Hyung In Yang

Estrogen receptor-α gene haplotype is associated with primary knee osteoarthritis in Korean population

Estrogen and estrogen receptors (ERs) are known to play important roles in the pathophysiology of osteoarthritis (OA). To investigate ER-α gene polymorphisms for its associations with primary knee OA, we conducted a case–control association study in patients with primary knee OA (n = 151) and healthy individuals (n = 397) in the Korean population. Haplotyping analysis was used to determine the relationship between three polymorphisms in the ER-α gene (intron 1 T/C, intron 1 A/G and exon 8 G/A) and primary knee OA. Genotypes of the ER-α gene polymorphism were determined by PCR followed by restriction enzyme digestion (PvuII for intron 1 T/C, XbaI for intron 1 A/G, and BtgI for exon 8 G/A polymorphism). There was no significant difference between primary knee OA patients and healthy control individuals in the distribution of any of the genotypes evaluated. However, we found that the allele frequency for the exon 8 G/A BtgI polymorphism (codon 594) was significantly different between primary knee OA patients and control individuals (odds ratio = 1.38, 95% confidence interval = 1.01–1.88; P = 0.044). In haplotype frequency estimation analysis, there was a significant difference between primary knee OA patients and control individuals (degrees of freedom = 7, χ2 = 21.48; P = 0.003). Although the number OA patients studied is small, the present study shows that ER-α gene haplotype may be associated with primary knee OA, and genetic variations in the ER-α gene may be involved in OA.

Adiponectin may contribute to synovitis and joint destruction in rheumatoid arthritis by stimulating vascular endothelial growth factor, matrix metalloproteinase-1, and matrix metalloproteinase-13 expression in fibroblast-like synoviocytes more than proinflammatory mediators.

IntroductionThe role of adiponectin in the pathogenesis of arthritis is still controversial. This study was performed to examine whether adiponectin is involved in joint inflammation and destruction in rheumatoid arthritis (RA) in relation to the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs).MethodsSynovial cells from RA patients were treated with adiponectin or interleukin (IL)-1β for 24 hours. The culture supernatant was collected and analyzed for the levels of IL-6, IL-8, prostaglandin E2 (PGE2), VEGF, and MMPs by enzyme-linked immunosorbent assay. The levels of adiponectin, VEGF, MMP-1, and MMP-13 in the joint fluids from 30 RA or osteoarthritis (OA) patients were also measured.ResultsAdiponectin at the concentration of 10 μg/mL stimulated the production of IL-6, IL-8, and PGE2 in RA fibroblast-like synoviocytes (FLSs), although the level of these was much lower than with 1 ng/mL IL-1β. However, adiponectin stimulated the production of VEGF, MMP-1, and MMP-13 at the same level as IL-1β. In addition, the level of adiponectin and MMP-1 in the joint fluid of RA patients was significantly higher than in OA patients. Adiponectin was positively correlated with VEGF in RA patients but not in OA patients, while the level of MMPs in joint fluid was not correlated with adiponectin in either RA or OA patients.ConclusionsAdiponectin may play a significant role in the pathogenesis of RA by stimulating the production of VEGF and MMPs in FLSs, leading to joint inflammation and destruction, respectively.

Analgesic effect of electroacupuncture on inflammatory pain in the rat model of collagen-induced arthritis: mediation by cholinergic and serotonergic receptors.

The analgesic effect and its mechanism of electroacupuncture (EA) on inflammatory pain, especially in the rat model of collagen-induced arthritis (CIA), have not yet been studied. This study was designed to investigate the analgesic effect and its cholinergic and serotonergic mechanism of EA in the CIA rat model. To induce CIA, male Sprague-Dawley rats were immunized with bovine type II collagen emulsified in Freunds incomplete adjuvant, followed by a booster injection 14 days later. The analgesic effect was evaluated by tail flick latency (TFL). After induction of arthritis, the inflammatory pain threshold decreased as time passed and there was no big change of the pain threshold after 3 weeks. Three weeks after the first immunization, low frequency EA stimulation (2 Hz, 0.07 mA, 0.3 ms) delivered to Zusanli (ST36) for 30 min showed the analgesic effect. Also, the analgesic effect of EA was blocked by pretreatment with atropine (muscarinic cholinergic receptor antagonist, 1 mg/kg i.p.), spiroxatrine (5-HT1a receptor antagonist, 1 mg/kg i.p.), and ondansetron (5-HT3 receptor antagonist, 0.5 mg/kg i.p.), but not by pretreatment with ketanserin (5-HT2 receptor antagonist, 1 mg/kg i.p.). These results suggest that low frequency EA can relieve inflammatory pain in CIA and the analgesic effect of EA can be mediated by muscarinic cholinergic receptor, 5-HT1a and 5-HT3 receptors, but not by 5-HT2 receptor.

Synergy between adiponectin and interleukin-1β on the expression of interleukin-6, interleukin-8, and cyclooxygenase-2 in fibroblast-like synoviocytes.

To determine whether adiponectin may have synergistic effects in combination with the proinflammatory cytokine interleukin (IL)-1β regarding the production of proinflammatory mediators during arthritic joint inflammation, synovial cells from rheumatoid arthritis (RA) patients were treated with adiponectin, IL-1β, and their combination for 24 h. Culture supernatant was collected and analyzed by enzyme-linked immunosorbent assay for levels of IL-6, IL-8, prostaglandin E2 (PGE2), vascular endothelial growth factor (VEGF), and matrix metalloproteinases (MMPs). Adiponectin-mediated intracellular signaling pathways were investigated to elucidate the molecular mechanisms underlying their synergy. The association of proinflammatory mediators with adiponectin was investigated in the synovial fluid of arthritis patients. Adiponectin functioned synergistically with IL-1β to activate IL-6, IL-8, and PGE2 expression in RA fibroblast-like synoviocytes; Levels of VEGF, MMP-1, and MMP-13 were not synergistically stimulated. Adiponectin and IL-1β each increased the expression of both adiponectin receptor 1 and IL-1 receptor 1. However, adiponectin and IL-1β did not synergistically support the degradation of IκB-α or the nuclear translocation of NF-κB. Synergistically increased gene expression was significantly inhibited by MG132, an NF-κB inhibitor. Supporting the in vitro results, IL-6 and IL-8 levels were positively associated with adiponectin in synovial joint fluid from patients with RA, but not osteoarthritis (OA). In conclusion, adiponectin and IL-1β may synergistically stimulate the production of proinflammatory mediators through unknown signaling pathways during arthritic joint inflammation. Adiponectin may be more important to the pathogenesis of RA than previously thought.

Taurine ameliorates hyperglycemia and dyslipidemia by reducing insulin resistance and leptin level in Otsuka Long-Evans Tokushima fatty (OLETF) rats with long-term diabetes

This study aimed to determine whether taurine supplementation improves metabolic disturbances and diabetic complications in an animal model for type 2 diabetes. We investigated whether taurine has therapeutic effects on glucose metabolism, lipid metabolism, and diabetic complications in Otsuka Long-Evans Tokushima fatty (OLETF) rats with long-term duration of diabetes. Fourteen 50-week-old OLETF rats with chronic diabetes were fed a diet supplemented with taurine (2%) or a non-supplemented control diet for 12 weeks. Taurine reduced blood glucose levels over 12 weeks, and improved OGTT outcomes at 6 weeks after taurine supplementation, in OLETF rats. Taurine significantly reduced insulin resistance but did not improve β-cell function or islet mass. After 12 weeks, taurine significantly decreased serum levels of lipids such as triglyceride, cholesterol, high density lipoprotein cholesterol, and low density lipoprotein cholesterol. Taurine significantly reduced serum leptin, but not adiponectin levels. However, taurine had no therapeutic effect on damaged tissues. Taurine ameliorated hyperglycemia and dyslipidemia, at least in part, by improving insulin sensitivity and leptin modulation in OLETF rats with long-term diabetes. Additional study is needed to investigate whether taurine has the same beneficial effects in human diabetic patients.

Anti-inflammatory effects of Radix Gentianae Macrophyllae (Qinjiao), Rhizoma Coptidis (Huanglian) and Citri Unshiu Pericarpium (Wenzhou migan) in animal models

BackgroundKHU14, an ethanolic extract of Radix Gentianae Macrophyllae (Qinjiao), Rhizoma Coptidis (Huanglian) and Citri Unshiu Pericarpium (Wenzhou migan) was tested for its anti-inflammatory effects.MethodsThree out of 20 herbs were found to have anti-inflammatory effects. The formulation of these herbs, i.e. KHU14 was tested for croton oil-induced ear edema, carrageenan-induced paw edema, acetic acid-induced capillary permeability, cotton pellet and delayed type hypersensitivity.ResultsKHU14 exhibited anti-inflammatory effects in animal models of acute and chronic inflammation. The anti-inflammatory activity of KHU14 observed was comparable to that of celecoxib. KHU14 inhibited the production of NO and PGE2 in LPS/IFN-gamma-stimulated peritoneal macrophages, and reduced edema and the amount of infiltrated cells in animal models.ConclusionKHU14 exhibited anti-inflammatory effects as demonstrated in typical immunological tests for anti-inflammation in vitro and in vivo.

Serum adipokine levels in rheumatoid arthritis patients and their contributions to the resistance to treatment

The aim of this study was to determine whether disease activity and the type of therapy differentially modulate serum adipokine levels in patients with rheumatoid arthritis (RA), and whether pre-therapy adipokine levels contribute to resistance to treatment. Fasting blood samples from 40xa0RA patients were obtained at baseline and sixxa0months following therapeutic treatment with disease-modifying antirheumatic drugs (DMARDs) and/or tumor necrosis factor (TNF)-α blockers. Serum levels of adiponectin, leptin, visfatin and resistin were measured by ELISA. Baseline adipokine levels did not exhibit a statistically significant difference when comparing patients with moderate and high disease activity, based on the disease activity score in 28xa0joints (DAS28). Of all the adipokines, only adiponectin was significantly increased in patients responding to DMARDs and/or TNF-α blocker therapy, based on the American College of Rheumatology 20%xa0improvement criteria (ACR20) at sixxa0months (2,964±1,237 to 3,683±1,511xa0ng/ml, P<0.01). However, adiponectin levels in non-responders did not significantly increase (3,192±2,090 to 3,222±1,150xa0ng/ml). By contrast, there were no statistically significant changes in leptin, resistin or visfatin levels in either the responders or non-responders. Serum adipokine (adiponectin, leptin, visfatin, and resistin) levels in RA patients did not significantly change following therapy, with the exception of adiponectin. Adipokine levels may not contribute to therapeutic resistance to DMARDs and/or TNF-α blocking agents.

Thymosin β4 in rheumatoid arthritis: Friend or foe (Review)

Rheumatoid arthritis (RA) has characteristic pannus tissues, which show tumor-like growth of the synovium through chronic joint inflammation. The synovium is highly penetrated by various immune cells, and the synovial lining becomes hyperplastic due to increased numbers of macrophage-like and fibroblast-like synoviocytes. Thus, a resultant hypoxic condition stimulates the expression of inflammation-related genes in various cells, in particular, vascular endothelial growth factor. Thymosin β4 (Tβ4), a 5-kDa protein, is known to play a significant role in various biological activities, such as actin sequestering, cell motility, migration, inflammation, and damage repair. Recent studies have provided evidence that Tβ4 may have a role in RA pathogenesis. The Tβ4 level has been shown to increase significantly in the joint fluid and serum of RA patients. However, whether Tβ4 stimulates or inhibits activation of RA immune responses remains to be determined. In the present study, we discuss the logical and clinical justifications for Tβ4 as a potential target for RA therapeutics.