Osteoarthritis and Cartilage

Identifying the human aggrecanase

A.J. Fosang, F.M. Rogerson — 2010-07-14

Summary: It is clear that A Disintegrin And Metalloproteinase with ThromboSpondin motif (ADAMTS)-5 is the major aggrecanase in mouse cartilage, however it is not at all clear which enzyme is the major aggrecanase in human cartilage. Identifying the human aggrecanase is difficult because multiple, independent, molecular processes determine the final level of enzyme activity. As investigators, we have good methods for measuring changes in the expression of ADAMTS mRNA, and good methods for detecting aggrecanase activity, but no methods that distinguish the source of the activity. In between gene expression and enzyme action there are many processes that can potentially enhance or inhibit the final level of activity. In this editorial we discuss how each of these processes affects ADAMTS activity and argue that measuring any one process in isolation has little value in predicting overall ADAMTS activity in vivo.

Efficacy of ultrasound therapy for the management of knee osteoarthritis: a systematic review with meta-analysis

A. Loyola-Sánchez, J. Richardson, N.J. MacIntyre — 2010-07-15

Summary: Objective: To assess the efficacy of ultrasound therapy (US) for decreasing pain and improving physical function, patient-perception of disease severity, and cartilage repair in people with knee osteoarthritis (OA).Methods: We conducted a systematic review (to February 2009) without language limits in MEDLINE, EMBASE, Cochrane Library, LILACS, MEDCARIB, CINAHL, PEDro, SPORT-discus, REHABDATA, and World Health Organization Clinical Trial Registry. We included randomized controlled trials of people with knee OA comparing the outcomes of interest for those receiving US with those receiving no US. Two reviewers independently selected studies, extracted relevant data and assessed quality. Pooled analyses were conducted using inverse-variance random effects models.Main results: Six small trials (378 patients) were included. US improves pain [Standardized Mean Difference (SMD) (95% confidence interval (CI))=−0.49 (−0.79, −0.18), P=0.002], and tends to improve self-reported physical function [SMD (CI)=−0.54 (−1.19, 0.12), P=0.11] along with walking performance [SMD (CI)=0.81 (−0.09, 1.72), P=0.08]. Results from two trials (128 patients), conducted by the same group, show a positive effect of US on pain [SMD (CI)=−0.77 (−1.15, −0.39), P<0.001], self-reported physical function [SMD (CI)=−1.25 (−1.69, −0.81), P<0.001], and walking performance [SMD (CI)=1.47 (1.06, 1.88), P<0.001] at 10 months after the intervention concluded. Heterogeneity observed between studies regarding the effect of US on pain was explained by US dose, mode and intensity. The quality of evidence supporting these effect estimates was rated as low.Conclusions: US could be efficacious for decreasing pain and may improve physical function in patients with knee OA. The findings of this review should be confirmed using methodologically rigorous and adequately powered clinical trials.

Vascular disease is associated with facet joint osteoarthritis

P. Suri, J.N. Katz, J. Rainville, L. Kalichman, A. Guermazi, D.J. Hunter — 2010-07-14

Summary: Objective: Epidemiologic studies have demonstrated associations between vascular disease and spinal degeneration. We sought to examine whether vascular disease was associated with lumbar spine facet joint osteoarthritis (FJ OA) in a community-based population.Design: 441 participants from the Framingham Heart Study multi-detector computed tomography (MDCT) Study were included in this ancillary study. We used a quantitative summary measure of abdominal aortic calcification (AAC) from the parent study as a marker for vascular disease. AAC was categorized into tertiles of ‘no’ (reference), ‘low’, and ‘high’ calcification. FJ OA was evaluated on computerised tomography (CT) scans using a four-grade scale. For analytic purposes, FJ OA was dichotomized as moderate FJ OA of at least one joint from L2–S1 vs no moderate FJ OA. We examined the association of AAC and FJ OA using logistic regression before and after adjusting for age, sex and body mass index (BMI). Furthermore, we examined the independent effect of AAC on FJ OA after including the known cardiovascular risk factors; diabetes, hypertension, hypercholesterolemia, and smoking.Results: Low AAC (OR 3.84 [2.33–6.34]; P≤0.0001) and high AAC (9.84 [5.29–18.3]; ≤0.0001) were strongly associated with FJ OA, compared with the reference group. After adjusting for age, sex, and BMI, the association with FJ OA was attenuated for both low AAC (1.81 [1.01–3.27]; P=0.05) and high AAC (2.63 [0.99–5.23]; P=0.05). BMI and age were independently and significantly associated with FJ OA. The addition of cardiovascular risk factors to the model did not substantially change parameter estimates for either AAC tertile.Conclusions: AACs were associated with FJ OA in this community-based population, when adjusting for epidemiologic factors associated with spinal degeneration, and cardiovascular risk factors. Potentially modifiable risk factors for facet degeneration unrelated to conventional biomechanical paradigms may exist. This study is limited by cross-sectional design; longitudinal studies are needed.

Changes of human menisci in osteoarthritic knee joints

2010-07-14

Summary: Objective: To investigate the changes of knee menisci in osteoarthritis (OA) in human.Methods: OA and control menisci were obtained from 42 end-stage OA knees with medial involvement and 28 non-arthritic knees of age-matched donors, respectively. The change of menisci in OA was evaluated by histology, and gene expression of major matrix components and anabolic factors was analyzed in the anterior horn segments by quantitative PCR (qPCR). In those regions of menisci, the rate of collagen neo-synthesis was evaluated by [3H]proline incorporation, and the change of matrix was investigated by ultrastructural observation and biomechanical measurement.Results: In OA menisci, the change in histology was rather moderate in the anterior horn segments. However, despite the modest change in histology, the expression of type I, II, III procollagens was dramatically increased in those regions. The expression of insulin-like growth factor 1 (IGF-1) was markedly enhanced in OA menisci, which was considered to be responsible, at least partly, for the increase in procollagen gene expression. Interestingly, in spite of marked increase in procollagen gene expression, incorporation of [3H]proline increased only modestly in OA menisci, and impaired collagen synthesis was suggested. This finding was consistent with the results of ultrastructural observation and biomechanical measurement, which indicated that the change of meniscal matrix was modest in the macroscopically preserved areas of OA menisci.Conclusion: Although the expression of major matrix components was markedly enhanced, matrix synthesis was enhanced only modestly, and the changes of matrix in human OA menisci were rather modest in the non-degenerated areas.

Evidence of association between GDF5 polymorphisms and congenital dislocation of the hip in a Caucasian population

2010-07-14

Summary: Objective: Congenital dislocation of the hip (CDH) is a multifactorial disease which involves genetic factors that are still unidentified. Recently, a functional polymorphism (rs143383) of the 5′-untranslated region of GDF5 (Growth/Differentiation Factor 5) – previously reported to be associated with osteoarthritis – has been associated with CDH in a Chinese population. The aim of our study was to determine whether GDF5, known to be involved in bone, joint and cartilage morphogenesis, is also associated with CDH in Caucasians.Design: We genotyped three tagSNPs (rs224334, rs143384, rs143383) in 239 cases and 239 controls from western Brittany (France) where CDH is frequent, and tested the association using both single-locus and haplotype-based approaches.Results: The most significant association was observed with rs143384. The T allele of this SNP was overrepresented in cases (65.9% vs 55.9%, P=0.002). Under a recessive model, carriers of the TT genotype had a 1.71-fold higher risk of developing CDH than carriers of the other genotypes (ORTT vs CT+CC=1.71, 95% CI: [1.18–2.48], P=0.005). At a nominal level, the association was also significant with rs143383 (ORTT vs CT+CC=1.52, 95% CI: [1.05–2.19], P=0.026). The haplotype carrying the susceptibility alleles of these SNPs was also more frequent in cases (65.9% vs 55.9%, OR=1.53, 95% CI: [1.18–1.98], P=0.002).Conclusion: This study reports, for the first time, the association between GDF5 polymorphisms and CDH in Caucasians, and points out another polymorphism of interest that requires further investigation. Reduction in GDF5 expression might lead to developmental deficiency of ligaments and capsule in hip joint, and therefore contribute to CDH pathogenesis.

Development of a novel clinical biomarker assay to detect and quantify aggrecanase-generated aggrecan fragments in human synovial fluid, serum and urine

2010-07-14

Summary: Objective: Proteolytic degradation of aggrecan in articular cartilage is a hallmark feature of osteoarthritis (OA). The present study was aimed at developing a sensitive enzyme linked immunosorbent assay (ELISA) for the detection of aggrecanase-cleaved fragments of aggrecan in human serum and urine to facilitate the clinical development of aggrecanase inhibitors for OA.Methods: The BC3 monoclonal antibody that detects the ARGS neoepitope sequence in aggrecanase-cleaved aggrecan was engineered and optimized using complementarity determining region (CDR)-saturation mutagenesis to improve its binding affinity to the neoepitope. A sandwich ELISA (BC3-C2 ELISA) was developed using the optimized α-ARGS antibody (BC3-C2) as capture antibody and a commercially available antibody directed against the hyaluronic-acid binding region (HABR) of aggrecan as detection antibody. Aggrecanase-cleaved fragments of aggrecan present in in vitro digests, human cartilage explant culture supernatants and in human synovial fluid, serum and urine were detected and quantified using this ELISA.Results: The optimized antibody had a 4-log improvement in affinity for the ARGS containing peptide compared to the parental BC3 antibody, while maintaining the ability to not cross-react with a spanning peptide. The BC3-C2 ELISA demonstrated the ability to detect aggrecanase-cleaved aggrecan fragments in the native state, without the need for deglycosylation. This ELISA was able to measure aggrecanase-generated ARGS containing aggrecan fragments in human articular cartilage (HAC) explant cultures in the basal state (without cytokine stimulation). Treatment with an aggrecanase inhibitor resulted in a dose-dependent inhibition of ARGS neoepitope released into the culture supernatant. The ELISA assay also enabled the detection of ARGS containing fragments in human synovial fluid, serum and urine, suggesting its potential utility as a biomarker of aggrecanase activity.Conclusions: We have developed a novel ELISA using an optimized ARGS antibody and have demonstrated for the first time, an ELISA-based measurement of aggrecan degradation products in human serum and urine. This assay has the potential to serve as a mechanistic drug activity biomarker in the clinic and is expected to significantly impact/accelerate the clinical development of aggrecanase inhibitors and other disease modifying drugs for OA.

A short-term pharmacodynamic model for monitoring aggrecanase activity: injection of monosodium iodoacetate (MIA) in rats and assessment of aggrecan neoepitope release in synovial fluid using novel ELISAs

2010-07-14

Summary: Objective: To develop a short-term in vivo model in rats, with an enzyme-linked immunosorbent assay (ELISA) readout for specific aggrecanase-cleaved aggrecan fragments, to facilitate testing of aggrecanase inhibitors.Methods: Monosodium iodoacetate (MIA), a metabolic inhibitor, was injected into the right knee joint of male Lewis rats and the release of aggrecanase-cleaved fragments of aggrecan containing the NITEGE or ARGN neoepitope was measured in the synovial fluid at 7 days post MIA injection using novel ELISAs. The ELISAs utilize a commercial antibody directed against the hyaluronic-acid binding region (HABR) of aggrecan, in combination with either an α-NITEGE antibody (NITEGE ELISA) or an α-ARGS/BC3 antibody (ARGS ELISA), to detect aggrecanase-cleavage of aggrecan within the interglobular domain (IGD). Aggrecan fragments present in in vitro digests, in cytokine-treated cartilage explant culture supernatants and in rat synovial fluid lavage samples were detected and quantified using the two ELISAs. Small molecule inhibitors of aggrecanase activity were dosed orally on days 3–7 to determine their ability to inhibit MIA-induced generation of the NITEGE and ARGN neoepitopes measured in the rat synovial fluid.Results: The NITEGE assay was shown to specifically detect the N-terminal fragment of aggrecan comprising the G1 domain and the NITEGE neoepitope sequence. This assay can readily measure aggrecanase-cleaved bovine, human and rat aggrecan without the need for deglycosylation. The ARGS assay specifically detects C-terminal fragments of aggrecan comprising the ARGS/ARGN neoepitope and the G2 domain. Keratan sulfate (KS) residues of aggrecan interfere with this ELISA, and hence this assay works well with native rat articular cartilage aggrecan (that lacks KS residues) and with deglycosylated bovine and human aggrecan. Injection of MIA into the rat knee joints resulted in a time-dependent increase in the release of aggrecanase-cleaved aggrecan fragments into the synovial fluid and treatment with an aggrecanase inhibitor resulted in a dose-dependent inhibition of the generation of these neoepitopes.Conclusions: We have established a short-term in vivo model in rats that involves measurement of synovial fluid biomarkers that are dependent on aggrecanase activity in the joint. The short duration of the model combined with the mechanistic biomarker readout makes it very useful for the initial in vivo screening of aggrecanase inhibitors prior to testing them in time and resource-intensive disease models of osteoarthritis (OA).

Hypoxia, RONS and energy metabolism in articular cartilage

B. Fermor, A. Gurumurthy, B.O. Diekman — 2010-07-14

Summary: Objective: Increased pro-inflammatory cytokines and reactive oxygen and nitrogen species (RONS) occur in osteoarthritis (OA). Oxygen tension can alter the levels of RONS induced by interleukin-1 (IL-1). RONS such as nitric oxide (NO) can alter energy metabolism. The aim of this study was to determine if oxygen tension alters energy metabolism, in articular cartilage, in response to IL-1 or NO and to determine if cell death occurred.Design: Porcine articular chondrocytes were incubated with IL-1 or the NO donor NOC-18 for 48h in either 1, 5 or 20% O2. Adenosine triphosphate (ATP) levels were measured and immunoblots for adenosine monophosphate-activated protein kinase (AMPK) were done. Protein translation was measured by S6 activation. Senescence and autophagy were determined by increased caveolin or conversion of LC3-I to LC3-II respectively.Results: One percent O2 significantly reduced ATP levels compared with 20% O2. Five percent O2 significantly increased ATP levels compared with 20% O2. One percent O2 significantly increased phospho-AMPK (pAMPK) protein expression compared with 5 or 20% O2. Oxygen tension had no effects on pS6, caveolin or LC3-II levels. IL-1-induced NO production was significantly reduced with decreased oxygen tension, and significantly reduced ATP levels at all oxygen tensions, but pAMPK was only significantly increased at 5% O2. IL-1 significantly reduced pS6 at all oxygen tensions. IL-1 had no effects on caveolin and significantly increased LC3-II at 20% O2 only. NOC-18 significantly reduced ATP levels at all oxygen tensions, and significantly increased pAMPK at 5% O2 only, and significantly decreased pAMPK at 1% O2. NOC-18 significantly reduced pS6 at 1% O2 and significantly increased caveolin at 5% O2, and LC3-II at 1% O2.Conclusion: Our data suggest 5% O2 is optimal for energy metabolism and protective to some effects of IL-1 and NO. NO has the greatest effects on ATP levels and the induction of autophagy at 1% O2.

Surface grafting of biocompatible phospholipid polymer MPC provides wear resistance of tibial polyethylene insert in artificial knee joints

2010-07-14

Summary: Objective: Aseptic loosening of artificial knee joints induced by wear particles from a tibial polyethylene (PE) insert is a serious problem limiting their longevity. This study investigated the effects of grafting with our original biocompatible phospholipid polymer 2-methacryloyloxyethyl phosphorylcholine (MPC) on the insert surface.Methods: The hydrophilicity of the PE surface was determined by the contact angle of a water droplet, and the friction torque was measured against a cobalt–chromium alloy component. The wear amount was compared among PE inserts with or without cross-linking and MPC grafting during 5×106 cycles of loading in a knee joint simulator. The surfaces of the insert and the wear particles in the lubricant were subjected to electron and laser microscopic analyses. The mechanical properties of the inserts were evaluated by the small punch test.Results: The MPC grafting increased hydrophilicity and decreased friction torque. In the simulator experiment, the wear of the tibial insert was significantly suppressed in the cross-linked PE (CLPE) insert, and even more dramatically decreased in the MPC-grafted CLPE insert, as compared to that in the non-cross-linked PE insert. Surface analyses confirmed the wear resistance by the cross-linking, and further by the MPC grafting. The particle size distribution was not affected by cross-linking or MPC grafting. The mechanical properties of the insert material remained unchanged during the loading regardless of the cross-linking or grafting.Conclusion: Surface grafting with MPC polymer furnished the PE insert with wear resistance in an artificial knee joint through increased hydrophilicity and decreased friction torque.

Pretreatment of periosteum with TGF-β1 in situ enhances the quality of osteochondral tissue regenerated from transplanted periosteal grafts in adult rabbits

2010-07-14

Summary: Objective: To compare the efficacy of in situ transforming growth factor-beta1 (TGF-β1)-pretreated periosteum to untreated periosteum for regeneration of osteochondral tissue in rabbits.Methods: In the pretreatment group, 12 month-old New Zealand white rabbits received subperiosteal injections of 200ng of TGF-β1 percutaneously in the medial side of the proximal tibia, 7 days prior to surgery. Control rabbits received no treatment prior surgery. Osteochondral transverse defects measuring 5mm proximal to distal and spanning the entire width of the patellar groove were created and repaired with untreated or TGF-β1-pretreated periosteal grafts. Post-operatively the rabbits resumed normal cage activity for 6 weeks.Results: Complete filling of the defects with regenerated tissue was observed in both the TGF-β1-pretreated and control groups with reformation of the original contours of the patellar groove. The total histological score (modified O’Driscoll) in the TGF-β1-pretreated group, 20 (95% Confidence Interval (CI), 19–21), was significantly higher (P=0.0001) than the control group, 18 (16–19). The most notable improvements were in structural integrity and subchondral bone regeneration. No significant differences in glycosaminoglycan or type II collagen content, or equilibrium modulus were found between the surgical groups. The cambium of the periosteum regenerated at the graft harvest site was significantly thicker (P=0.0065) in the TGF-β1-pretreated rabbits, 121μm (94–149), compared to controls, 74μm (52–96), after 6 weeks.Conclusions: This study demonstrates that in situ pretreatment of periosteum with TGF-β1 improves osteochondral tissue regeneration at 6-weeks post-op compared to untreated periosteum in 12 month-old rabbits.

Glucosamine sulfate reduces experimental osteoarthritis and nociception in rats: association with changes of mitogen-activated protein kinase in chondrocytes

2010-05-31

Summary: Objective: To study the effects of oral glucosamine sulfate on the development of osteoarthritis (OA) and to examine concomitant changes in the nociceptive behavior of rats.Methods: OA was induced in Wistar rats by anterior cruciate ligament transection (ACLT) of the right knee; the left knee was untreated. The OA+glucosamine group received oral glucosamine sulfate (250mg/kg/day) in a 2-g wafer once a day for 10 consecutive weeks starting at week 5 after ACLT. The OA group was treated as above with 2-g wafers (placebo). The control group of naïve rats received 2-g wafers only. The glucosamine alone group comprised naïve rats receiving glucosamine sulfate only. Nociceptive behavior (mechanical allodynia and weight-bearing distribution of hind paws) during OA development was analyzed pre- and 3, 6, 9, 12, 15, and 18 weeks post-ACLT. Macroscopic and histologic studies were then performed on the cartilage and synovia. Immunohistochemical analysis was performed to examine the effect of glucosamine on expression of mitogen-activated protein kinases (MAPKs) in the articular cartilage chondrocytes.Results: OA rats receiving glucosamine showed a significantly lower degree of cartilage degeneration than the rats receiving placebo. Glucosamine treatment also suppressed synovitis. Mechanical allodynia and weight-bearing distribution studies showed significant improvement in the OA+glucosamine group as compared to the OA group. Moreover, glucosamine attenuated p38 and c-Jun N-terminal kinase (JNK) but increased extracellular signal-regulated kinase 1/2 (ERK) expression in OA-affected cartilage.Conclusion: Our results indicate that treatment with oral glucosamine sulfate in a rat OA model (1) attenuates the development of OA, (2) concomitantly reduces nociception, and (3) modulates chondrocyte metabolism, possibly through inhibition of cell p38 and JNK and increase of ERK expression.

p38γ mitogen-activated protein kinase suppresses chondrocyte production of MMP-13 in response to catabolic stimulation

D.L. Long, R.F. Loeser — 2010-07-14

Summary: Objective: The signaling protein p38 mitogen-activated protein kinase is required for inflammatory signaling in chondrocytes that regulates matrix metalloproteinase (MMP) production. We sought to determine the role of specific p38 isoforms in chondrocyte catabolic signaling in response to IL-1β and fibronectin fragments (Fn-f).Methods: Human articular chondrocytes isolated from normal ankle cartilage from tissue donors or from osteoarthritic knee cartilage obtained during knee replacement were stimulated with IL-1β or Fn-f, with or without pretreatment with p38 inhibitors (SB203580 or BIRB796) or growth factors (IGF-1 and OP-1). p38 isoform phosphorylation was measured by antibody array and immunoblotting. MMP-13 expression was measured by real-time polymerase chain reaction (PCR), enzyme-linked immunosorbent assay (ELISA), and immunoblotting. Chondrocytes were transfected with plasmids expressing constitutively active (CA) p38γ or with adenovirus expressing dominant negative (DN) p38γ.Results: Stimulation of chondrocytes with either IL-1β or Fn-f led to enhanced phosphorylation of p38α and p38γ, with little phosphorylation of p38β or p38δ isoforms. p38α localized to the nucleus and p38γ to the cytosol. Inhibition of both p38α and p38γ with BIRB796 resulted in less inhibition of MMP-13 production in response to IL-1β or FN-f than did inhibition of only p38α with SB203580. Transfection with CA p38γ resulted in decreased MMP-13 production while transduction with DN p38γ resulted in increased MMP-13 production. IGF-1 and OP-1 pretreatment inhibited p38α phosphorylation but not p38γ phosphorylation.Conclusions: p38γ is activated by catabolic stimulation of human articular chondrocytes, but interestingly suppresses MMP-13 production. Treatments that increase p38γ activation may be of therapeutic benefit in reducing chondrocyte production of MMP-13.

Detection of degenerative cartilage disease: comparison of high-resolution morphological MR and quantitative T2 mapping at 3.0 Tesla

2010-07-14

Summary: Objective: The aim of the study was to investigate the association of T2 relaxation times of the knee with early degenerative cartilage changes. Furthermore the impact of unloading the knee on T2 values was evaluated.Methods: Forty-three patients with knee pain and an ICRS (International Cartilage Repair Society) cartilage defect grade ≤2 were examined with 3T magnetic resonance imaging (MRI). Morphological cartilage grading was based on high-resolution proton-density (PD), turbo-spin-echo (TSE) and three-dimensional (3D) isotropic True fast imaging with steady-state precession (FISP) images of slices covering the cartilage layer above the posterior horn of the meniscus. T2 maps were calculated from a multi-echo, spin-echo (MESE) sequence, performed at the beginning and at the end of the scan (time interval 40min). Influence of cartilage defect grading on deep, superficial, and global T2 values as well as on T2 values for zonal variation was assessed using analysis of variance (ANOVA) and Spearman rank correlation test. Differences among both T2 measurements were compared using paired t-test.Results: Global and superficial T2 values significantly increased with cartilage defect grade regardless of the time elapsed from unloading (global T2: ICRS grade 0, 38.9 and 40.1ms; grade 1, 41.2 and 44.5ms; grade 2, 47.7 and 53.4ms; P=0.041 and 0.008) with stronger correlation for second T2 measurement. In contrast there were no significant differences among grades in the zonal variation at any time. Significant differences for T2 values between the two subsequent measurements were consistently found.Conclusion: T2 mapping might be a sensitive method for the detection of early cartilage degeneration. From our results we would recommend to measure T2 after unloading.

Mitochondrial function is altered in articular chondrocytes of an endemic osteoarthritis, Kashin–Beck disease

J.T. Liu, X. Guo, W.J. Ma, Y.G. Zhang, P. Xu, J.F. Yao, Y.D. Bai — 2010-07-21

Summary: Objective: Kashin–Beck disease (KBD) is an endemic degenerative osteoarthritis (OA) associated with extracellular matrix degradation and chondrocyte necrosis in the articular and growth plate cartilage. The role of mitochondria in degenerative diseases is widely recognized but its function in KBD is unknown. The aim of this investigation was to evaluate mitochondrial function to understand the mitochondria-mediated caspase activation and apoptosis in adult KBD chondrocytes.Methods: Mitochondrial function was evaluated by analyzing the activities of respiratory chain enzyme complexes and citrate synthase (CS), intracellular adenosine triphosphate (ATP) contents, as well as changes in mitochondrial membrane potential (ΔΨm). Apoptotic cell death was evaluated by analyzing the cytochrome c release from mitochondria to the cytosol, caspase-9 and 3 activities, and the apoptosis rate of KBD articular chondrocytes.Results: Activities of complexes II, III, IV and V were reduced in KBD articular chondrocytes compared with cells from normal controls. However, the mitochondrial mass was increased in KBD samples. Cultured KBD chondrocytes had a reduction of cellular ATP levels and contained a higher proportion of cells with de-energized mitochondria. Mitochondrial cytochrome c release and activation of caspase-9 and 3 were also observed. The percentages of positive apoptotic chondrocytes from the KBD patient group stained by Hoechst nuclear stain and Annexin V/PI for flow cytometry exhibited higher levels than that of the healthy controls.Conclusion: These findings suggest the involvement of mitochondrial function and apoptotic cell death in the pathophysiology of KBD. The dysfunction of the mitochondria may play an important role in KBD articular chondrocytes apoptosis.

Association of radiographic and symptomatic knee osteoarthritis with health-related quality of life in a population-based cohort study in Japan: the ROAD study

2010-07-14

Summary: Objective: Knee osteoarthritis (OA) is a major public health issue causing chronic pain and disability. However, there is little information on the impact of this disease on quality of life (QOL) in Japanese men and women. The objective of the present study was to clarify the impact of radiographic and symptomatic knee OA on QOL in Japan.Methods: This study examined the association of radiographic and symptomatic knee OA with QOL parameters such as the Medical Outcomes Study Short Form-8 (SF-8), EuroQOL (EQ-5D) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Radiographic knee OA was defined according to Kellgren/Lawrence (KL) grades, and symptomatic knee OA was defined as KL=3 or 4 with knee pain. We also examined the independent association of symptomatic knee OA and grip strength with QOL.Results: From the 3040 participants in the Research on Osteoarthritis Against Disability (ROAD) study, the present study analyzed 2126 subjects older than 40 years who completed the questionnaires (767 men and 1359 women; mean age, 68.9±10.9 years). Subjects with KL=3 or 4 had significantly lower physical QOL as measured by the physical component summary (PCS) score of the SF-8 and pain domains of the WOMAC, whereas mental QOL, as measured by the mental component summary (MCS) score of the SF-8, was higher in subjects with KL=3 or 4 than KL=0 or 1. Symptomatic knee OA was significantly more likely than radiographic knee OA without pain to be associated with physical QOL loss as measured by the PCS score and physical domains of the WOMAC. Symptomatic knee OA and grip strength were independently associated with physical QOL.Conclusion: This cross-sectional study revealed that subjects with symptomatic knee OA had significantly lower physical QOL than subjects without it.

OARSI update on the evidence for osteoarthritis therapies: comment on the nomenclature used for intra-articular hyaluronan

P.A. Band — 2010-07-14

Please allow me to clarify the terminology used to describe the intra-articular hyaluronan (IAHA) class of osteoarthritis (OA) treatments, in the excellent evidence update reported by Zhang et al. (OARSI recommendations for the management of hip and knee osteoarthritis part III: changes in evidence following systematic cumulative update of research published through January 2009. Osteoarthritis and Cartilage, February 17, 2010; 18(4); 473–99).

Response from authors: ‘OARSI update on the evidence for osteoarthritis therapies’

W. Zhang, G. Nuki — 2010-07-14

We appreciate Dr Philip Band’s letter in response to our recent publication OARSI recommendations for the management of hip and knee osteoarthritis Part III: changes in evidence following systematic cumulative update of research published through January 2009 (Osteoarthritis & Cartilage 2010; 18: 476–499). The meta-analysis (Reichenberg et al. Arthritis Rheum (Arthritis Care and Research) 2007; 57: 1410–1418) reported in Table IV showed that treatment with IA hylan G-F 20 (Synvisc) was associated with an increased relative risk of flares of joint pain (RR 2.04; 95% CI 1.18, 3.53; I2=0%) compared with IA avian hyaluronans (Hyalgan and Orthovisc), or the bacterial hyaluronan (Ostentil). Although the average molecular weight of hylan G-F 20 (6000kD), is considerably greater than that of uncrosslinked Hyalgan (700kD), Orthovisc (2000kD) or Ostentil (1200kD), and it can fairly be described as a high molecular weight preparation (Gomis, Pawlak, Balazs et al. Arthritis Rheum 2004; 50: 314–326), it was not our intention to imply that all high molecular weight hyaluronan formulations will carry the risk of adverse events associated with hylan G-F 20 in these trials.