Chien-Chung Huang

CCN1 Promotes VEGF Production in Osteoblasts and Induces Endothelial Progenitor Cell Angiogenesis by Inhibiting miR-126 Expression in Rheumatoid Arthritis.

Angiogenesis is the formation of new capillaries from preexisting vasculature. The perpetuation of angiogenesis plays a critical role in the pathogenesis of various disease states including rheumatoid arthritis (RA). Cysteine‐rich 61 (Cyr61 or CCN1) is an important proinflammatory cytokine in RA. Here, we investigated the role of CCN1 in angiogenesis associated with vascular endothelial growth factor (VEGF) production and osteoblasts. We found higher expression of CCN1 and VEGF in synovial fluid from RA patients compared with healthy controls. CCN1 induced VEGF expression in osteoblasts and increased endothelial progenitor cells (EPCs) angiogenesis by inhibiting miR‐126 via the protein kinase C‐alpha (PKC‐α) signaling pathway. CCN1 knockdown inhibited angiogenesis in both in vitro and in vivo models. Inhibition of CCN1 expression with lentiviral vectors expressing short hairpin RNA (shRNA) ameliorated articular swelling, cartilage erosion, and angiogenesis in the ankle joint of mice with collagen‐induced arthritis (CIA). Our study is the first to describe how CCN1 promotes VEGF expression in osteoblasts and increased EPCs angiogenesis in RA disease. CCN1 may serve as a potential target for RA treatment.

Osteopontin inhibition of miR-129-3p enhances IL-17 expression and monocyte migration in rheumatoid arthritis

BACKGROUND Osteopontin (OPN) is an important proinflammatory cytokine in rheumatoid arthritis (RA). Levels of OPN have been shown to be significantly correlated with interleukin-17 (IL-17) production and expression of Th17 cells in the synovial fluid of RA patients. Here, we investigated the role of OPN in monocyte migration, IL-17 production and osteoblasts. METHODS OPN and IL-17 expression profiles in osteoarthritis (OA) and RA synovial fluid were determined by enzyme-linked immunosorbent assay (ELISA). The expression of the microRNA, miR-129-3p, in osteoblasts was analyzed by real-time quantitative polymerase chain reaction (qPCR). Immunoreactive proteins were spotted by Western blotting. We used the collagen-induced arthritis (CIA) mouse model to investigate the role of OPN in monocyte migration during RA. RESULTS OPN and IL-17 expression were higher in RA synovial fluid as compared to OA samples. We also found that OPN promotes IL-17 expression in osteoblasts and thereby enhances monocyte migration via the Syk/PI3K/Akt signaling pathway. miR-129-3p expression was found to be negatively regulated by OPN via the Syk/PI3K/Akt signal cascade. In contrast, lentiviral vectors expressing short hairpin RNA inhibited OPN expression and ameliorated articular swelling, cartilage erosion and monocyte infiltration in the ankle joints of CIA mice. CONCLUSION To our knowledge, our study is the first to describe how OPN promotes monocyte migration by upregulating IL-17 expression in osteoblasts in RA disease. SIGNIFICANCE These findings indicate that OPN could serve as a potential therapeutic target for the treatment of RA.

Enhancement of CCL2 expression and monocyte migration by CCN1 in osteoblasts through inhibiting miR-518a-5p: implication of rheumatoid arthritis therapy

Cysteine-rich 61 (Cyr61 or CCN1), a secreted protein from the CCN family, is an important proinflammatory cytokine. Migration and infiltration of mononuclear cells to inflammatory sites play a critical role in the pathogenesis of rheumatoid arthritis (RA). Monocyte chemoattractant protein-1 (MCP-1/CCL2) is the key chemokine that regulates migration and infiltration of monocytes. Here, we examined the role of CCN1 in monocyte migration, and CCL2 expression in osteoblasts. We found higher levels of CCN1 and CCL2 in synovial fluid from RA patients compared with levels from non-RA controls. We also found that the CCN1-induced increase in CCL2 expression is mediated by the MAPK signaling pathway and that miR-518a-5p expression was negatively regulated by CCN1 via the MAPK cascade. In contrast, inhibition of CCN1 expression with lentiviral vectors expressing short hairpin RNA ameliorated articular swelling, cartilage erosion, and infiltration of monocytes in the ankle joints of mice with collagen-induced arthritis. Our study describes how CCN1 promotes monocyte migration by upregulating CCL2 expression in osteoblasts in RA disease. CCN1 could serve as a potential target for RA treatment.

YKL-40-Induced Inhibition of miR-590-3p Promotes Interleukin-18 Expression and Angiogenesis of Endothelial Progenitor Cells

YKL-40, also known as human cartilage glycoprotein-39 or chitinase-3-like-1, is a pro-inflammatory protein that is highly expressed in rheumatoid arthritis (RA) patients. Angiogenesis is a critical step in the pathogenesis of RA, promoting the infiltration of inflammatory cells into joints and providing oxygen and nutrients to RA pannus. In this study, we examined the effects of YKL-40 in the production of the pro-inflammatory cytokine interleukin-18 (IL-18), and the stimulation of angiogenesis and accumulation of osteoblasts. We observed that YKL-40 induces IL-18 production in osteoblasts and thereby stimulates angiogenesis of endothelial progenitor cells (EPCs). We found that this process occurs through the suppression of miR-590-3p via the focal adhesion kinase (FAK)/PI3K/Akt signaling pathway. YKL-40 inhibition reduced angiogenesis in in vivo models of angiogenesis: the chick embryo chorioallantoic membrane (CAM) and Matrigel plug models. We report that YKL-40 stimulates IL-18 expression in osteoblasts and facilitates EPC angiogenesis.

Myostatin Promotes Interleukin-1β Expression in Rheumatoid Arthritis Synovial Fibroblasts through Inhibition of miR-21-5p

Rheumatoid arthritis (RA) is characterized by the infiltration of a number of pro-inflammatory cytokines into synovial fluid and patients with RA often develop joint destruction and deficits in muscle mass. The growth factor myostatin is a key regulator linking muscle mass and bone structure. We sought to determine whether myostatin regulates rheumatoid synovial fibroblast activity and inflammation in RA. We found that levels of myostatin and interleukin (IL)-1β (a key pro-inflammatory cytokine in RA) in synovial fluid from RA patients were overexpressed and positively correlated. In in vitro investigations, we found that myostatin dose-dependently regulated IL-1β expression through the ERK, JNK, and AP-1 signal-transduction pathways. Computational analysis confirmed that miR-21-5p directly targets the expression of the 3′ untranslated region (3′ UTR) of IL-1β. Treatment of cells with myostatin inhibited miR-21-5p expression and miR-21-5p mimic prevented myostatin-induced enhancement of IL-1β expression, showing an inverse correlation between miR-21-5p and IL-1β expression during myostatin treatment. We also found significantly increased paw swelling in an animal model of collagen-induced arthritis (CIA), compared with controls; immunohistochemistry staining revealed substantially higher levels of myostatin and IL-1β expression in CIA tissue. Our evidence indicates that myostatin regulates IL-1β production. Thus, targeting myostatin may represent a potential therapeutic target for RA.

Prognostic significance of high-mobility group box protein 1 genetic polymorphisms in rheumatoid arthritis disease outcome

Rheumatoid arthritis (RA) is a systemic inflammatory disease that causes chronic inflammation of the joints. Analysis of genetic variants offers promise for guiding treatment and improving outcomes in RA. High-mobility group box protein 1 (HMGB1) is a ubiquitous nuclear protein found in all mammal eukaryotic cells that participates in several biological functions including immune response, cell survival and apoptosis. We investigated the effects of HMGB1 gene polymorphisms on the risk of RA disease progression in a cohort of Chinese Han individuals. Four single nucleotide polymorphisms (SNPs) from the HMGB1 gene were selected and genotyped in 232 patients with RA and 353 healthy controls. We found that having one C allele in rs1360485 and one G allele in rs2249825 polymorphisms lowered the risk of RA in females. Moreover, among healthy controls, those who bore the C/G/T haplotype at SNPs rs1360485, rs2249825 and rs1412125 were at reduced risk of developing RA by 0.13-fold (p <0.05). This is the first report to examine the risk factors associated with HMGB1 SNPs in the development of RA disease in the Chinese Han population.

An Independent risk of gout on the development of deep vein thrombosis and pulmonary embolism: A nationwide, population-based cohort study

AbstractPrevious studies indicated that gout is a risk factor of cardiovascular diseases. This study aimed to determine if patients with gout have an increased risk of deep vein thrombosis (DVT) or pulmonary embolism (PE).We used the Longitudinal Health Insurance Database, a subset of the national insurance claim dataset, which enrolled 1 million Taiwanese to identify 57,981 patients with gout and 115,961 reference subjects matched by sex, age, and entry date of diagnosis. The risk of DVT and PE was analyzed using the Cox proportional hazards model.In this Taiwanese dataset observed from 2000 to 2010, we found the incidence of DVT was 5.26 per 104 person-years in the gout cohort, which was twofold higher than the incidence of 2.63 per 104 person-years in the reference cohort. After adjusting for age, sex, and 9 comorbidities, the hazard ratio (HR) of developing DVT was 1.66 (95% confidence interval [CI] = 1.37–2.01). Among patients with gout, the youngest age group had the highest increase in the risk of developing DVT (HR [95% CI] = 2.04 [1.24–3.37] for ages 20 to 49 years, 1.80 [1.28–2.51] for ages 50 to 64 years, and 1.45 [1.11–1.91] for ages ≥65 years). The incidence of PE was about one-fifth that of DVT in gout patients, but the effect of gout on the risk was similar (HR [95% CI] = 1.53 [1.01–2.29]).Our analysis confirmed that gout increased the risk of DVT and PE. Further exploration is needed in the future.

Chemokine C-C Motif Ligand 4 Gene Polymorphisms Associated with Susceptibility to Rheumatoid Arthritis

Chemokine C-C motif ligand 4 (CCL4) gene is a chemokine-encoding gene, and the polymorphism of CCL4 gene has been shown to predict risk of various diseases. We want to investigate whether the single nucleotide polymorphisms (SNPs) of the CCL4 gene can predict the risk of rheumatoid arthritis (RA). Between 2007 and 2015, we recruited 217 patients diagnosed with RA and 371 control participants. Comparative genotyping of the rs1634507, rs10491121, and rs1719153 SNPs was performed. When compared with participants with the A/A genotype of rs1719153, those with the A/T genotype were less likely to develop RA, as were those with the A/T+T/T genotype. The protective effect of the T-containing genotype was even more prominent among females. Those with A/T in rs1719153 were 56% less likely to develop RA compared with females with A/A; a similar protective effect was seen for females with the A/T+T/T genotype compared with those with A/A. The GTEx database revealed that patients carrying the T/T genotype had lower levels of CCL4 gene expression than those carrying the A/A genotype. These results indicate that the nucleotide T over the rs1719153 is associated with decreased CCL4 gene expression and decreased risk for RA.

Risk of obstructive sleep apnoea in patients with rheumatoid arthritis: a nationwide population-based retrospective cohort study

Objective Sleep disorders are prevalent medical disorders in patients with rheumatoid arthritis (RA). However, whether patients with RA are at an increased risk of developing obstructive sleep apnoea (OSA) is unclear. Design Using population-based retrospective cohort study to examine the risk of OSA in patients with RA. Setting We used claims data of the National Health Insurance Research Database (NHIRD) of Taiwan. Participants We identified a RA cohort with 33 418 patients newly diagnosed in 2000–2010 and a randomly selected non-RA comparison cohort with 33 418 individuals frequency matched by sex, age and diagnosis year. Primary and secondary outcome measures Incident OSA was estimated by the end of 2011. The HRs of OSA were calculated using the Cox proportional hazards regression analysis. Results The overall incidence rate of OSA was 75% greater in the RA cohort than in the non-RA cohort (3.04 vs 1.73/10 000 person-years, p<0.001), with an adjusted HR (aHR) of 1.75 (95% CI 1.18 to 2.60). Stratified analyses by sex, age group and comorbidity revealed that the incidence rates of OSA associated with RA were higher in all subgroups. Conclusions This population-based retrospective cohort study suggested that patients with RA should be monitored for the risk of developing OSA.

Dumbbell-shaped cervical spine schwannoma causing myelopathy in a patient with rheumatoid arthritis.

Joint Bone Spine - In Press.Proof corrected by the author Available online since samedi 21 juin 2014