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Background/aims To define standard reference values for musculoskeletal ultrasonography (MSUS) in Korea. Methods A total of 251 healthy adults were recruited for this study. Ultrasonography was performed by experienced rheumatologists who had undergone four appropriate training programs in Korea. A General Electric LOGIQ electronic ultrasound device fitted with a 12 MHz linear transducer was employed. Mean values ± standard deviations (SDs) were defined as standard reference values. Intraclass correlation coefficients was employed to evaluate the extent of inter- and intraobserver agreement when MSUS measurements were made. Results The 251 study participants included 122 males. Mean subject age was 28.6 years. The average bone-to-capsule distance of the right-side second and third metacarpophalangeal (MCP) joints were 0.68 and 0.72 mm respectively, and those of the left-side joints 0.62 and 0.68 mm. The cartilage thicknesses of the rightside second and third MCP joints were 0.55 and 0.55 mm, and those of the leftside joints were 0.55 and 0.56 mm, respectively. The bone-to-capsule distances of the right and left wrists were 0.80 and 0.82 mm. In 12.4% of participants (31/251), the erosion score of the humeral head was 1.71. In the right-side knee joint, mean cartilage thicknesses of the medial and lateral condyles were 1.86 and 2.03 mm in longitudinal scans. High overall interobserver agreement was evident after appropriate training that included instruction on standard MSUS methodology. Conclusion We defined standard reference values for MSUS in healthy Korean adults. The reliabilities of interobserver agreements were high after appropriate training program.

Objective The aim of this study was to identify the susceptibility genes responsible for lumbar spondylosis (LS) in Korean patients. Methods Data from 1427 subjects were made available for radiographic grading and genome wide association studies (GWAS) analysis. Lateral lumbar spine radiographs were obtained and the various degrees of degenerative change were semi-quantitatively scored. A pilot GWAS was performed using the AffymetrixGenome-Wide Human single-nucleotide polymorphisms (SNPs), 500K array. A total of 352228 SNPs were analyzed and the association between the SNPs and case-control status was analyzed by stepwise logistic regression analyses. Results The top 100 SNPs with a cutoff p-value of less than 3.7×10-4 were selected for joint space narrowing, while a cutoff p-value of 6.0×10-4 was applied to osteophytes and the Kellgren-Lawrence (K-L) osteoarthritis grade. The SNPs with the strongest effect on disc space narrowing, osteophytes, and K-L grade were serine incorporator 1 (rs155467, odds ratio [OR]=17.58, p=1.6×10-4), stromal interaction molecule 2 (STIM1, rs210781, OR=5.53, p=5×10-4), and transient receptor potential cation channel, subfamily C (rs11224760, OR=3.99, p=4.8×10-4), respectively. Leucine-rich repeat-containing G protein-coupled receptor 4 was significantly associated with both disc space narrowing and osteophytes (rs1979400, OR=2.01, p=1.1×10-4 for disc space narrowing, OR=1.79, p=3×10-4 for osteophytes), while zinc finger and BTB domain containing 7C was significantly and negatively associated with both osteophytes and a K-L grade >2 (rs12457004,OR=0.25, p=5.8×10-4 and OR=0.27, p=5.3×10-4, respectively). Conclusion We identified SNPs that potentially contribute to the pathogenesis of LS. This is the first report of a GWAS in an Asian population.

To identify the prevalence of interstitial lung disease (ILD) in Korean patients with rheumatoid arthritis (RA) and assess its effect on mortality. A total of 3555 patients with RA, with chest X-ray or chest computed tomography (CT) data at enrollment were extracted from the KORean Observational study Network for Arthritis cohort, a nationwide prospective cohort for patients with RA in Korea. The patients were classified into two groups: (1) an ILD group by chest X-ray or chest CT scan, and (2) a non-ILD group by these modalities. After comparing the characteristics of the groups at enrollment, mortalities were compared using the log-rank test. To explore the impact of ILD on mortality, Cox proportional hazard models were used. Sixty-four patients (1.8%) were identified with ILD. Male and older patients were more common in the ILD group. During a mean follow-up of 24 months, 6 patients (9.4%) in the ILD group and 25 patients (0.7%) in the non-ILD group died; the survival rate was significantly worse in the ILD group (p

This study was supported by the Korea Healthcare Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (HI10C2020). The authors wish to acknowledge the assistance of the following investigators who enrolled patients in KORONA: Joong Kyoung Ahn (Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul), Sung Jae Choi (Korea University Ansan Hospital, Ansan), Minyoung Her (Inje University Busan Paik Hospital, Busan), Chung- Il Joung (Konyang University Hospital, Daejeon), Young Mo Kang (Kyungpook National University Hospital, Daegu), Dong- Yook Kim (Inje University Busan Paik Hospital, Busan), Hae- Rim Kim (Konkuk University Medical Center, Seoul), Hyoun Ah Kim (Ajou University Hospital, Suwon), Choong Ki Lee (Yeungnam University Medical Center, Daegu), Sang- Hoon Lee (Kyung Hee University Hospital at Gangdong, Seoul), Seong- Su Nah (Soon Chun Hyang University Cheonan Hospital, Cheonan), Sung- Hoon Park (Catholic University of Daegu School of Medicine, Daegu), Dong Hyuk Sheen (Eulji University Hospital, Daejeon), Gwan Gyu Song (Korea University Guro Hospital, Seoul), Chang- Hee Suh (Ajou University Hospital, Suwon), and Yoo Wan- Hee (Chonbuk National University Hospital, Jeonju).

Objective The purpose of this study was to investigate the prevalence of and the relevant risk factors for lumbar spondylosis (LS) among middle-aged and elderly rural Korean residents and to explore the association between radiographic LS and lower back pain (LBP) in relation to age and gender. Methods This community-based, cross-sectional study evaluated 1512 subjects with available radiograph. The prevalence of LBP was obtained using a questionnaire and disability resulting from LBP was measured using a validated Korean version of the Oswestry disability index (ODI). In lumbar spine radiographs, vertebral levels from L1/2 to L4/5 were evaluated for the presence of osteophytes and joint-space narrowing (JSN), and Kellgren-Lawrence (KL) grading was applied. Results Of 4261 subjects aged 40-79 years, data from 1512 subjects were included. The prevalence of radiographic LS indicated by grade ≥2 osteophytes and JSN were 53.9 and 15.8%, respectively. Seventy-three percent of subjects had KL grade ≥2 spondylosis and LBP was present in 36.5% of subjects. Although LS was more common among males, the prevalence of LBP was higher among females. Age, male gender and history of hand or knee arthritis were risk factors for LS. LS was significantly associated with LBP mostly among females over 60 years old and correlated with the ODI after adjusting for age and gender. Conclusion Our study among rural Korean residents revealed a high prevalence of LS and LBP. The association between LS and LBP was observed mostly among females and LS was significantly correlated with the severity of back pain.

To determine characteristics of rheumatoid arthritis (RA) patients in Korea using disease-modifying anti-rheumatic drugs (DMARDs) for at least 6 months, and to identify factors associated with poor health-related outcomes.A total of 2000 RA patients aged20 years, treated with DMARDs for at least 6 months, and signed informed consent, were enrolled in this non-interventional, multicenter, cross-sectional observational study from December 2012 to June 2013. Health-related quality of life (HRQoL) was measured using EuroQuol 5D (EQ-5D) and functional disability was measured using the Korean Health Assessment Questionnaire (KHAQ). Univariate and multivariate linear regression analyses were used to determine the association between patient characteristics and patient-reported outcomes (PROs).Of all RA patients, 84% were female, patients with low Disease Activity Score of 28 joints erythrocyte sedimentation rate (DAS-28-ESR3.2) was 54%, while moderate (DAS-28-ESR 3.2-5.1) and high disease activity score (DAS-28-ESR5.1) were 38% and 7.6%, respectively. Mean EQ-5D index score and KHAQ score were 0.6 ± 0.28 and 0.7 ± 0.67, respectively. In multivariate analysis with both PROs, average HRQoL and functional disability score appeared to be worse in persons with older age compared to younger age (P0.001), and worse in females compared to males (P0.001). Compared to patients having lower DAS (3.2), those with moderate and highest DAS (3.2-5.1 and5.1) had worse outcome measures (P0.001).In this study, higher DAS was one of the most influential factors for poor PROs among all other factors. Therefore, we could suggest appropriate treatment approaches according to DAS along with other significantly associated factors with PROs in the early stage of RA.

Ultra-thin HfO2 films of 3.5, 5.0, and 8.0 nm nominal thicknesses were prepared, respectively, on silicon substrates by using atomic layer deposition method. Through the analyses of X-ray reflectometry (XRR), X-ray photoelectron spectroscopy, and transmission electron microscopy for HfO2 films with and without sample cleaning, the effects of surface contamination on XRR curve and film thickness were investigated, and contamination layer was observed and the thickness of the layer was determined. X-ray photoelectron spectroscopy results indicated that the amount of surface contamination varied considerably because of the surface cleaning. XRR curve shapes and the positions of thickness fringes changed and the thickness from Fourier analyses of the curves were different for the same sample due to the different surface contamination. Contamination layer of about 1 nm thickness was observed by Fourier analysis of XRR curve. Simulation for XRR curve showed the best fit to data when contamination layer of about 1 nm thickness was considered, and the result was consistent with that of the Fourier analysis. Copyright © 2016 John Wiley & Sons, Ltd.

Objective We hypothesized that chronic gouty arthritis patients would develop an immune response to type II collagen that would be revealed by the presence of anti-type II collagen (CII) antibodies in serum, which may in turn be involved in progression to non-remitting arthritis. Methods Chronic gouty arthritis was defined as crystal-confirmed gout in patients with no pain-free intercritical period, with or without the presence of tophi, who did not have clinical features of other forms of chronic arthritis. Age-matched gout patients suffering acute gouty attacks who had definite intercritical periods were selected as a control group. Four RA patients who had active disease were enrolled as a positive control group. Anti-CII antibodies were quantified in patient sera via ELISA using a human IgG anti-CII antibody assay kit. Correlations between anti-CII levels and clinical parameters were sought. Results Fifteen chronic gouty arthritis patients were identified. The anti-CII level was significantly higher among subjects with chronic gout compared to controls, but did not significantly differ in control gout patients during acute attacks and in the intercritical periods. Five patients with chronic gouty arthritis had anti-CII antibody levels higher than 200 AU/mL, whereas only one control gout patient exhibited this feature. Two of four patients with active RA had anti-CII antibody levels higher than 200 U/mL.Patients with tophi had significantly higher anti-CII levels than those without, whereas patients showing radiographic erosion tended to have higher anti-CII levels than those without. Conclusion Patients with chronic gouty arthritis had significantly higher levels of anti-CII antibodies than control gout patients. Such antibody production would be triggered by initiation of cartilage damage but may also play a role in perpetuation of inflammation.

Purpose: This study was conducted to determine the effects of middle-aged women's social support, self-efficacy, and perceived health status on aging anxiety. Methods: Research subjects were 210 middle-aged women between 40 - 60 years living in G-city. Data were collected from July 2014 to August using a structured questionnaire and analyzed using t-test, One way ANOVA, and multiple regression analysis using the SPSS/WIN 21.0 program. Results: Aging anxiety showed statistically significant differences in religion (t=2.44, p=.015), satisfaction with married life (F=4.39, p=.014), type of leisure activity (F=8.09, p, p, p, p=.010), and religious affiliation (, p=.038). The predictive power of these variables was 25% (F=18.63, p

Objective Intravenous immunoglobulin (IVIG) is used as a therapeutic agent in various autoimmune diseases. The aims of this study were to investigate the therapeutic effects of IVIG on collagen-induced arthritis (CIA) and identify the mechanism responsible for any therapeutic effects. Methods IVIG was administered to mice with CIA, and the in vivo effects were determined. Th17 and Treg cell frequencies were analyzed by flow cytometry, and cytokine levels in the supernatant were measured by enzyme-linked immunosorbent assay. Subpopulations of T cells and B cells in the spleen were assessed by confocal microscopy. Results The arthritis severity score and incidence of arthritis were lower in mice treated with IVIG compared with untreated mice. Histopathologic analysis showed less joint damage in mice treated with IVIG. The expression of proinflammatory cytokines, specific type II collagen antibodies, and osteoclast markers was significantly reduced in mice treated with IVIG. Administration of IVIG induced increased FoxP3 expression and inhibited Th17 cell development. The number of FoxP3+ Treg cells was increased, and the number of Th17 cells was decreased in the spleens of mice treated with IVIG. The number of FoxP3+ follicular helper T cells was increased, and subsequent maturation of germinal center B cells was inhibited by IVIG. In addition, IVIG up-regulated interleukin-10 (IL-10) and Fcγ receptor IIB expression. The treatment effects of IVIG on arthritis were lost in IL-10–knockout mice. Conclusion These results showed that IVIG has therapeutic effects by modulating CD4+ T cell differentiation. The therapeutic effects of IVIG are dependent on IL-10.

Takayasu arteritis is an uncommon chronic inflammatory arteritis affecting large vessels, predominantly the aorta and its main branches. This disease, primarily known to be frequent in Asia and Latin America region, occurs mainly in young people between the ages of 15 and 25 years, with a male to female ratio of 1:9. Here, we report a young Asian female patient with Takayasu arteritis affecting multiple arteries and treated with percutaneous transluminal angioplasty.

Background: Foxp3 is a key regulator of the development and function of regulatory T cells (Tregs), and its expression is thought to be T cell-restricted. We found that B cells in mice can express Foxp3 and B cells expressing Foxp3 may play a role in preventing the development of collagen-induced arthritis (CIA) in DBA/1J mice. Methods: Foxp3 expression was modulated in CD19(+) B cells by transfection with shRNA or using an over-expression construct. In addition, Foxp3-transfected B cells were adoptively transferred to CIA mice. We found that LPS or anti-IgM stimulation induced Foxp3 expression in B cells. Foxp3-expressing B cells were found in the spleens of mice. Results: Over-expression of Foxp3 conferred a contact-dependent suppressive ability on proliferation of responder T cells. Down-regulation of Foxp3 by shRNA caused a profound induction in proliferation of responder T cells. Adoptive transfer of Foxp3(+)CD19(+) B cells attenuated the clinical symptoms of CIA significantly with concomitant suppression of IL-17 production and enhancement of Foxp3 expression in CD4(+) T cells from splenocytes. Conclusion: Our data indicate that Foxp3 expression is not restricted to T cells. The expression of Foxp3 in B cells is critical for the immunoregulation of T cells and limits autoimmunity in a mouse model.

Interleukin (IL)-27 is a heterodimeric cytokine that is known to have both stimulatory and inhibitory functions during immune responses. We investigated the effects of IL-27 on arthritis and bone erosion in the murine collagen-induced arthritis (CIA) model. We demonstrate that the inhibitory effect of IL-27 on osteoclastogenesis is associated with interferon-γ (IFN-γ) production by using an IFN-γ knockout mouse model. The IL-27-Fc was injected into both CIA and IFN-γ-deficient mice. The effects of IL-27-Fc on osteoclast differentiation were evaluated both in vitro and in vivo. The IL-27-Fc-injected mice showed significantly lower arthritis indices and fewer tartrate-resistant acid-phosphatase-positive osteoclasts in their joint tissues than untreated mice. Interleukin-27 inhibited osteoclastogenesis from bone marrow-derived mononuclear cells in vitro, which was counteracted by the addition of anti-IFN-γ antibody. The IL-27-Fc did not affect arthritis in IFN-γ knockout mice. Interleukin-27 also suppressed osteoclast differentiation in human and intriguingly, it could promote the expression of IFN-γ on priming osteoclasts. These results imply that IL-27 suppressed the generation of CIA and osteoclastogenesis, which were mediated by the induction of IFN-γ.

Study Design. A community-based, cross-sectional study that is part of the prospective Korean Health and Genome Study. Objective. To determine the prevalence of low back pain (LBP) among middle-aged and elderly rural community residents in Korea and to examine the relevant risk factors, including activities reflecting the Asian lifestyle, and the relationship between radiographical features of degenerative changes in the lumbar spine and LBP. Summary of Background Data. The prevalence and implication of LBP among the elderly, particularly Asians, are under-represented in previous reports. Methods. Data for LBP were collected for 4181 subjects from a rural farming community. The point and cumulative lifetime prevalences of LBP were obtained in addition to measurement of the severity of LBP. Lateral lumbar spine radiographs were obtained according to a standard protocol. Results. The mean age of the study subjects was 56 years and 55% were women. The lifetime prevalence of LBP was 61.3%, with women having a higher prevalence. The point and 6-month prevalences were also higher among women. The lifetime, point, and 6-month prevalences increased with age in both sexes, except for lifetime prevalence in men. The prevalence of LBP of grade 3 or more was significantly higher in women and increased significantly with age, particularly in women. Both lifetime and point of prevalence of LBP were significantly associated with age, female sex, and time spent squatting. After adjusting for age and sex, the presence of disc space narrowing, osteophytes, and advanced Kellgren-Lawrence grade in lumbar radiograph was associated with LBP. Conclusion. The prevalence of LBP is comparable between these Korean community residents and other population groups. Risk factors associated with LBP included advanced age, female sex, squatting, the presence of osteophytes, joint space narrowing, and advanced Kellgren-Lawrence grading on lumbar radiograph.

Rheumatoid arthritis (RA) is a progressive inflammatory disease with severe symptoms of pain and stiffness. Chronic persistent inflammation of RA often leads to joint destruction, deformity and limitation of function, which ultimately results in significant deterioration of quality of life (QoL). RA is characterized pathogenetically by immunologically driven, chronic synovitis, and production of autoantibodies, such as rheumatoid factor and anti-cyclic citrullinated peptide antibodies. Although the cause of RA is yet unknown, advances in the molecular biology led to in-depth understanding of its pathogenesis, and have fostered the recent development of novel treatments. The last decade has seen the dramatic change in the landscape of RA treatment with more aggressive therapy early in the disease course and with treatment guided by a structured assessment of disease activity, with the ultimate goal of reaching remission. In addition, prevention and control of joint damage and improvement in QoL are important goals. To achieve these goals, a multidisciplinary approach to reduce disease activity with disease modifying antirheumatic drugs and biological therapy is needed. We also need to find ways to identify those patients who are at risk for more rapid disease progression who would benefit from intensive therapy early in the course of disease.

The aim of this study was to determine whether stimulation of toll-like receptor 2 (TLR2), TLR4, and TLR6 by their specific ligands induces the production of tumor necrosis factor-alpha (TNF-alpha) in fibroblast-like synoviocytes (FLS) from interleukin-1 receptor antagonist (IL-1Ra)-deficient mice. FLS were isolated from synovial tissues from IL-1Ra-deficient mice and stimulated with various ligands of TLRs. The concentrations of TNF-alpha, interleukin (IL)-1beta, and IL-10 in the culture supernatants of spleen cells were measured by ELISA, and mRNA levels were assessed by real-time PCR. The expression of TLR2, TLR4, TLR6, and TNF-alpha in the synovial tissue was quantified by immunohistochemistry. Cytokine production and TLR expression were measured in FLS stimulated in the presence of the TLR2 ligand PAM3, the TLR4 ligand lipopolysaccharide (LPS), and the TLR6 ligand zymosan, with and without blocking antibody to TNF-alpha and IL-1beta. Stimulation of TLR2, TLR4, and TLR6 by their specific ligands increased the production of TNF-alpha in FLS from IL-1Ra-deficient mice. The stimulatory effect of these TLR ligands showed a dose-dependent pattern. The combination of TLR2, TLR4, and TLR6 synergistically increased the production of TNF-alpha, IL-1beta, TLR2, TLR4, and TLR6. Addition of blocking antibodies to TNF-alpha and IL-1beta abrogated the stimulatory effect of the ligands of TLR2, TLR4, and TLR6 on the production of TNF-alpha, IL-1beta, TLR2, TLR4, and TLR6. These data show that TLR2, TLR4, and TLR6 ligation synergistically stimulates the production of TNF-alpha and IL-1beta in IL-1Ra-deficient mice and suggest that TLRs contribute to the perpetuation of spontaneous arthritis in this animal model.

Cytokine and chemokine receptors play a key role in inflammation caused by rheumatoid arthritis (RA). Two isoforms of human CC chemokine receptor R2 (CCR2), the receptor of monocyte chemoattractant protein 1 (MCP-1), have been identified but their relative expression in fibroblast-like synoviocytes (FLS) and their contribution to inflammatory responses mediated by MCP-1 or inflammatory cytokines in patients with RA remain uncertain. We examined the pattern of expression of two CCR2 isoforms upon stimulation by proinflammatory cytokines and CD40 ligation. FLS were prepared from the synovial tissues of RA patients and cultured in the presence of MCP-1, soluble CD40 ligand (sCD40L), TGF-beta, IL-1beta, IL-18, IL-15, and LPS. CCR2A and CCR2B expression was examined by immunohistochemistry, RT-PCR and western blot analysis. IL-15, TNF-alpha and MCP-1 production was determined by ELISA. Immunohistochemistry showed that CCR2A is highly expressed in RA synovium compared with OA synovium. Transcripts of both CCR2A and CCR2B were detected in FLS. Exogenous MCP-1, CD40L, TGF-beta, and IL-15 significantly increased the expression of CCR2A but not CCR2B. Exposure of FLS to sCD40L caused strong upregulation of CCR2A but not of CCR2B protein expression. MCP-1 increased the proliferation of FLS and the production of IL-15, TNF-alpha, and IL-18. Because CCR2A is the main target of regulation by cytokines and CD40 ligation, the relatively higher expression of CCR2A on the cell surface suggests that this isoform of MCP-1 receptor functions as the principal mediator of inflammatory signals in RA FLS.

Toll-like receptors (TLRs) are pattern-recognition receptors that connect innate and adaptive immunity. Interleukin-15 (IL-15) is a proinflammatory, innate response cytokine that mediates pleiotropic effector functions in inflammatory synovitis of rheumatoid arthritis (RA). The aim of this study was to clarify whether stimulation of TLR2 and TLR4 by their specific ligands induces the production of IL-15 in fibroblast-like synoviocytes (FLS) from RA patients. FLS were isolated from RA synovial tissues and stimulated with the TLR2 ligand bacterial peptidoglycan (PGN) and the TLR4 ligand lipopolysaccharide (LPS). IL-15 in the culture supernatants was measured by ELISA, and mRNA levels were assessed by RT-PCR and real time PCR. The expression of TLR2, TLR4, and IL-15 in the RA synovium was quantified by immunohistochemistry and compared with values obtained in osteoarthritis synovium. IL-15 production increased in culture supernatants of RA FLS stimulated with PGN or PGN plus LPS, and this was upregulated at the transcriptional level. In contrast, LPS did not increase the level of IL-15 although it augmented the stimulatory effect of PGN on IL-15 production. Inhibition of nuclear factor (NF)-kappaB with a specific inhibitor abrogated the stimulatory effect of PGN or PGN plus LPS on IL-15. Neutralization of TLR2 with a blocking monoclonal antibody significantly reduced IL-15 production (P0.05), reflecting the functional relevance of TLR2 activation in the induction of IL-15 production. These data suggest that TLR2 activation in RA FLS by microbial constituents is involved in the induction of IL-15 and that TLR2 promotes inflammation through NF-kappaB. TLR4 augmented the stimulatory effect of TLR2 on IL-15, possibly contributing to the maintenance of synovitis in patients with RA.

Objective.Rheumatoid arthritis (RA) is a chronic autoimmune disease that is often painful and debilitating. Patients with RA are increasingly receiving complementary and alternative medicine (CAM). We aimed to identify the patient characteristics and disease-specific factors associated with Korean patients with RA who decide to start treatment with CAM.Methods.Among the total 5371 patients with RA in the KORean Observational study Network for Arthritis (KORONA), 2175 patients who had no experience with CAM were included in our study. In our study, we assessed the frequency of new incident CAM use, its patterns, and the predictive factors of new CAM use.Results.Of the 2175 patients, 229 patients (10.5%) newly started receiving CAM within a year of enrolling in the cohort. Of those who started treatment with CAM, 17.0% received only herbal medicine, 54.6% only acupuncture treatments (7.0% used a combination of both), and 21.4% “Other” (e.g., physical therapy and placental extract injections). Women (OR 1.89, 95% CI 1.13–3.14) and patients with depression (OR 3.52, 95% CI 1.65–7.50) were significantly more likely to be treated with CAM. Regarding household types, patients who lived in an extended family (OR 1.78, 95% CI 1.08–2.95) or as part of a couple (OR 1.55, 95% CI 1.07–2.24) were more likely to be treated with CAM than patients living in a nuclear family.Conclusion.Our study found, within a year, an incidence rate of 10.5% for new CAM use among patients with no previous experience with CAM. Sex, depression, and household type were significantly associated with new CAM use.

Coenzyme Q10 (CoQ10) is a lipid-soluble antioxidant synthesized in human body. This enzyme promotes immune system function and can be used as a dietary supplement. Rheumatoid arthritis (RA) is an autoimmune disease leading to chronic joint inflammation. RA results in severe destruction of cartilage and disability. This study aimed to investigate the effect of CoQ10 on inflammation and Th17 cell proliferation on an experimental rheumatoid arthritis (RA) mice model. CoQ10 or cotton seed oil as control was orally administrated once a day for seven weeks to mice with zymosan-induced arthritis (ZIA). Histological analysis of the joints was conducted using immunohistochemistry. Germinal center (GC) B cells, Th17 cells and Treg cells of the spleen tissue were examined by confocal microscopy staining. mRNA expression was measured by real-time PCR and protein levels were estimated by enzyme-linked immunosorbent assay (ELISA). Flow cytometric analysis (FACS) was used to evaluate Th17 cells and Treg cells. CoQ10 mitigated the severity of ZIA and decreased serum immunoglobulin concentrations. CoQ10 also reduced RANKL-induced osteoclastogenesis, inflammatory mediators and oxidant factors. Th17/Treg axis was reciprocally controlled by CoQ10 treatment. Moreover, CoQ10 treatment on normal mouse and human cells cultured in Th17 conditions decreased the number of Th17 cells and enhanced the number of Treg cells. CoQ10 alleviates arthritis in mice with ZIA declining inflammation, Th17 cells and osteoclast differentiation. These findings suggest that CoQ10 can be a potential therapeutic substance for RA.

The 12 kDa FK506-binding protein (FK506BP12), an immunosuppressor, modulates T cell activation via calcineurin inhibition. In this study, we investigated the ability of PEP-1-FK506BP12, consisting of FK506BP12 fused to the protein transduction domain PEP-1 peptide, to suppress catabolic responses in primary human chondrocytes and in a mouse carrageenan-induced paw arthritis model. Western blotting and immunofluorescence analysis showed that PEP-1-FK506BP12 efficiently penetrated chondrocytes and cartilage explants. In interleukin-1β (IL-1β)-treated chondrocytes, PEP-1-FK506BP12 significantly suppressed the expression of catabolic enzymes, including matrix metalloproteinases (MMPs)-1, -3, and -13 in addition to cyclooxygenase-2, at both the mRNA and protein levels, whereas FK506BP12 alone did not. In addition, PEP-1-FK506BP12 decreased IL-1β-induced phosphorylation of the mitogen-activated protein kinase (MAPK) complex (p38, JNK, and ERK) and the inhibitor kappa B alpha. In the mouse model of carrageenan-induced paw arthritis, PEP-1-FK506BP12 suppressed both carrageenan-induced MMP-13 production and paw inflammation. PEP-1-FK506BP12 may have therapeutic potential in the alleviation of OA progression. [BMB Reports 2015; 48(7): 407-412]

IL-23 is the key cytokine that induces the expansion of Th17 cells. It is composed of p19 and p40 subunits of IL-12. The p40 subunit binds competitively to the receptor of IL-23 and blocks its activity. Our aim was to assess the preventive and therapeutic effect of the IL-12p40 homodimer (p40)2 subunit in autoimmune arthritis animal models. In the current study, using IL-1R antagonist–knockout mice and a collagen-induced arthritis model, we investigated the suppressive effect of (p40)2 on inflammatory arthritis. We demonstrated that the recombinant adenovirus-expressing mouse (p40)2 model prevented the development of arthritis when given before the onset of arthritis. It also decreased the arthritis index and joint erosions in the mouse model if transferred after arthritis was established. (p40)2 inhibited the production of inflammatory cytokines and Ag-specific T cell proliferation. It also induced CD4+CD25+Foxp3 regulatory T (Treg) cells in vitro and in vivo, whereas the generation of retinoic acid receptor–related organ receptor γt and Th17 cells was suppressed. The induction of Treg cells and the suppression of Th17 cells were mediated via activated STAT5 and suppressed STAT3. Our data suggest that (p40)2 suppressed inflammatory arthritis successfully. This could be a useful therapeutic approach in autoimmune arthritis to regulate the Th17/Treg balance and IL-23 signaling.

Interleukin-18 (IL-18) is a novel pro-inflammatory cytokine which has been implicated to play a pathogenic role in rheumatoid arthritis (RA). Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis in rheumatoid synoviocytes. In present study, we examined the effect of IL-18 on VEGF production in fibroblast-like synoviocytes (FLS) isolated from the patients with RA. FLS were prepared from the synovial tissues of patients with RA and osteoarthritis (OA) and cultured in the presence of IL-18. The production of VEGF from FLS was measured in culture supernatants by enzyme-linked immunosorbent assay (ELISA). The VEGF messenger RNA (mRNA) expression and AP-1 binding activity of VEGF transcript were determined by reverse transcription-polymerase chain reaction (RT-PCR) and electrophoretic mobility shift assay (EMSA). IL-18 and VEGF levels of sera and synovial fluids (SF) of RA patients (n=30) were significantly higher than those of OA patients (n=20). IL-18 dose-dependently increased the production of VEGF. The effect of IL-18 on VEGF production appeared to be as potent as IL-1beta, whereas tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma showed little effects on VEGF production. AP-1-specific inhibitor Curcumin dose-dependently abrogated the effect of IL-18 on VEGF production. The VEGF enhancement of IL-18 was associated with increased AP-1 binding activity to the VEGF promoter site. These findings suggest IL-18 as an angiogenic factor in RA and down-regulation of IL-18 activity or AP-1 signal pathway can be potential therapeutic targets for RA.

The green tea polyphenol epigallocatechin-3-gallate is a potent antioxidant. Here, we describe the effects of epigallocatechin-3-gallate on T cell differentiation and osteoclast differentiation in an animal model of arthritis. Mice with collagen-induced arthritis were injected intraperitoneally with epigallocatechin-3-gallate, 3 times/wk after the primary immunization. Surface markers of T helper 17 cells and regulatory T cells were analyzed by flow cytometry. Flow cytometry, Western blotting, and enzyme-linked immunosorbent assays were used to evaluate the effect of epigallocatechin-3-gallate on cell signaling in the collagen-induced arthritis model. Epigallocatechin-3-gallate decreased the arthritis index and showed protective effects against joint destruction in collagen-induced arthritis mice. The expression of cytokines, oxidative stress proteins, and phosphorylated-signal transducer and activator of transcription-3, 705 and 727, were significantly less in mice treated with epigallocatechin-3-gallate than it was in controls. Epigallocatechin-3-gallate reduced the expression of osteoclast markers in vitro and in vivo relative to the control, and the antiosteoclastic activity was observed in epigallocatechin-3-gallate–treated, interferon-γ knockout mice. The proportion of forkhead box protein 3–positive regulatory T cells was increased in the spleens of mice treated with epigallocatechin-3-gallate compared with control mice, whereas the proportion of T helper 17 cells was reduced. In vitro, the expression of nuclear respiratory factor 2, heme oxygenase-1, and extracellular signal-regulated kinase was increased significantly by epigallocatechin-3-gallate. We demonstrated that the administration of epigallocatechin-3-gallate attenuated the symptoms of arthritis, inhibited osteoclastogenesis and T helper 17 cell activation, and increased the number of regulatory T cells. At the molecular level, the antiarthritic effects of epigallocatechin-3-gallate may be due to induction of phosphorylated–extracellular signal-regulated kinase, nuclear respiratory factor 2, and heme oxygenase-1 and inhibition of signal transducer and activator of transcription-3 activation.

PAI-1 deficiency attenuates the fibrogenic response to ureteral obstruction . Background Progressive renal disease is characterized by the induction of plasminogen activator inhibitor-1 (PAI-1), suggesting that impaired activity of the renal plasmin cascade may play a role in renal fibrosis. Methods To test this hypothesis, the severity of renal fibrosis caused by unilateral ureteral obstruction (UUO) was compared in PAI-1 wild-type (+/+) and PAI-1 deficient (-/-) mice. The extent of interstitial inflammation and fibrosis, renal plasminogen activator and plasmin activity, and renal expression of profibrotic genes was evaluated after 3, 7, and 14 days of UUO. Results Renal PAI-1 mRNA levels increased 8- to 16-fold in the +/+ mice after UUO surgery, and PAI-1 protein was detected in kidney homogenates. Interstitial fibrosis was significantly attenuated in -/- mice compared with +/+ mice at day 7 and day 14, based on the interstitial area stained with picrosirius red and total kidney collagen content. However, neither the mean renal plasminogen activator nor plasmin activities were increased in -/- mice compared with +/+ mice. The number of interstitial macrophages were significantly lower in the -/- mice three and seven days after UUO; interstitial myofibroblasts were significantly fewer at three days. At the same time points, this altered interstitial cellularity was associated with a significant reduction in renal mRNA levels for transforming growth factor-β and procollagens α1(I) and α1(III). Conclusions These studies establish an important fibrogenic role for PAI-1 in the renal fibrogenic response. The results demonstrate that one important fibrosis-promoting function of PAI-1 is its role in the recruitment of fibrosis-inducing cells, including myofibroblasts and macrophages.

Background. Lamivudine is a potent inhibitor of hepatitis B virus replication. Little has been reported about the efficacy and safety of lamivudine in the treatment of chronic hepatitis B in the setting of renal transplantation. Methods. Two patients were treated for chronic hepatitis B with lamivudine and subsequently underwent renal transplantation. Four other patients were treated with lamivudine for reactivation of hepatitis B after renal transplantation. Chronic hepatitis B was proven histologically in all the patients. The doses of lamivudine ranged from 100 to 150 mg/day. Hepatic enzyme and viral markers were monitored. Results. Lamivudine was well tolerated for a median duration of 8 months (range, 4-14 months) without significant side effects. Viral replication was suppressed, as evidenced by negative conversion of serum hepatitis B virus DNA in all the patients. Hepatic enzyme was also normalized. Modification of doses of immunosuppressant regimen was not required in using lamivudine in all patients. One patient experienced acute rejection and responded to solumedrol pulse therapy with normalization of graft function. Normal graft function was maintained in other patients while they were treated with lamivudine. Conclusion. Lamivudine was a safe and effective therapy for activated hepatitis B in renal transplant recipients in the short term.

Epigallocatechin-3-gallate (EGCG) is a green tea polyphenol exerting potent anti-oxidant and anti-inflammatory effects by inhibiting signaling and gene expression. The objective of the study was to evaluate the effect of EGCG on interleukin (IL)-1 receptor antagonist knockout (IL-1RaKO) autoimmune arthritis models. IL-1RaKO arthritis models were injected intraperitoneally with EGCG three times per week after the first immunization. EGCG decreased the arthritis index and showed protective effects against joint destruction in the IL-1RaKO arthritis models. The expression of pro-inflammatory cytokines, oxidative stress proteins, and p-STAT3 (Y705) and p-STAT3 (S727), mTOR and HIF-1α were significantly lower in mice treated with EGCG. EGCG reduced osteoclast markers in vivo and in vitro along with anti-osteoclastic activity was observed in EGCG-treated IL-1RaKO mice. The proportion of Foxp3(+) Treg cells increased in the spleens of mice treated with EGCG, whereas the proportion of Th17 cells reduced. In vitro, p-STAT3 (Y705) and p-STAT3 (S727), HIF1α and glycolytic pathway molecules were decreased by EGCG. EGCG suppressed the activation of mTOR and subsequently HIF-1α, which is considered as a metabolic check point of Th17/Treg differentiation supporting the therapeutic potential of EGCG in autoimmune arthritis.

Intravenous immunoglobulin (IVIG) is used as a therapeutic agent in various autoimmune diseases. The aims of this study were to investigate the therapeutic effects of IVIG on collagen-induced arthritis (CIA) and identify the mechanism responsible for any therapeutic effects.IVIG was administered to mice with CIA, and the in vivo effects were determined. Th17 and Treg cell frequencies were analyzed by flow cytometry, and cytokine levels in the supernatant were measured by enzyme-linked immunosorbent assay. Subpopulations of T cells and B cells in the spleen were assessed by confocal microscopy.The arthritis severity score and incidence of arthritis were lower in mice treated with IVIG compared with untreated mice. Histopathologic analysis showed less joint damage in mice treated with IVIG. The expression of proinflammatory cytokines, specific type II collagen antibodies, and osteoclast markers was significantly reduced in mice treated with IVIG. Administration of IVIG induced increased FoxP3 expression and inhibited Th17 cell development. The number of FoxP3+ Treg cells was increased, and the number of Th17 cells was decreased in the spleens of mice treated with IVIG. The number of FoxP3+ follicular helper T cells was increased, and subsequent maturation of germinal center B cells was inhibited by IVIG. In addition, IVIG up-regulated interleukin-10 (IL-10) and Fcγ receptor IIB expression. The treatment effects of IVIG on arthritis were lost in IL-10-knockout mice.These results showed that IVIG has therapeutic effects by modulating CD4+ T cell differentiation. The therapeutic effects of IVIG are dependent on IL-10.

Chronic autoimmune inflammation, which is commonly observed in rheumatoid arthritis (RA), disrupts the delicate balance between bone resorption and formation causing thedestruction of the bone and joints. We undertook this study to verify the effects of natural grape-seed proanthocyanidin extract (GSPE), an antioxidant, on chronic inflammation and bone destruction. GSPE administration ameliorated the arthritic symptoms of collagen-induced arthritis (CIA), which are representative of cartilage and bone destruction. GSPE treatment reduced the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells and osteoclast activity and increased differentiation of mature osteoblasts. Receptor activator of NFkB ligand expression in fibroblasts from RA patients was abrogated with GSPE treatment. GSPE blocked human peripheral blood mononuclear cell-derived osteoclastogenesis and acted as an antioxidant. GSPE improved the arthritic manifestations of CIA mice by simultaneously suppressing osteoclast differentiation and promoting osteoblast differentiation. Our results suggest that GSPE may be beneficial for the treatment of inflammation-associated bone destruction.

To investigate the prevalence of knee pain and its influence on physical function and quality of life (QOL), we examined 504 community residents of Chuncheon, aged ≥ 50 yr. Demographic information was obtained by questionnaire, and radiographic evaluations consisted of weight-bearing semi-flexed knee anteroposterior radiographs. Self-reported QOL and function were assessed using the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index and Short Form 12 (SF-12). Performance-based lower extremity function was assessed using the tests consisting of standing balance, usual walk and chair stands. The prevalence of knee pain was 46.2% (32.2% in men and 58.0% in women) and increased with age in women. After adjustment of confounders including the presence of knee OA, the subjects with knee pain had significantly worse WOMAC function and SF-12 scores compared to subjects without knee pain. Among the subjects with knee pain, women had worse WOMAC and SF-12 scores than men. Subjects with knee pain had worse physical performance score compared to those without knee pain, especially among females. In conclusion, the prevalence of knee pain is high (32.2% in men and 58.0% in women) in this elderly community population in Korea. Independent of knee OA and other confounding factors, subjects with knee pain have more than 5-fold increase in the risk of belonging to the worst lower extremity function compared to subjects without knee pain.

Introduction The receptor for advanced glycation end-products (RAGE) has been implicated in the pathogenesis of arthritis. We conducted this study to determine the effect of interleukin (IL)-17 on the expression and production of RAGE in fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA). The role of nuclear factor-κB (NF-κB) activator 1 (Act1) in IL-17-induced RAGE expression in RA-FLS was also evaluated. Methods RAGE expression in synovial tissues was assessed by immunohistochemical staining. RAGE mRNA production was determined by real-time polymerase chain reaction. Act-1 short hairpin RNA (shRNA) was produced and treated to evaluate the role of Act-1 on RAGE production. Results RAGE, IL-17, and Act-1 expression increased in RA synovium compared to osteoarthritis synovium. RAGE expression and production increased by IL-17 and IL-1β (*P

To investigate the role of CD8alpha(+) DCs in the development of collagen-induced arthritis (CIA). The immunogenic properties of CD8alpha(+) and CD8alpha(-) DC subsets were investigated by mixed-lymphocyte reaction and cytokine enzyme-linked immunoassay. CII-pulsed CD8alpha(+) DCs or CD8alpha(-) DCs with CD4(+) T cells from CIA mice were adoptively transferred onto the hind footpad of DBA mice. The onset of arthritis and the arthritis index were examined for 14 weeks after adoptive transfer. Expression of MHC-II and CD80 but not CD86 and CD40 was higher in CD8alpha(+) DCs than in CD8alpha(-) DCs from the spleens of CIA mice. Culturing CD8alpha(+) DCs with CD4(+) T cells significantly increased the proliferative response of CD4(+) T cells in the presence of CII. The production of interleukin (IL)-12p70, IL-17, interferon (IFN)-gamma, and tumor necrosis factor (TNF)-alpha was slightly increased in CD8alpha(+) DCs than in CD8alpha(-) DCs. DBA/1 mice that were adoptively transferred with CII-pulsed CD8alpha(+) DCs and CD4(+) T cells into the footpads showed accelerated onset of CIA compared to control group. By contrast, CD8alpha(-) DCs showed a partial inhibitory effect on CIA. These findings show that CD8alpha(+) DCs accelerated the onset of CIA when aoptively transferred with CD4(+) T cells and that CD8alpha(+) DCs provoke the development of CIA probably by stimulating the immune responses of CII-reactive CD4(+) T cells and by increasing the production of inflammatory cytokines.

Interleukin (IL)-23 is the key cytokine that induces the expansion of helper T (Th) 17 cells. It is composed of p19 and p40 subunits of IL-12. The p40 subunit binds competitively to the receptor of IL-23 and blocks its activity. Our aim was to assess the preventive and therapeutic effect of the (p40)2 subunit in autoimmune arthritis animal models. In the present study, by using IL-1receptor antagonist knockout mice (IL-1RaKO) and a collagen-induced arthritis (CIA) model, we inspected the suppressive effect of the IL-12p40 homodimer ((p40)2) on inflammatory arthritis. We demonstrated that the recombinant adenovirus expressing mouse (p40)2 (rAd/(p40)2) model prevented the development of arthritis when given before the onset of arthritis. It also decreased the arthritis index and joint erosions after it was transferred once arthritis was established in the mouse model. (p40)2 inhibited the production of inflammatory cytokines and antigen-specific T cell proliferation. It also induced the CD4+CD25+Foxp3 regulatory T (Treg) cells in vitro and in vivo, whereas the generation of RORgt and Th17 cells was suppressed. The induction process of Treg cells and the suppression of Th17 cells were mediated via the activated STAT5 and suppressed STAT3. Conclusion: Our data suggested that (p40)2 suppressed inflammatory arthritis successfully. This could be a useful therapeutic approach in autoimmune arthritis to regulate the Th17/Treg balance and IL-23 signaling.

Pinched inlet gravitational split-flow thin fractionation (PI-GSF) has been applied to the continuous size fractionation of marine sediments in order to study the difference in sediment size distribution and the concentration of PCDD/Fs contained in different particle sizes. A PI-GSF channel, known to improve the separation efficiency by reducing the sample inlet thickness, was utilized to fractionate sediments collected from three different bay areas (Geoje, Ulsan, and Pohang) in Korea into 5 different sub-populations (

To determine the effect of interleukin 15 (IL-15) on cyclooxygenase-2 (COX-2) expression in rheumatoid synoviocytes.Fibroblast-like synoviocytes (FLS) were prepared from the synovial tissues of patients with rheumatoid arthritis (RA) and cultured in the presence of IL-15. Levels of COX-2 mRNA and protein expression were determined by reverse transcription-polymerase chain reaction and Western blot, respectively. ELISA was used to measure concentrations of IL-1beta, tumor necrosis factor-a (TNF-a), and prostaglandin E2 (PGE2) in the culture supernatants.IL-15 dose-dependently increased COX-2 mRNA and protein expression in FLS, but not the COX-1 mRNA level. Both IL-1beta and TNF-a upregulated COX-2 mRNA comparably to IL-15, but neither IL-2 nor interferon-g had any effect on the COX-2 mRNA level. Treatment with anti-IL-1beta or anti-TNF-a antibodies partially reduced the IL-15-stimulated COX-2 mRNA expression, suggesting that these cytokines may take part in modulating COX-2 by IL-15. Dexamethasone and pyrolidine dithiocarbamate, but not curcumin, completely blocked the IL-15-induced upregulation of COX-2 mRNA. A gel mobility shift assay revealed that nuclear factor-kB (NF-kB) was one of the major signal molecules to mediate IL-15-induced COX-2 upregulation. The increase of COX-2 by IL-15 is PGE2-dependent because exogenous PGE2 reversed the suppressive effect of NS-398, a selective COX-2 inhibitor, on COX-2 mRNA and protein expression.This study confirms the effect of IL-15 on upregulation of COX-2 in a PGE2-dependent manner. The activation of NF-kB bound to the COX-2 promoter appears to be a downstream target of IL-15 stimulation in FLS, exerted either directly or through the increase in IL-1beta and TNF-a production.

This review summarizes the autoimmune reaction to type II collagen (CII) autoimmunity with regard not only to antibody response to CII but also to the clinical significance or biological characteristics of the CII-reactive T cell, focusing on studies of human RA rather than on animal models. The authors investigated the effect of the interaction between CII-reactive T cells and fibroblast-like synoviocytes (FLSs) on the production of inflammatory cytokines. When the CII-reactive T cells were co-cultured with FLS, the production of interleukin-15 and tumor necrosis factor-alpha from FLSs were significantly increased, and this increase was clearly presented in accord with the expansion of CII-reactive T cells. In addition, the production of interferon- γ and interleukin-17, T cell–derived cytokines, was increased by the co-incubation of CII-reactive T cells with FLSs. When FLSs were co-cultured with CII-stimulated T cells, the production of interleukin-8, monocyte chemoattractant protein-1, and macrophage inflammatory protein-1 α was significantly enhanced. The increased production of these chemokines was strongly correlated with an increase in T-cell response to CII. Conclusively, high reactivity to CII was frequently found in RA patients. Enhanced T-cell responses to CII were associated with increased production of proinflammatory cytokines and chemokines, which were critical for inflammatory responses in RA. Interaction of CII-reactive T cells with FLS further augmented this phenomenon. Taken together, the authors' recent studies have suggested that autoimmunity to CII could play a crucial role not only in the initiation but also in the amplification and perpetuation of the inflammatory process in RA.

Background: Bone morphogenetic protein-7 (BMP-7) plays a critical role in renal development, accelerates recovery from acute renal injury, and more recently it has been shown to delay progressive renal disease. The present study was designed to investigate the effect of BMP-7 on interstitial fibrosis in the rat protein-overloaded model. Methods: Renal disease was induced in 26 rats by daily intraperitoneal injections of bovine serum albumin (BSA); controls (n = 28) were injected with saline. Half of the rats in each group were treated with human recombinant BMP-7 (300 µg/kg i.p. 3 times weekly) and half with placebo. Animals were killed after 3 or 6 weeks. Results: Compared to the saline control groups, the BSA groups had evidence of chronic renal disease: significantly increased urinary protein excretion rates; total kidney collagen content, and increased fibronectin and collagen III interstitial areas. By 6 weeks the BSA + BMP-7 group compared to the BSA + placebo group had a nonsignificant decrease in blood urea nitrogen (40 ± 13 vs. 46 ± 11 mg/dl), total kidney collagen (10.8 ± 2.1 vs. 12.2 ± 3.5 µg/kidney), fibronectin interstitial area (23 ± 4 vs. 25 ± 8%) and collagen III interstitial area (22 ± 6 vs. 28 ± 7%). Despite these results, renal gene expression profiles actually predicted worse fibrosis in the BSA + BMP-7 group with significantly higher total kidney mRNA levels for α1(III) procollagen (2.8 ± 0.5 vs. 1.6 ± 0.6, p < 0.05) and fibronectin at 6 weeks (1.9 ± 0.3 vs. 1.2 ± 0.5, p < 0.05). Renal BMP-7 mRNA levels at 6 weeks were significantly increased in the BSA + placebo group compared to the saline + placebo group with no difference between the BSA + BMP-7 and the BSA + placebo groups. Both cortical and medullary tubules expressed BMP-7 protein but BMP-7 was only detected in the tubular lumina and urine of proteinuric animals. Conclusions: In rats with protein-overload proteinuria, renal tubules continue to express BMP-7 but some of the endogenous protein is secreted into the urinary space. Administration of exogenous recombinant BMP-7 had no effect on proteinuria but was associated with a nonsignificant trend towards less interstitial fibrosis at 6 weeks despite significantly higher kidney extracellular matrix gene mRNA levels. These findings suggest that BMP-7 treatment may have anti-fibrotic effects through enhancement of matrix turnover, although overall these effects are modest in proteinuric states in the absence of significant tubular epithelial cell apoptosis and epithelial-mesenchymal transition.