Exosomes from osteoarthritic fibroblast-like synoviocytes promote cartilage ferroptosis and damage via delivering microRNA-19b-3p to target SLC7A11 in osteoarthritis.

Objective: Our previous studies revealed that normal synovial exosomes promoted chondrogenesis, and microRNA (miR)-19b-3p independently related to osteoarthritis (OA) risk. Subsequently, this study intended to further explore the effect of OA fibroblast-like synoviocyte (OA-FLS) exosomal miR-19b-3p on OA ferroptosis and its potential mechanisms. Methods: Interleukin (IL)-1ß-stimulated chondrocytes and medial meniscus surgery were used to construct the OA cellular model and the OA rat model, respectively. OA-FLS exosomes with/without miR-19b-3p modification were added to the IL-1ß-stimulated chondrocytes and OA rat models, followed by direct miR-19b-3p mimic/inhibitor transfection with/without SLC7A11 overexpression plasmids. miR-19b-3p, ferroptosis-related markers (malondialdehyde (MDA), glutathione (GSH)/oxidized glutathione (GSSG), ferrous ion (Fe2+), glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), and acyl-CoA synthetase long-chain family member 4 (ACSL4)), mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) levels were detected. Results: Enhanced ferroptosis reflected by dysregulated ferroptosis-related markers, a reduced MMP, and an increased ROS was observed in cartilage tissues from OA patients vs. controls, IL-1ß-stimulated chondrocytes vs. normal ones, and OA rat models vs. sham, so did miR-19b-3p. OA-FLS exosomes promoted MDA, Fe2+, ACSL4, and ROS but reduced cell viability, GSH/GSSG, GPX4, SLC7A11, and MMP in IL-1ß-stimulated chondrocytes, whose effect was enhanced by miR-19b-3p mimics and attenuated by miR-19b-3p inhibitors. miR-19b-3p negatively regulated SLC7A11 and directly bound to SLC7A11 via luciferase reporter gene assay. Furthermore, SLC7A11 overexpression weakened miR-19b-3p mimics' effect on ferroptosis-related markers, MMP, or ROS in IL-1ß-stimulated chondrocytes. OA-FLS exosomes also induced cartilage damage and ferroptosis in OA rats whose influence was tempered by miR-19b-3p inhibitors. Conclusion: OA-FLS exosomal miR-19b-3p enhances cartilage ferroptosis and damage by sponging SLC7A11 in OA, indicating a potential linkage among synovium, cartilage, and ferroptosis during the OA process.

Treatment of knee osteoarthritis with intra-articular injection of autologous adipose-derived mesenchymal progenitor cells: a prospective, randomized, double-blind, active-controlled, phase IIb clinical trial.

OBJECTIVE: Human adipose-derived mesenchymal progenitor cells (haMPCs) are stem cells with multiple differentiation potential and immunomodulatory function. Re-Join® comprises in vitro expanded haMPCs from adipose tissue of patients combined with cell suspension solution. This study was undertaken to evaluate the efficacy and safety of Re-Join® in patients with symptomatic knee osteoarthritis (OA). METHODS: Patients with Kellgren-Lawrence grade 1-3 knee OA were recruited from two centers and randomized to receive intra-articular injection of Re-Join® or HA. Pain and function were assessed by using WOMAC score, VAS, and SF-36. Magnetic resonance imaging (MRI) analysis was performed to measure cartilage repair. Adverse events (AEs) were collected. RESULTS: Fifty-three patients were randomized. Significant improvements in WOMAC, VAS, and SF-36 scores were observed in both groups at months 6 and 12 compared with baseline. Compared with the HA group, significantly more patients achieved 50% improvement of WOMAC and a trend of more patients achieved a 70% improvement rate in Re-Join® group after 12 months. Meanwhile, there was notably more increase in articular cartilage volume of both knees in the Re-Join® group than in the HA group after 12 months as measured by MRI. AEs were comparable between two groups. Most AEs were mild and moderate except one SAE of right knee joint infection in the HA group. CONCLUSIONS: Significant improvements in joint function, pain, quality of life, and cartilage regeneration were observed in Re-Join®-treated knee OA patients with good tolerance in a period of 12 months. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02162693 . Registered 13 June 2014.

The efficacy and safety of total glucosides of peony in the treatment of primary Sjögren's syndrome: a multi-center, randomized, double-blinded, placebo-controlled clinical trial.

To evaluate the efficacy and safety of total glucosides of peony (TGP) in adults with primary Sjögren's syndrome (pSS). A multi-center, randomized, double-blinded, placebo-controlled study was conducted between March 2012 and July 2014 at ten Chinese hospitals. In total, 320 pSS patients-classified according to the 2002 American-European Consensus Group Criteria-were randomized (2:1 ratio) to receive TGP(600 mg, tid) in the TGP group or placebo for 24 weeks in the placebo group. Study personnel, investigators, and patients were blinded to the treatment grouping. The primary endpoint was the improvement of EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) at week 24. The secondary endpoints were dry eyes/mouth/skin/nose/throat/vagina visual analogue scale (VAS), pain and discomfort VAS, fatigue VAS, mental discomfort VAS, patient global assessment (PGA), EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI), Schirmer's test, basal/stimulated salivary flow-rate values, and erythrocyte sedimentation rate (ESR). All adverse events were recorded during the trial period. ESSPRI improved more in the TGP than the placebo group (p < 0.001). Dry eyes/throat/vagina VAS, fatigue VAS, mental discomfort VAS, PGA, Schirmer's test, and ESR also improved more in the TGP group than in the placebo group (all p < 0.05). Stimulated salivary flow-rate values increased in the TGP group at week 12 but not at week 24. Adverse events in TGP group were 10.9%. TGP can alleviate some dryness symptoms as well as disease activity in pSS patients over 24 weeks. TGP was well tolerated by study subjects. TGP seems to be an effective and safe treatment for pSS.

Correction to: the efficacy and safety of total glucosides of peony in the treatment of primary Sjögren's syndrome: a multi-center, randomized, double-blinded, placebo-controlled clinical trial.

The authors regret that the Fig. 1 in the original version of this article contained an error. In the left column, 211 cases in the TGP group should be followed up for 8 weeks before 12 weeks. The correct figure presented in this article.

Genetic variants in two pathways influence serum urate levels and gout risk: a systematic pathway analysis.

The aims of this study were to identify candidate pathways associated with serum urate and to explore the genetic effect of those pathways on the risk of gout. Pathway analysis of the loci identified in genome-wide association studies (GWASs) showed that the ion transmembrane transporter activity pathway (GO: 0015075) and the secondary active transmembrane transporter activity pathway (GO: 0015291) were both associated with serum urate concentrations, with PFDR values of 0.004 and 0.007, respectively. In a Chinese population of 4,332 individuals, the two pathways were also found to be associated with serum urate (PFDR = 1.88E-05 and 3.44E-04, separately). In addition, these two pathways were further associated with the pathogenesis of gout (PFDR = 1.08E-08 and 2.66E-03, respectively) in the Chinese population and a novel gout-associated gene, SLC17A2, was identified (OR = 0.83, PFDR = 0.017). The mRNA expression of candidate genes also showed significant differences among different groups at pathway level. The present study identified two transmembrane transporter activity pathways (GO: 0015075 and GO: 0015291) were associations with serum urate concentrations and the risk of gout. SLC17A2 was identified as a novel gene that influenced the risk of gout.

Effects of multiple genetic loci on the pathogenesis from serum urate to gout.

Gout is a common arthritis resulting from increased serum urate, and many loci have been identified that are associated with serum urate and gout. However, their influence on the progression from elevated serum urate levels to gout is unclear. This study aims to explore systematically the effects of genetic variants on the pathogenesis in approximately 5,000 Chinese individuals. Six genes (PDZK1, GCKR, TRIM46, HNF4G, SLC17A1, LRRC16A) were determined to be associated with serum urate (PFDR < 0.05) in the Chinese population for the first time. ABCG2 and a novel gene, SLC17A4, contributed to the development of gout from hyperuricemia (OR = 1.56, PFDR = 3.68E-09; OR = 1.27, PFDR = 0.013, respectively). Also, HNF4G is a novel gene associated with susceptibility to gout (OR = 1.28, PFDR = 1.08E-03). In addition, A1CF and TRIM46 were identified as associated with gout in the Chinese population for the first time (PFDR < 0.05). The present study systematically determined genetic effects on the progression from elevated serum urate to gout and suggests that urate-associated genes functioning as urate transporters may play a specific role in the pathogenesis of gout. Furthermore, two novel gout-associated genes (HNF4G and SLC17A4) were identified.

Common UCP2 variants contribute to serum urate concentrations and the risk of hyperuricemia.

Elevated serum urate, which is regulated at multiple levels including genetic variants, is a risk factor for gout and other metabolic diseases. This study aimed to investigate the association between UCP2 variants and serum urate as well as hyperuricemia in a Chinese population. In total, 4332 individuals were genotyped for two common UCP2 variants, -866G/A and Ala55Val. These loci were not associated either serum urate level or with a risk of hyperuricemia in the total group of subjects. However, in females, -866G/A and Ala55Val were associated with a lower serum urate (P = 0.006 and 0.014, seperately) and played a protective role against hyperuricemia (OR = 0.80, P = 0.018; OR = 0.79, P = 0.016). These associations were not observed in the males. After further stratification, the two loci were associated with serum urate in overweight, but not underweight females. The haplotype A-T (-866G/A-Ala55Val) was a protective factor for hyperuricemia in the female subgroup (OR = 0.80, P = 0.017). This present study identified a novel gene, UCP2, that influences the serum urate concentration and the risk of hyperuricemia, and the degree of association varies with gender and BMI levels.

Plasma Interleukin-37 Is Elevated in Patients with Rheumatoid Arthritis: Its Correlation with Disease Activity and Th1/Th2/Th17-Related Cytokines.

Interleukin- (IL-) 37 is a novel anti-inflammatory cytokine that suppresses immune response and inflammation. This study was performed to determine whether IL-37 was elevated in patients with rheumatoid arthritis (RA) and investigate the correlation between IL-37 level and disease activity and the concentration of Th1/Th2/Th17-related cytokines. Clinical parameters of disease activity, including the 28-joint disease activity score (DAS28) and C-reactive protein (CRP), were collected in 34 RA patients and 34 age- and sex-matched healthy controls. Plasma IL-37 was measured by ELISA. Plasma levels of TNF-α, IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, G-CSF, GM-CSF, IFN-γ, MCP-1, and MIP-1ß were analyzed using the Bio-Plex suspension array system. It was found that IL-37 levels were elevated markedly in RA patients and almost undetectable in healthy controls. In addition, IL-37 levels in patients with active RA were significantly enhanced as compared with those in patients of remission. More importantly, IL-37 showed a significant correlation with disease activity (DAS28) and IL-4, IL-7, IL-10, IL-12, and IL-13 concentrations in RA patients. These findings suggest that IL-37 plays an important role in the pathogenesis of RA and may prove to be a potential biomarker of active RA.

Common Variants in LRP2 and COMT Genes Affect the Susceptibility of Gout in a Chinese Population.

Gout is a common inflammation disease resulting from an increase in serum uric acid. Nearly 70% of uric acid is excreted via the kidneys. To date, evidence for an association between genetic loci and gout is absent, equivocal or not replicated. Our study aims to test variants in two genes abundantly expressed in the kidney, LRP2 and COMT, for their association with uric acid and gout. In total, 1318 Chinese individuals were genotyped for rs2544390 in LRP2 and rs4680 in COMT. These LRP2 and COMT gene polymorphisms showed no significant effect on uric acid (P = 0.204 and 0.188, separately); however, rs2544390 in LRP2 did influence uric acid levels in individuals with BMI ≥ 25 (P = 0.009). In addition, the allele frequency distributions of the two loci showed a significant difference between gout patients and healthy controls. A missense variation in rs4680 (G > A) decreased the risk of gout (OR = 0.77, P = 0.015), whereas the T allele of rs2544390 was associated with gout pathogenesis risk (OR = 1.26, P = 0.020). The present study provides the first evidence for an association between COMT and gout. Rs2544390 in LRP2 only influenced uric acid levels in individuals with BMI ≥ 25, which might explain the discrepant results among previous studies. In addition, we are the first to identify the association between LRP2 and gout in a Chinese population and to confirm this association in Asians.

Indirect comparison of teriparatide, denosumab, and oral bisphosphonates for the prevention of vertebral and nonvertebral fractures in postmenopausal women with osteoporosis.

OBJECTIVE: This study aims to compare the efficacy of teriparatide, denosumab, and oral bisphosphonates for reducing fracture risk in postmenopausal women with osteoporosis. METHODS: We searched the literature, via PubMed, Medline, Embase, and the Cochrane Library, to screen citations from January 1996 to October 2014 for inclusion in this study. A mixed-treatment comparison meta-analysis within a Bayesian framework was performed by WinBUGS version 1.4.3 software. The proportions of women with vertebral fractures and women with nonvertebral fractures were analyzed. RESULTS: Our meta-analysis results indicated that all of the therapies-except etidronate-achieved a statistically significant reduction of fractures compared with placebo. Teriparatide and denosumab were more effective than alendronate and risedronate for reducing vertebral fracture (teriparatide vs alendronate: odds ratio [OR], 1.76; 95% CI, 1.03-2.98; teriparatide vs risedronate: OR, 1.92; 95% CI, 1.13-3.19; denosumab vs alendronate: OR, 1.67; 95% CI, 1.06-2.67; denosumab vs risedronate: OR, 1.84; 95% CI, 1.16-2.92). Teriparatide, denosumab, alendronate, and risedronate also reduced the risk of nonvertebral fracture compared with placebo. Results of subgroup analysis showed that denosumab (OR, 0.6; 95% CI, 0.37-0.98), alendronate (OR, 0.61; 95% CI, 0.39-0.96), and risedronate (OR, 0.63; 95% CI, 0.46-0.86) can reduce the risk of hip fracture and that risedronate (OR, 0.59; 95% CI, 0.4-0.88) can also reduce the risk of upper-arm fracture. CONCLUSIONS: Teriparatide, denosumab, alendronate, and risedronate are effective in reducing the risk of vertebral and nonvertebral fractures in postmenopausal women with osteoporosis. Furthermore, denosumab, alendronate, and risedronate can reduce the risk of hip fracture, and risedronate can also reduce the risk of upper-arm fracture.

FCGR3B copy number loss rather than gain is a risk factor for systemic lupus erythematous and lupus nephritis: a meta-analysis.

AIM: Some studies have been performed to elucidate the association between Fc gamma receptor 3B (FCGR3B) copy number (CN) and the risk of systemic lupus erythematosus (SLE) and/or lupus nephritis (LN), yet the results remain conflicting. Therefore, we have undertaken a systematic review of all the studies published and carried out a meta-analysis to obtain a better understanding of the role of FCGR3B CN in the susceptibility of SLE and LN. METHOD: A computerized literature search was conducted in databases of PubMed, ISI Web of Knowledge for all studies investigating the association between FCGR3B CN and SLE and/or LN, published up to May 2013. RESULTS: A total of six articles meeting all of the criteria were included in this study. There were five comparisons of SLE between 2490 patients and 4286 controls, and four comparisons of LN between 689 patients and 1924 controls. Our results showed that individuals with FCGR3B CN gain did not suffer an increased risk of SLE or LN as compared to the normal genotype in the total analysis (SLE: OR = 1.07, 95% CI = 0.79-1.45, P = 0.65; LN: OR = 0.83, 95% CI = 0.47-1.46, P = 0.52). However, individuals with FCGR3B CN loss exhibited an increased risk of SLE or LN (SLE: OR = 1.77, 95% CI = 1.51-2.06, P < 0.00001; LN: OR = 2.02, 95% CI = 1.59-2.57, P < 0.00001). CONCLUSION: Our meta-analysis indicated that FCGR3B CN loss rather than CN gain was associated with susceptibility to SLE and LN.

Performance evaluation of dual-frequency driving plate ultrasonic motor based on an analytical model.

An analytical model is presented to explain the effects of dual-frequency drive on the plate ultrasonic motor in this paper. The experimental prototype is a plate ultrasonic motor using single-phase asymmetric excitation, which can work under a single vibration or multiple vibration modes. Based on the linear superposition of vibrations with two different excitation frequencies, an analytical model is established using the classic Coulomb friction model, and the non-load rotation speed and maximum stall torque are deduced. Moreover, some crucial parameters such as preload and dead-zone in dual-frequency superposition model are identified or modified automatically by searching for the maximum correlation coefficient between simulation and experimental data using single-frequency drive. It is found that simulation and experiment results agree well when no excitation frequency component is at resonance.

In vitro identification of four-element windkessel models based on iterated unscented Kalman filter.

Mock circulatory loops (MCLs) have been widely used to test left ventricular assist devices. The hydraulic properties of the mock systemic arterial system are usually described by two alternative four-element windkessel (W4) models. Compared with three-element windkessel model, their parameters, especially the inertial term, are much more difficult to estimate. In this paper, an estimator based on the iterated unscented Kalman filter (IUKF) algorithm is proposed to identify model parameters. Identifiability of these parameters for different measurements is described. Performance of the estimator for different model structures is first evaluated using numerical simulation data contaminated with artificial noise. An MCL is developed to test the proposed algorithm. Parameter estimates for different models are compared with the calculated values derived from the mechanical and hydraulic properties of the MCL to validate model structures. In conclusion, the W4 model with an inertance and an aortic characteristic resistance arranged in series is proposed to represent the mock systemic arterial system. Once model structure is appropriately selected, IUKF can provide reasonable estimation accuracy in a limited time and may be helpful for future clinical applications.

[Research status and trend of heart modeling].

It is significant to research the heart modeling for the diagnosis and treatment of heart disease. With the development of biomedical technology, material and computer science, there are new requirements for heart modeling and simulation in terms of heart data acquisition, modeling approach, clinical application and so on. The research status of heart geometric/anatomical model, heart electrophysiological model and mechanical dynamic model has been summarized in this paper, and the problems and trends of heart modeling have been analyzed synthetically.