Eun Ha Kang

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.

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.

Role of innate immunity in a murine model of histidyl–transfer RNA synthetase (Jo-1)–mediated myositis†

OBJECTIVE Previous studies in humans and in animal models support a key role of histidyl-transfer RNA synthetase (HisRS; also known as Jo-1) in the pathogenesis of idiopathic inflammatory myopathy. While most investigations have focused on the ability of HisRS to trigger adaptive immune responses, in vitro studies clearly indicate that HisRS possesses intrinsic chemokine-like properties capable of activating the innate immune system. The purpose of this study was therefore to examine the ability of HisRS to direct innate immune responses in a murine model of myositis. METHODS Following intramuscular immunization with soluble HisRS in the absence of exogenous adjuvant, selected strains of mice were evaluated at different time points for histopathologic evidence of myositis. Enzyme-linked immunosorbent assay-based assessment of autoantibody formation and carboxyfluorescein succinimidyl ester proliferation studies provided complementary measures of B cell and T cell responses triggered by HisRS immunization. RESULTS Compared to appropriate control proteins, a murine HisRS fusion protein induced robust, statistically significant muscle inflammation in multiple congenic strains of C57BL/6 and NOD mice. Time course experiments revealed that this inflammatory response occurred as early as 7 days postimmunization and persisted for up to 7 weeks. Parallel immunization strategies in DO11.10/RAG-2(-/-) and C3H/HeJ (TLR-4(-/-) ) mice indicated that the ability of murine HisRS to drive muscle inflammation was not dependent on B cell receptor or T cell receptor recognition and did not require Toll-like receptor 4 signaling. CONCLUSION Collectively, the findings of these experiments support a model in which HisRS can trigger both innate and adaptive immune responses that culminate in severe muscle inflammation that is the hallmark of idiopathic inflammatory myopathy.

Vascular endothelial growth factor polymorphisms in patients with steroid-induced femoral head osteonecrosis

To investigate an association between steroid‐induced femoral head osteonecrosis (FHON) and functional vascular endothelial growth factor (VEGF) gene (−2578A/C, −1154A/G, −634C/G, and +405C/G) polymorphisms polymerase chain reaction‐restriction fragment length polymorphism genotyping was performed in 160 patients (86 idiopathic FHON and 74 steroid‐induced FHON) and 160 gender‐ and age‐matched controls. The steroid‐induced subgroup had a significantly lower prevalence of −1154A allele (7.4% vs. 18.1%, odds ratio (OR) = 0.363) and genotype carrying −1154A (14.9% vs. 32.5%, OR = 0.333 in a recessive model) than controls. In a dominant model, the frequency of genotype carrying +405G (74.3% vs. 84.4%, OR = 0.492) was significantly lower in steroid‐induced FHON than in controls. The distribution of haplotypes was significantly different between controls and FHON patients (p = 0.00011). Especially, when haplotypes were classified into high (CGCG and AAGG) or low (CGGC and AGGC) VEGF inducing haplotypes, patients with steroid‐induced FHON had a significantly lower prevalence of high inducing haplotypes (7.4% vs. 15.9%, OR = 0.424) and a significantly higher prevalence of low inducing haplotypes (4.7% vs. 0.6%, OR = 7.894) than controls. Low inducing VEGF haplotypes may confer an increased risk and high inducing haplotypes have a protective effect for the development of steroid‐induced FHON in Korea.

Associations between the HLA-A polymorphism and the clinical manifestations of Behcet's disease.

IntroductionThe objective was to investigate associations between the HLA-A gene and Behcets disease (BD) and its clinical manifestations.MethodsGenotyping for the HLA-A locus was performed using the polymerase chain reaction-Luminex typing method in 223 BD patients and 1,398 healthy controls.ResultsThe phenotypic frequencies of HLA-A*02:07 (odds ratio (OR) = 2.03, P = 0.002), A*26:01 (OR = 1.85, P = 0.008), and A*30:04 (OR = 2.51, P = 0.006) tended to be higher in BD patients than in normal controls, but the frequency of A*33:03 (OR = 0.59, P = 0.003) tended to be lower in BD patients. A meta-analysis adopting our and the Japanese data confirmed the associations of HLA-A*02:07, A*26:01, and A*33:03 with BD. Furthermore, the frequencies of the HLA-A*02:07, A*26:01, and A*30:04 were significantly higher in patients with skin lesions (OR = 2.37, P < 0.0005, Pc < 0.012) and arthritis (OR = 2.32, P = 0.002, Pc = 0.048), with uveitis (OR = 3.01, P < 0.0005, Pc < 0.012), and with vascular lesions (OR = 9.80, P < 0.0005, Pc < 0.012) and a positive pathergy test (OR = 4.10, P = 0.002, Pc = 0.048), respectively, than in controls. In HLA-B*51 non-carriers, these associations were also significant, being much stronger between HLA-A*26:01 and uveitis (OR = 4.19, P < 0.0005, Pc < 0.012) and between HLA-A*30:04 and vascular lesions (OR = 13.97, P < 0.00005, Pc < 0.0012). In addition, HLA-A*30:04 was associated with genital ulcers in HLA-B*51 non-carriers (OR = 3.89, P = 0.002, Pc = 0.048).ConclusionsHLA-A*02:07, A*26:01, and A*30:04 were associated with increased risk for BD, while HLA-A*33:03 with decreased risk. HLA-A*02:07, A*26:01, and A*30:04 were associated with skin lesions and arthritis, with uveitis, and with vascular lesions, genital ulcers, and a positive pathergy test, respectively.

The EULAR Sjögren’s syndrome patient reported index as an independent determinant of health-related quality of life in primary Sjögren’s syndrome patients: in comparison with non-Sjögren’s sicca patients

OBJECTIVE To investigate the significant determinants of health-related quality of life (HRQOL) and the association of the EULAR Sjögrens syndrome patient reported index (ESSPRI) with clinical parameters including HRQOL in Korean patients with primary Sjögrens syndrome (pSS) compared with non-SS sicca patients. METHODS We prospectively analysed 104 pSS and 42 non-SS sicca patients. Clinical data including Short Form 36 (SF-36) scores, self-assessments for symptoms and ESSPRI were cross-sectionally collected. RESULTS Although most self-assessments and HRQOL statuses were comparable, different association patterns between HRQOL and symptoms were observed in pSS and non-SS sicca patients. pSS patients with low HRQOL had significantly higher ESSPRI scores [P = 7.6 × 10(-6) for physical component summary (PCS) subgroups and P = 0.0015 for mental component summary (MCS) subgroups] and ESSPRI scores showed a significant association with all SF-36 scales in pSS patients (all P ≤ 0.0020). Moreover, in multivariate linear regression analyses, ESSPRI (P = 0.035) and depression (P = 4.1 × 10(-14)) were significantly correlated with the PCS and the MCS, respectively. However, in the non-SS sicca group, xerostomia inventory (XI) scores were higher in the low PCS subgroup (P = 0.031) and this correlated with five SF-36 scales (all P ≤ 0.046). XI scores (P = 0.0039) and anxiety (P = 7.9 × 10(-10)) were the main determinants of the PCS and MCS, respectively. CONCLUSION HRQOL levels were differentially associated with clinical facets in pSS and non-SS sicca patients, although the groups had similar clinical symptoms and HRQOL reduction. Because depression and ESSPRI are major determinants of HRQOL in Korean pSS patients, ESSPRI is suggested to be disease-specific for pSS.

Comparison of radioimmunoprecipitation versus antigen-specific assays for identification of myositis-specific autoantibodies in dermatomyositis patients

Abstract Background. To confirm the antigen specificities of autoantibodies that precipitate 140-kDa (anti-p140) or 155/140-kDa polypeptides (anti-p155/140) previously identified by radioimmunoprecipitation in Korean patients with dermatomyositis (DM) and to look into the relationship between each MSA and clinical features of DM. Methods. Seventeen serum samples of classic DM patients who had been found to have either anti-p140 antibodies (n = 9) or anti-p155/140 (n = 8) antibodies in our previous study were examined using enzyme-linked immunosorbent assay (for anti-MDA5 antibodies) and immunoblotting (for anti-MJ/NXP-2 and anti-TIF-1γ antibodies). Results. Seven out of nine anti-p140 antibody positive patients were found to have anti-MDA5 antibodies. Two out of nine had anti-MJ/NXP-2 antibodies with no interstitial lung disease (ILD). All eight anti-p155/140 antibody positive patients were found to have anti-TIF-1γ antibodies. Anti-TIF-1γ and anti-MDA5 antibodies were simultaneously detected in one patient with anti-p155/140 antibody, who suffered HIV infection and non-Hodgkins lymphoma. The associations between anti-MDA5 antibody and rapidly progressive ILD and between anti-TIF-1γ antibody and cancer-associated DM were confirmed to be significant. Conclusions. Although radioimmunoprecipitation still looks to be a good screening tool, confirmation with antigen-specific assays seems mandatory. The associations between anti-MDA5 and rapidly progressive ILD and between anti-TIF-1γ and cancer-associated DM were confirmed in Korean patients with DM.

Behçet’s disease and genes within the major histocompatibility complex region

The role of genetic background in the development of Behçet’s disease (BD) is best reflected by the strong association between HLA-B*51 and BD that has been demonstrated across various ethnic groups. The contributions made by other HLA or non-HLA genes to disease susceptibility have been suggested by the results of a number of gene association studies, although the true associations between the genes located within the major histocompatibility complex (MHC) region and BD have often been doubted due to the possibility of linkage disequilibrium of those genes with HLA-B*51. The presence of a true susceptibility gene in the vicinity of HLA-B*51 has also been extensively investigated because of the limited evidence that directly relates HLA-B*51 to the pathogenesis of BD. However, recent genome-wide association studies have confirmed that HLA-B*51 is primarily associated with BD and that there are multiple susceptibility loci other than HLA-B*51. In this review, we discuss BD-associated genes within the MHC region and their biological roles in the pathogenesis of BD.

Genetic and non-genetic factors affecting the visual outcome of ocular Behcet’s disease

OBJECTIVE To examine the prognostic factors for visual outcome in Korean BD patients with uveitis. METHODS Seventy-seven Korean BD patients with uveitis were enrolled. HLA-B and HLA-A genotypes were determined by PCR-based method. Visual acuity was measured by Snellen chart. Vision loss was graded into visual impairment (VI) defined as VA<20/40 for more than 6 months, loss of useful vision (LUV) as VA < 20/200, and near total blindness (NTB) as VA of light perception or worse. RESULTS VI was associated with a longer duration of uveitis, posterior uveitis, and cataract, LUV with male gender, a longer duration of uveitis, posterior uveitis, and cataract, and NTB with a longer duration of uveitis, cataract, and glaucoma. HLA-B*51 and HLA-A*26:01 did not show any association with VI, LUV, or NTB. However, HLA-B*51 carriers had earlier onset of uveitis and HLA-A*26:01 was strongly associated with posterior uveitis. In patients with posterior uveitis, VI was associated with a longer duration of uveitis and cataract, LUV with a longer duration, and NTB with HLA-B*51. CONCLUSION Longer duration of uveitis, posterior uveitis, male gender, cataract, and glaucoma were found to be associated with poor visual outcome in BD-related uveitis. HLA-B*51 was associated with NTB in patients with posterior uveitis. HLA-A*26:01 showed no association with VI, LUV, or NTB, however, was strongly associated with posterior uveitis.

Cytokine signaling-1 suppressor is inducible by IL-1beta and inhibits the catabolic effects of IL-1beta in chondrocytes: its implication in the paradoxical joint-protective role of IL-1beta.

IntroductionAlthough IL-1β is believed to be crucial in the pathogenesis of osteoarthritis (OA), the IL-1β blockade brings no therapeutic benefit in human OA and results in OA aggravation in several animal models. We explored the role of a cytokine signaling 1 (SOCS1) suppressor as a regulatory modulator of IL-1β signaling in chondrocytes.MethodsCartilage samples were obtained from patients with knee OA and those without OA who underwent surgery for femur-neck fracture. SOCS1 expression in cartilage was assessed with immunohistochemistry. IL-1β-induced SOCS1 expression in chondrocytes was analyzed with quantitative polymerase chain reaction and immunoblot. The effect of SOCS1 on IL-1β signaling pathways and the synthesis of matrix metalloproteinases (MMPs) and aggrecanase-1 was investigated in SOCS1-overexpressing or -knockdown chondrocytes.ResultsSOCS1 expression was significantly increased in OA cartilage, especially in areas of severe damage (P < 0.01). IL-1β stimulated SOCS1 mRNA expression in a dose-dependent pattern (P < 0.01). The IL-1β-induced production of MMP-1, MMP-3, MMP-13, and ADAMTS-4 (aggrecanase-1, a disintegrin and metalloproteinase with thrombospondin motifs 4) was affected by SOCS1 overexpression or knockdown in both SW1353 cells and primary human articular chondrocytes (all P values < 0.05). The inhibitory effects of SOCS1 were mediated by blocking p38, c-Jun N-terminal kinase (JNK), and nuclear factor κB (NF-κB) activation, and by downregulating transforming growth factor-β-activated kinase 1 (TAK1) expression.ConclusionsOur results show that SOCS1 is induced by IL1-β in OA chondrocytes and suppresses the IL-1β-induced synthesis of matrix-degrading enzymes by inhibiting IL-1β signaling at multiple levels. It suggests that the IL-1β-inducible SOCS1 acts as a negative regulator of the IL-1β response in OA cartilage.