Yun Jong Lee

Adiponectin is a potential catabolic mediator in osteoarthritis cartilage

IntroductionAdiponectin has been implicated in the pathogenesis of osteoarthritis (OA). We studied the effects of adiponectin on the OA cartilage homeostasis.MethodsImmunohistochemical analysis was performed to evaluate differential expression of adiponectin receptors (AdipoRs) in nonlesional and lesional areas of OA cartilage. Cartilage and chondrocytes from the knee joints of primary OA patients were cultured in the presence of adiponectin (0~30 μg/ml). The levels of total nitric oxide (NO), matrix metalloproteinase (MMP)-1, -3, and -13, and tissue inhibitor of metalloproteinase (TIMP)-1 were measured in the conditioned media. The levels of inducible NO synthase (iNOS) and MMPs were determined with the quantitative real-time reverse transcription-polymerase chain reaction. The concentrations of collagenase-cleaved type II collagen neoepitope (C1-2C) were determined in the supernatant of adiponectin-stimulated OA cartilage explants. The effects of kinase and NOS inhibitors were evaluated in the adiponectin-stimulated chondrocytes.ResultsThe expression levels of both AdipoR1 and AdipoR2 were significantly higher in lesional than in nonlesional areas of OA cartilage. The increased rate of AdipoR1-positive chondrocytes was twice that of AdipoR2-positive chondrocytes when compared between nonlesional and lesional areas. Adiponectin-stimulated OA chondrocytes showed increased total NO and MMP-1, -3, and -13 levels compared with nonstimulated cells. The TIMP-1 level was not affected. The C1-2C levels were increased by adiponectin in OA cartilage explant culture. AMP-activated protein kinase (AMPK) and c-Jun N-terminal kinase (JNK) inhibitors (compound C and SP600125) significantly suppressed adiponectin-induced production of total NO and MMP-1, -3, and -13. Inducible NOS inhibitors enhanced the expression of the adiponectin-induced MMPs.ConclusionsAdiponectin causes matrix degradation in OA cartilage and increases MMPs and iNOS expression via the AMPK and JNK pathways in human OA chondrocytes. The catabolic effects of adiponectin may be counteracted by NO.

HLA-DPB1 and DPB2 are genetic loci for systemic sclerosis: A genome-wide association study in Koreans with replication in North Americans

OBJECTIVE To identify systemic sclerosis (SSc) susceptibility loci via a genome-wide association study. METHODS A genome-wide association study was performed in 137 patients with SSc and 564 controls from Korea using the Affymetrix Human SNP Array 5.0. After fine-mapping studies, the results were replicated in 1,107 SSc patients and 2,747 controls from a US Caucasian population. RESULTS The single-nucleotide polymorphisms (SNPs) (rs3128930, rs7763822, rs7764491, rs3117230, and rs3128965) of HLA-DPB1 and DPB2 on chromosome 6 formed a distinctive peak with log P values for association with SSc susceptibility (P=8.16x10(-13)). Subtyping analysis of HLA-DPB1 showed that DPB1*1301 (P=7.61x10(-8)) and DPB1*0901 (P=2.55x10(-5)) were the subtypes most susceptible to SSc in Korean subjects. In US Caucasians, 2 pairs of SNPs, rs7763822/rs7764491 and rs3117230/rs3128965, showed strong association with SSc patients who had either circulating anti-DNA topoisomerase I (P=7.58x10(-17)/4.84x10(-16)) or anticentromere autoantibodies (P=1.12x10(-3)/3.2x10(-5)), respectively. CONCLUSION The results of our genome-wide association study in Korean subjects indicate that the region of HLA-DPB1 and DPB2 contains the loci most susceptible to SSc in a Korean population. The confirmatory studies in US Caucasians indicate that specific SNPs of HLA-DPB1 and/or DPB2 are strongly associated with US Caucasian patients with SSc who are positive for anti-DNA topoisomerase I or anticentromere autoantibodies.

Genome-wide association study identifies GIMAP as a novel susceptibility locus for Behçet's disease

Objectives To identify non-major histocompatibility complex susceptible genes that might contribute to Behçets disease (BD). Methods We performed a genome-wide association study using DNA samples from a Korean population consisting of 379 BD patients and 800 controls. A replication study was performed in a Japanese population (363 BD patients and 272 controls). To evaluate the functional implication of the target single nucleotide polymorphisms (SNP), gene expression levels in peripheral T cells, allele-specific modulation of promoter activity and biological effect of mRNA knockdown were investigated. Results We found a novel association of BD to the GIMAP locus, mapped to chromosome 7q36.1 (rs1608157, p=6.01×10−8 in a minor allele dominant model; rs11769828, allele based p=1.60×10−6). A fine mapping study identified an association with four additional SNP: rs1522596 (OR=1.45, p=7.70×10−6) in GIMAP4; rs10266069 (OR=1.32, p=2.67×10−4) and rs10256482 (OR=1.27, p=5.27×10−4) in GIMAP2; and rs2286900 (OR=1.61, p=3.53×10−5) in GIMAP1 areas. Replication study using DNA samples from the Japanese population validated the significant association between BD and the GIMAP locus. The GIMAP4 promoter construct plasmid with the minor allele of rs1608157 displayed significantly lower activity than one with the major allele. Moreover, CD4 T cells from BD patients showed a lower level of GIMAP4 mRNA, and GIMAP4 knockdown was protective against Fas-mediated apoptosis. Conclusions These results suggest that a GIMAP cluster is a novel susceptibility locus for BD, which is involved in T-cell survival, and T-cell aberration can contribute to the development of BD.

Comparison of [18F]fluorodeoxyglucose uptake with glucose transporter-1 expression and proliferation rate in human glioma and non-small-cell lung cancer

To clarify the biological significance of [18F]fluorodeoxyglucose (18F-FDG) accumulation in patients with cancer, we assessed the relationships between 18F-FDG uptake and glucose transporter-1 (GLUT-1) expression and proliferation rate in human glioma and lung cancer. We obtained FDG PET images and measured standardized uptake values (SUVs) of primary tumours in 13 patients with brain glioma and 25 patients with non-small-cell lung cancer. After surgery, portions of respected tumours were obtained, and the proliferation rate was measured as proliferation index (per cent of (S+G2+M)/(G0+G1+S+G2+M)) using DNA flow cytometry. The expression of GLUT-1 in a tumour was evaluated by using immunostaining. We classified GLUT-1 expression as grade 0 (no positive cell), grade 1 (<10% cells positive), grade 2 (11-50% cells positive) and grade 3 (51-100% cells positive). Based on the expression of GLUT-1, cases with grades 0, 1, 2 and 3 showed SUVs of 6.1±2.8, 5.0±3.2, 8.3±3.3 and 10.4±6.6, respectively (P<0.05). Non-small-cell lung cancer showed higher FDG uptake (SUV, 8.5±5.1) and higher GLUT-1 expression (grade, 2.0±1.0) than did brain glioma (SUV, 4.7±2.5; grade, 0.8±0.8). Based on the total number of cases, SUVs did not relate to proliferation index (r = 0.19). In non-small-cell lung cancer, SUVs did not correlate with proliferation index, whereas in glioma, SUVs were strongly related to proliferation index (r = 0.79, P<0.01). In conclusion, FDG uptake generally correlated with GLUT-1 expression in non-small-cell lung cancer and glioma. In the case of glioma, FDG uptake also indicated increased cellular proliferation, which was not demonstrated in non-small-cell lung cancer.

Coagulation parameters and plasma total homocysteine levels in Behcet's disease.

Behcets disease (BD) is a multisystemic inflammatory disorder of unknown etiology that is sometimes associated with thrombosis in addition to systemic manifestations. However, the mechanism of hypercoagulability is not known. We evaluated the coagulation and fibrinolytic activities and the plasma total homocysteine levels of Korean BD patients in two cross-sectional studies. In the first study regarding coagulation and fibrinolytic activities, the levels of fibrinogen and von Willebrand factor (vWF) antigen were significantly higher in the BD patients than in the healthy controls (387.7+/-24.3 versus 240.6+/-8.8 mg/dl, p<0.001, and 131.9+/-8.8 versus 105.2+/-0.3%, p<0.01, respectively). The level of antithrombin III (AT III) was significantly lower in the BD patients (92.8+/-3.2 versus 106.3+/-2.6%, p<0.005). No differences were observed in the levels of plasminogen, protein C, or protein S activities. Activated protein C (APC) resistance was not observed in any BD patients. In the second study, the plasma total homocysteine levels of patients with a history of thrombosis (11.9+/-3.0 micromol/l) or disease activity (12.5+/-3.8 micromol/l) were found to be significantly higher than those of the controls (9.2+/-2.6 micromol/l, p<0.05, both). The plasma homocysteine concentrations in the thrombosis patients were positively correlated with plasma vWF levels; a relationship which suggests injury of the vascular endothelium (Spearman coefficient=0.857, p<0.01). Therefore, coagulation abnormality did not contribute to thrombotic complications, and higher levels of homocysteine may play a role in the hypercoagulablity of BD patients.

Osteopenia in men with mild and severe ankylosing spondylitis

We investigated the frequency and distribution of osteopenia according to the clinical severity in ankylosing spondylitis (AS). Bone mass was measured in men with mild (n=45) and severe AS (n=31) with dual-energy X-ray absorptiometry (DEXA). Definition of clinical severity was based on the Schober’s test. Osteopenia was commonly detected (48% in mild AS and 39% severe AS) and, in mild disease, more frequently observed at the lumbar spine than any of the proximal femur sites. In severe AS, however, the frequency of osteopenia at the femoral neck and Ward’s triangle was as high as at the lumbar spine. Both bone mineral density and T-scores in severe disease were lower than in mild disease at the femur neck, Ward’s triangle, and total proximal femur, but not in the lumbar spine. The progression of osteopenia may be reflected more reliably at proximal femur sites than at the lumbar spine.

Developmental hemispheric asymmetry of interregional metabolic correlation of the auditory cortex in deaf subjects

The functional connectivity of the auditory cortex might be altered in deaf subjects due to the loss of auditory input. We studied the developmental changes of functional connectivity of the primary auditory cortex (A1) in deaf children, deaf adults, and normal hearing adults by examining interregional metabolic correlation with (18)F-FDG PET. The mean activity of FDG uptake in the cytoarchitectonically defined A1 region served as a covariate in the interregional and interhemispheric correlation analysis. A1 metabolic rate was correlated with that of the ipsilateral superior temporal lobe in both normal and deaf subjects. This correlated area was larger in deaf children than in deaf or normal hearing adults. Concerning the functional connectivity of A1, a hemispheric asymmetry was found in that the extent of interregional correlation was clearly larger in the right than in the left hemisphere. This asymmetry was particularly pronounced in the younger deaf children. Both extent and asymmetry of the functional connectivity of A1 subsided with age. Contrary to this, a correlation between the left and the right primary auditory cortices was absent in younger deaf children but became apparent as they grew older.

Myositis autoantibodies in Korean patients with inflammatory myositis: anti-140-kDa polypeptide antibody is primarily associated with rapidly progressive interstitial lung disease independent of clinically amyopathic dermatomyositis.

BackgroundTo investigate the association between myositis autoantibodies and clinical subsets of inflammatory myositis in Korean patients.MethodsImmunoprecipitation was performed using the sera of classic polymyositis (PM) (n = 11) and dermatomyositis (DM) (n = 38) patients who met the Bohan and Peter criteria for definite inflammatory myositis. A panel of defined myositis autoantibodies was surveyed to investigate the association between each autoantibody and clinical subsets of inflammatory myositis.ResultsEither MSAs, anti-p140, or anti-p155/140 antibodies were found in 63.3% (31/49) of the study subjects. Anti-140-kDa-polypeptide (anti-p140) (18.4%, 9/49) and anti-155/140-kDa polypeptide (anti-p155/140) (16.3%, 8/49) antibodies were the most common, followed by anti-Mi2 (14.3%, 7/49), anti-ARS (12.2%, 6/49) and anti-SRP (2.0%, 1/49) antibodies. All MSAs and anti-p140 and anti-p155/140 antibodies were mutually exclusive. Anti-p140 (23.7%, 9/38), anti-p155/140 (21.1%, 8/38), and anti-Mi2 (18.4%, 3/38) antibodies were found exclusively in DM patients. Anti-p140 antibody was associated with rapidly progressive interstitial lung disease (ILD) (p = 0.001), with a sensitivity of 100.0% (4/4) and a specificity of 85.3% (29/34) in DM patients. Anti-p155/140 antibody was associated with cancer-associated DM (p = 0.009), with a sensitivity of 55.6% (5/9) and a specificity of 89.7% (26/29). Cancer-associated survival was significantly worse when anti-p155/140 antibody was present (19.2 ± 7.6 vs. 65.0 ± 3.5 months, p = 0.032). Finally, anti-ARS antibodies were associated with stable or slowly progressive ILD in PM and DM patients (p = 0.005).ConclusionsAnti-p140 and anti-p155/140 antibodies were commonly found autoantibodies in Korean patients with inflammatory myositis. Despite the lack of clinically amyopathic DM patients in the study subjects, a strong association was observed between anti-p140 antibody and rapidly progressive ILD. Anti-p155/140 antibody was associated with cancer-associated myositis and poor survival.

Spondylitis is the most common pattern of psoriatic arthritis in Korea

Abstract We assessed the prevalence and clinical features of psoriatic arthritis (PsA) in Korean patients with psoriasis. The prevalence of PsA in patients with psoriasis was 9%. Patients with PsA were older and had a longer duration of skin disease than those with psoriasis alone (median age, 40 vs 35 years, P = 0.03, and 15.3 vs 11.7 years, P = 0.04, respectively). Spondylitis was the most common pattern of PsA (50%). Nail change, dactylitis, and enthesopathy were observed in 36%, 15.4%, and 15.6% of patients with PsA, respectively. Increased erythrocyte sedimentation rate (ESR), antinuclear antibody, and radiological sacroiliitis were more frequent in patients with PsA than in those with uncomplicated psoriasis (25.8% vs 10.3%, P = 0.04; 37.9% vs 16.7%, P = 0.02; and 37.8% vs 1.1%, P < 0.01, respectively). The onset ages of psoriasis and arthritis in the spondylitis group were significantly lower than those in the non-spondylitis group (median age, 21.5 vs 31 years, P = 0.03, and 28.5 vs 43.5 years, P = 0.01, respectively). HLA-B27 was prevalent in 8% of patients with PsA.

TNF and TNF receptor polymorphisms in Korean Behcet’s disease patients

Behcets disease (BD) is an autoimmune disease characterized by recurrent oral ulcers, genital ulcers, erythema nodosum, and uveitis. Genetic factors are considered important in its pathogenesis. The serum level of tumor necrosis factor (TNF) is elevated in patients with active BD, and its production is elevated in monocytes and in the gamma delta T cells of BD patients. A dramatic response to anti-TNF-alpha antibody treatment further supports the role of TNF in BD. In this study, we investigated genetic polymorphisms of TNF alpha -308 G/A, TNF beta +252 G/A, and TNFR2 196 R/M in 94 Korean BD patients and age- and sex-matched healthy controls to investigate the role of TNF and TNF receptor polymorphisms in BD. The polymerase chain reaction-restriction fragment length polymorphism was used to identify the TNF-alpha promoter (G = TNFA1, A = TNFA2) and TNF-beta intron polymorphisms (G = TNFB1, A = TNFB2), and polymerase chain reaction-singly-strand conformation polymorphism was used to identify TNFR2 196R/M polymorphism (T = TNFR2M, G = TNFR2R). No differences were found in the TNF-alpha, TNF-beta or TNFR2 polymorphisms of the patients and the healthy controls. The allele frequencies of TNFA1/A2 were 0.94/0.06 in patients and 0.96/0.04 in healthy controls (p = 0.36, OR = 0.65, 95% CI = 0.26-1.63), for TNFB1/TNFB2 these were 0.42/0.58 in patients and 0.44/0.56 in controls (p = 0.68, OR = 0.91, 95% CI = 0.61-1.38), and for TNFR2R/TNFR2M 0.23/0.77 in patients and 0.21/0.79 in controls (p = 0.62, OR = 1.13, 95% CI = 0.69-1.84). In conclusion, this study found no differences of TNF alpha -308 G/A, TNF beta +252 G/A or of the TNFR2 196R/M polymorphisms in Korean BD patients versus healthy controls. These findings suggest that the role of TNF in BD is not genetically determined, but can be functionally explained.