteoarthritis (OA) development and the genes that protect and predispose individuals to it. This study was designed to compare strain-dependent development of OA and its association with tissue regeneration in mice. Two recombinant inbred lines LGXSM-6 and LGXSM-33 generated from LG/J and SM/J intercross were used. Previous studies indicated that LGXSM-6 can regenerate both articular cartilage and ear hole punch while LGXSM-33 cannot.Methods: Transection of the medial meniscotibial ligament was performed on 10-week-old male mice to induce OA. Cartilage damage was analyzed by histology and bone morphology was evaluated using micro-computed tomography (CT). Ear punches were performed and evaluated by measurement of residual hole diameter.Results: Cartilage analysis showed that LGXSM-33 developed a significantly higher grade of OA than LGXSM-6. Bone analysis showed that LGXSM-33 had substantial subchondral bone and trabecular bone thickening 8 weeks post-surgery, while LGXSM-6 showed bone loss over time. We also confirmed that LGXSM-6 can heal ear tissues significantly better than LGXSM-33.Conclusions: OA was found to be negatively correlated with the degree of tissue regeneration. LGXSM-33, a poor healer of ear tissues (and articular cartilage), developed more OA compared to LGXSM-6, which had better regenerative ability for ear tissues and articular cartilage. The phenotypic differences observed here are due to genetic differences further suggesting that similar sets of physiological processes and gene variants may mediate variation in OA development and tissue regeneration.

Relationship between cartilage and subchondral bone lesions in repetitive impact trauma-induced equine osteoarthritis

M. Lacourt, C. Gao, A. Li, C. Girard, G. Beauchamp, J.E. Henderson, S. Laverty — 2012-03-27

Summary: Objective: To correlate degenerative changes in cartilage and subchondral bone in the third carpal bone (C3) of Standardbred racehorses with naturally occurring repetitive trauma-induced osteoarthritis.Design: Fifteen C3, collected from Standardbred horses postmortem, were assessed for cartilage lesions by visual inspection and divided into Control (CO), Early Osteoarthritis (EOA) and Advanced Osteoarthritis (AOA) groups. Two osteochondral cores were harvested from corresponding dorsal sites on each bone and scanned with a micro-computed tomography (CT) instrument. 2D images were assembled into 3D reconstructions that were used to quantify architectural parameters from selected regions of interest, including bone mineral density and bone volume fraction. 2D images, illustrating the most severe lesion per core, were scored for architectural appearance by blinded observers. Thin sections of paraffin–embedded decalcified cores stained with Safranin O-Fast Green, matched to the micro-CT images, were scored using a modified Mankin scoring system.Results: Subchondral bone pits with deep focal areas of porosity were seen more frequently in AOA than EOA but never in CO. Articular cartilage damage was seen in association with a reduction in bone mineral and loss of bone tissue. Histological analyses revealed significant numbers of microcracks in the calcified cartilage of EOA and AOA groups and a progressive increase in the score compared with CO bones.Conclusion: The data reveal corresponding, progressive degenerative changes in articular cartilage and subchondral bone, including striking focal resorptive lesions, in the third carpal bone of racehorses subjected to repetitive, high impact trauma.

High dietary fat and the development of osteoarthritis in a rabbit model

2012-03-29

Summary: Objective: Osteoarthritis (OA) is associated with obesity, although this relationship remains unclear. Proposed etiologies of OA in obesity include mechanical loading of malaligned joints and possible toxicity of dietary fat. The hypothesis tested in the present study was that increased dietary fat worsens OA in both malaligned and normal joints, detected by biochemical and histological cartilage markers.Method: 83 New Zealand white rabbits were divided among two conditions related to OA: bowing of the knee and a 14%kcal vs 47.8%kcal fat diet. Rabbit weights and knee angles were compared throughout the experiment. At 28 and 38 weeks, intra-articular forces were measured, animals sacrificed, and knee cartilage examined for histological changes, glycosaminoglycan content, 35S uptake, and aggrecanase-1 expression.Results: There were no differences in animal weights or intra-articular forces between the two diets. Despite increased fat content in their diet, animals on the 47.8%kcal fat diet did not gain excess weight. Representative histology showed atypical shearing of articular cartilage among animals on the high fat diet. Animals on the 47.8%kcal fat diet had suppression of protein synthesis compared to the 14%kcal fat diet: lower glycosaminoglycan content and aggrecanase-1 expression in all knee compartments at both times, and lower 35S uptake at 38 weeks.Conclusion: These results suggest dietary fat, independent of animal weight, results in altered chondrocyte function. Increased dietary fat was associated with changes in rabbit cartilage in vivo and appears to be a risk factor for the development of OA.

MicroRNA-337 is associated with chondrogenesis through regulating TGFBR2 expression

2012-04-12

Summary: Objective: MicroRNAs (miRNAs) have been implicated in regulating diverse cellular pathways and involved in development and inflammation. This study aimed to examine six miRNAs expression during the cartilage development and identify the key miRNA which is associated with chondrogenesis.Methods: The expression of six miRNAs in cartilage tissue during development was screened by real-time quantitative polymerase chain reaction (RT-qPCR). Rat models of bone matrix gelatin induced endochondral ossification, collagen-induced arthritis and pristane-induced arthritis were established to examine whether miR-337 is involved in chondrogenesis. Furthermore, the regulation of transforming growth factor-b type II receptor (TGFBR2) expression by miR-337 was determined with the luciferase reporter gene assay and Western blot. The expression of some specific genes relevant to cartilage tissue was tested by RT-qPCR after miR-337 mimic or inhibitor transfection.Results: MiR-337 expression was significantly down-regulated and almost disappeared in the maturation phases of endochondral ossification. The results of histology and RT-qPCR from three rat models showed that miR-337 is directly bound up with chondrogenesis. Furthermore, the results from the luciferase reporter gene assay and Western blot indicated that miR-337 regulated TGFBR2 expression. Our study also found that the enhancement of miR-337 may modulate the expression of cartilage-specific genes such as AGC1 in C-28/I2 chondrocytes.Conclusion: We proved that miRNA-337 is associated with chondrogenesis through regulating TGFBR2 expression, and miRNA-337 can also influence cartilage-specific gene expression in chondrocytes. These findings may provide an important clue for further research in the arthritis pathogenesis and suggest a new remedy for arthritis treatment.