Synovial mesenchymal stem cell-derived exosomal microRNA-320c facilitates cartilage damage repair by targeting ADAM19-dependent Wnt signalling in osteoarthritis rats.

OBJECTIVE: Our previous study revealed that synovial mesenchymal stem cell (SMSC)-derived exosomal microRNA-302c enhanced chondrogenesis by targeting a disintegrin and metalloproteinase 19 (ADAM19) in vitro. This study aimed to validate the potential of SMSC-derived exosomal microRNA-302c for the treatment of osteoarthritis in vivo. METHODS: After 4 weeks of destabilization of the medial meniscus surgery (DMM) to establish an osteoarthritis model, the rats received weekly articular cavity injection of SMSCs with or without GW4869 treatment (exosome inhibitor) or exosomes from SMSCs with or without microRNA-320c overexpression for another 4 weeks. RESULTS: SMSCs and SMSC-derived exosomes reduced the Osteoarthritis Research Society International (OARSI) score, improved cartilage damage repair, suppressed cartilage inflammation, suppressed extracellular matrix (ECM) degradation, and inhibited chondrocyte apoptosis in DMM rats. However, these effects were largely hampered in rats that were injected with GW4869-treated SMSCs. Moreover, exosomes from microRNA-320c-overexpressing SMSCs exerted a better effect than exosomes from negative control SMSCs on decreasing the OARSI score, enhancing cartilage damage repair, suppressing cartilage inflammation, and inhibiting ECM degradation and chondrocyte apoptosis. Mechanistically, exosomes from microRNA-320c-overexpressing SMSCs reduced the levels of ADAM19, as well as ß-catenin and MYC, which are two critical proteins in Wnt signalling. CONCLUSION: SMSC-derived exosomal microRNA-320c suppresses ECM degradation and chondrocyte apoptosis to facilitate cartilage damage repair in osteoarthritis rats by targeting ADAM19-dependent Wnt signalling.

Iguratimod ameliorates rheumatoid arthritis progression through regulating miR-146a mediated IRAK1 expression and TRAF6/JNK1 pathway: an in vivo and in vitro study.

OBJECTIVES: This study aimed to evaluate the therapeutic effect of iguratimod and its regulatory role on microRNA (miR-146a) and the downstream genes in treating rheumatoid arthritis-fibroblast-like synoviocytes (RA-FLS) and collagen-induced arthritis (CIA) rat model. METHODS: RA-FLS was isolated from knee synovial tissue of an active RA patient. In vitro, the effect of miR-146a mimic/inhibition on RA-FLS functions was investigated. Then the effect of Iguratimod on cell viability, proliferation, apoptosis, migration, invasion, inflammatory cytokines, miR-146a and its downstream gene/pathway in RA-FLS was evaluated. In vivo, the collagen induced arthritis (CIA) rat model was constructed, then the effects of iguratimod, miR-146a inhibition and their combination on treating CIA rat were assessed. RESULTS: Iguratimod treatment increased miR-146a while decreased cell proliferation, IRAK1 and TRAF6/JNK1 pathway in RA-FLS in a dose-dependent manner. Notably, iguratimod treatment repressed cell proliferation, migration, invasion, TNF-α, IL-1ß, IL-6, IL-17, IRAK1 and TRAF6/JNK1 pathway in RA-FLS, while miR-146a inhibition alleviated the abovementioned effects of Iguratimod on RA-FLS. The in vivo experiments disclosed that iguratimod reduced systemic arthritis score, and decreased TNF-α, IL-1ß, IL-6, IL-17, IRAK1 as well as TRAF6/JNK1 pathway, while enhanced apoptosis in synovial tissue of CIA rat model; and in miR-146a inhibition treated CIA rat model, the effect of iguratimod was diminished. CONCLUSIONS: Iguratimod ameliorates RA progression via regulating miR-146a mediated IRAK1 expression and TRAF6/JNK1 pathway.

Correction to: MiRNA-126 expression inhibits IL-23R mediated TNF-α or IFN-γ production in fibroblast-like synoviocytes in a mice model of collagen-induced rheumatoid arthritis.

The authors would like to add an article note stating that "The authors Jie Gao and Ruina Kong have equally contributed to the article".

Autophagy exerts pivotal roles in regulatory effects of 1α,25-(OH)2D3 on the osteoclastogenesis.

As an active form of vitamin D3, 1α,25-(OH)2D3 has a positive therapeutical effect on osteoporosis. However, 1α,25-(OH)2D3 can not only promote the osteoclastogenesis, but also inhibit the proliferation of osteoclast precursors (OCPs). Autophagy is regulated by 1α,25-(OH)2D3 and is considered to promote the osteoclastogenesis. Nevertheless, the role of 1α,25-(OH)2D3 in OCPs' autophagy remains unknown. Our study aims to explore whether the effect of 1α,25-(OH)2D3 on osteoclastogenesis is related to its regulation in autophagy. The results showed that 1α,25-(OH)2D3 exhibited a direct inhibitory effect on the autophagy activity and the proliferation of OCPs derived from bone marrow-derived macrophages (BMMs), which was reversed by the overexpression of autophagy-related gene. In presence of RANKL, the autophagy capacity of OCPs and the differentiation from OCPs into mature osteoclasts were significantly enhanced by 1α,25-(OH)2D3, while the suppression of autophagy with spautin-1 or 3-MA downregulated the osteoclastogenesis capacity. In summary, 1α,25-(OH)2D3 can directly suppress OCPs autophagy, which negatively regulates the proliferation of OCPs without RANKL. 1α,25-(OH)2D3 can indirectly upregulate the autophagy response of OCPs, thereby enhancing the osteoclasts formation in presence of RANKL. Therefore, our study found that 1α,25-(OH)2D3 had a dual effect on osteoclastogenesis by regulating autophagy, suggesting that some drugs targeting autophagy may act as an effective supplement of 1α,25-(OH)2D3 in treating osteoporosis.

MiRNA-126 expression inhibits IL-23R mediated TNF-α or IFN-γ production in fibroblast-like synoviocytes in a mice model of collagen-induced rheumatoid arthritis.

Both miR-126 and IL-23R affect rheumatoid arthritis (RA) procession. This study aimed to investigate the association of miR-126 and IL-23R and the possible modulation of miR-126 to RA pathogenesis. Serum, synovial tissue and synovial fluid were collected from patients with RA, and expression of miR-126, IL-23R, TNF-α and IFN-γ were detected. Fibroblast-like synoviocytes (FLS) was established using a collagen-induced arthritis mice model. The expression of miR-126 was manual intervened using pro-miR-126 and anti-miR-126 encoding lentivirus plasmids, or miR-126 agonists and corresponding negative controls. MiR-126 expression was inhibited in RA patients when compared with controls (P < 0.05). TNF-α and IFN-γ production and IL-23R expression were significantly upregulated in RA patients when compared to controls (P < 0.05). In pro-miR-126 treated FLS cells, the administration of pro-miR-126 plasmids upregulated miR-126, but inhibited IL-23R, TNF-α and IFN-γ expression or production. Moreover, the miR-126 agonist reversed the effects of the anti-miR-126 plasmid on FLS. These results revealed that miR-126 negative regulated the expression of IL-23R, TNF-α and IFN-γ. These results suggest the key impact of miR-126 on RA procession. Moreover, pro-miR-126 might be explored to be a potential therapy for RA.

microRNA-126 targeting PIK3R2 promotes rheumatoid arthritis synovial fibro-blasts proliferation and resistance to apoptosis by regulating PI3K/AKT pathway.

OBJECTIVE: The purpose of our study was to elucidate the impact of microRNA-126 (miR-126) targeting PIK3R2 gene on cell proliferation and apoptosis of rheumatoid arthritis synovial fibro-blasts (RASFs) by regulating PI3K/AKT signal pathway. METHODS: The synovial tissue samples of this study were from 55 RA patients undergoing joint replacement and 27 healthy people undergoing joint repair due to trauma. The target genes of miR-126 were collected by the TargetScan and PIK3R2 as the direct target gene of miR-126 was confirmed by dual-luciferase reporter assay system. Our experiment had five groups including the blank control, miR-126 mimic, miR-126 mimic control, miR-126 inhibitor and miR-126 inhibitor control groups. Additionally, real-time quantitative polymerase chain reaction (RT-qPCR), Western-Blot, cell counting kit (CCK-8) and flow cytometry were carried out in this study. RESULTS: Compared with healthy individuals, the RA patients had increased miR-126, but decreased PIK3R2 mRNA expressions in the synovial tissues. Pearson correlation analysis indicated that miR-126 expression was negatively correlated with PIK3R2 mRNA expression (all P<0.05). When compared with the blank group respectively, the miR-126 mimic group had raising cell proportions in S and G2/M phases with reduced rate of cell apoptosis, while the miR-126 inhibitor group had raising cell proportions in G0/G1 and G2/M phases with increased rate of cell apoptosis (all P<0.05). Besides, compared with the blank control group, the miR-126 mimic group had declined expression of PIK3R2 protein with ascended expression of PI3K and p-AKT (all P<0.05), while the miR-126 inhibitor group had increased expression of PIK3R2 protein with decreased expression of PI3K and p-AKT (all P<0.05). CONCLUSION: Our study demonstrated that down-regulation of miR-126 may indirectly inhibit PI3K/AKT signaling pathway to disrupt the imbalance between growth and death of RASFs by targeting PIK3R2, which may be clinically helpful to find therapeutic strategies directed toward miR-126 function for RA patients.

Myositis as a prominent manifestation of primary skeletal muscle peripheral T-cell lymphoma: a case report and literature review.

The patient presented to the clinic with painful muscle swelling in the right lower extremity, which improved with immunosuppressive therapy. Initially, the condition was diagnosed as polymyositis but recurred soon after. After imaging and biopsy, the final diagnosis was primary skeletal muscle peripheral T-cell lymphoma, not otherwise specified (PSM-PTCL, NOS). In this report, we discuss the challenges in diagnosing and treating this aggressive malignancy and review the literature on PSM-PTCL, NOS. Key Points • To date, there are few reports of PSM-PTCL, NOS, and our case is the tenth. • It is crucial to consider PSM-PTCL, NOS, when presenting with localized muscle edema and unexplained pain. • Histopathological examination is likely the most effective method for diagnosing this rare disease.

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.

Synovial mesenchymal stem cell-derived exosomal miR-320c enhances chondrogenesis by targeting ADAM19.

Background: Synovial mesenchymal stem cell (SMSC)-derived exosomes show treatment potential in osteoarthritis, although their functional mechanism is still unclear. Materials & methods: Osteoarthritis chondrocytes and normal SMSC were cultured. Subsequently, chondrocytes were co-cultured with SMSC or miR-320c-overexpressing SMSC-derived exosomes, or directly transfected with miR-320c mimic. Furthermore, compensate experiments were conducted. Results: SMSC promoted chondrocyte proliferation, migration, COL2A1 and ACAN expressions while suppressing apoptosis by transmitting exosomes. Furthermore, miR-320c-overexpressing SMSC-derived exosomes and direct miR-320c overexpression in chondrocytes presented more significant effect on enhancing chondrogenesis. In addition, miR-320c directly targeted ADAM19, and ADAM19 overexpression compensated the regulation of miR-320c on chondrogenesis. Conclusion: SMSC-derived exosomal miR-320c enhances chondrogenesis through targeting ADAM19, highlighting a potentially novel mechanism of SMSC in treating osteoarthritis.

Prevalence, clinical features, risk factors, and outcomes of SLE patients with aortic aneurysm: a cross-sectional retrospective study in a Chinese single center.

OBJECTIVES: The prevalence, clinical features, and outcomes of patients with systemic lupus erythematosus (SLE) complicated with or without aortic aneurysm (AA) were compared in a Chinese single-center cohort. METHODS: Included in this study were SLE patients who received treatment at Shanghai Changhai Hospital between 2000 and 2020. The prevalence, clinical features, and outcomes of these SLE patients with or without AA were compared by Student's t-tests or Fisher's exact tests as appropriate. Risk factors associated with AA occurrence in SLE were evaluated by univariable and multivariable logistic regression analyses. The survival analysis between SLE patients with or without AA was conducted by the Kaplan-Meier method. RESULTS: Of the 1843 SLE patients included in this study, 16 (0.86%) were identified as having AA, and 160 of the remaining 1825 SLE patients without AA were selected as a simple random sample for comparison. The SLE patients with AA showed a higher proportion of smoking and hypertension as compared with those with no AA. Multivariable logistic regression analysis showed that a long SLE duration and anti-RNP positivity were two independent risk factors associated with AA occurrence in SLE patients. The log rank test showed that SLE patients with AA had a significantly higher risk of progression to death. Renal disorder was associated with an even poorer outcome in SLE patients with AA. CONCLUSION: The incidence of AA in SLE patients may be underestimated. The association between AA and SLE, especially in patients with multiple risk factors, should not be ignored. Key Points • The risk of SLE patients developing AA may be higher than that previously estimated. • The risk of SLE patients especially with multiple risk factors developing AA should not be ignored. • The diagnosis of AA should not be forgot when SLE patients present with chest, back, or abdominal symptoms with unexplained causes.

Epidemiology of Takayasu arteritis in Shanghai: A hospital-based study and systematic review.

BACKGROUND: Takayasu arteritis (TAK) is a rare large vessel vasculitis, and epidemiological data on TAK are lacking in China. Thus, we designed this study to estimate the TAK prevalence and incidence in residential Shanghai, China. METHODS: Data on diagnosed TAK cases aged over 16 years were retrieved from 22 tertiary hospitals in Shanghai through hospital electronic medical record systems between January 1, 2015 and December 31, 2017 to estimate the prevalence and incidence. A systematic literature review based on searches in PubMed, Ovid-Medline, Excerpta Medica Database (EMBASE), Web of Science, and China National Knowledge Infrastructure (CNKI) was performed to summarize TAK distribution across the world. RESULTS: In total 102 TAK patients, with 64% female, were identified. The point prevalence (2015-2017) was 7.01 (95% CI 5.65-8.37) cases per million, and the mean annual incidence was 2.33 (1.97-3.21) cases per million. The average age of TAK patients was 44 ± 16 years, with the highest prevalence (11.59 [9.23-19.50] cases per million) and incidence (3.55 [0.72 3.74] cases per million) in the 16 to 34 years population. Seventeen reports were included in the system review, showing that the epidemiology of TAK varied greatly across the world. The incidence and prevalence were both relatively higher in Asian countries, with the prevalence ranging 3.3-40 cases per million and annual incidence ranging 0.34-2.4 cases per million. CONCLUSIONS: The prevalence and incidence of TAK in Shanghai was at moderate to high levels among the previous reports. The disease burden varied globally among racial populations.

MicroRNA-126 promotes proliferation, migration, invasion and endothelial differentiation while inhibits apoptosis and osteogenic differentiation of bone marrow-derived mesenchymal stem cells.

Bone marrow-derived mesenchymal stem cells (BMSCs) are widely used for the treatment of inflammatory and immune diseases, and microRNA-126 (miR-126) is a critical regulator in inflammation as well as immunity. However, the mediating role of miR-126 in BMSCs is still not clear. Thus, this study aimed to preliminarily investigate the effect of miR-126 on proliferation, apoptosis, migration, invasion, differentiation, and its potential regulating pathways in BMSCs. Human BMSCs were obtained and infected with miR-126 overexpression lentivirus, control overexpression lentivirus, miR-126 knock-down lentivirus and control knock-down lentivirus, then cell functions, the PI3 K/AKT pathway and MEK1/ERK1 pathway were evaluated. Subsequently, PI3 K overexpression plasmid and MEK1 overexpression plasmid were transfected into BMSCs with miR-126 knockdown, then the cell functions were assessed as well. BMSCs with miR-126 overexpression displayed elevated proliferation, migration and invasion while decreased apoptosis; however, BMSCs with miR-126 knockdown presented with decreased proliferation, migration, invasion but increased apoptosis. As for differentiation, BMSCs with miR-126 overexpression showed higher levels of CD31, eNOS and VE-cadherin but lower expressions of ALP, OPN and RUNX2, while BMSCs with miR-126 knockdown disclosed the opposite results. Additionally, BMSCs with miR-126 overexpression showed elevated PI3 K, pAKT, MEK1 and pERK1 expressions, while BMSCs with miR-126 knockdown displayed opposite results. Furthermore, PI3 K overexpression and MEK1 overexpression both reversed the effects of miR-126 on cell functions in BMSCs. In conclusion, miR-126 is a genetic regulator in BMSCs via modulating multiple cell functions through the PI3 K/AKT and MEK1/ERK1 signaling pathways.

Combination of circulating miR-19b-3p, miR-122-5p and miR-486-5p expressions correlates with risk and disease severity of knee osteoarthritis.

The aim of this study was to investigate the association of circulating miRNAs profile with the risk of knee osteoarthritis (OA), and evaluate their correlation with clinical characteristics. This study was divided into two parts: exploration stage and validation stage. In exploration stage, 8 knee OA patients and 8 age and gender highly matched health controls (HCs) were recruited, and plasma sample were collected for microarray examination. Differentially expressed miRNAs and enrichment analysis were subsequently performed. In validation stage, 100 knee OA patients and 100 age and gender matched HCs were enrolled, and Top 8 differentially expressed miRNAs in microarray were selected for further validation by qPCR. In exploration stage, 41 up-regulated miRNAs and 29 down-regulated miRNAs were identified by microarray, and enrichment analysis disclosed these miRNAs were involved in inflammation- and immunity- related process. Top 8 differentially expressed miRNAs in microarray were determined in the validation stage, and miR-19b-3p, miR-92a-3p, miR-122-5p, miR-486-5p and miR-320b expression were increased in knee OA. Univariate and multivariate logistic analysis showed only miR-19b-3p, miR-122-5p and miR-486-5p were independent factors for knee OA risk, and ROC curve showed combination of miR-19b-3p, miR-122-5p and miR-486-5p has a great diagnostic value for knee OA. Besides, miR-19b-3p and miR-486-5p positively correlates with disease severity. This study revealed that circulating miRNA profiles played a key role in knee OA diagnosis, and combined measurement of miR-19b-3p, miR-122-5p and miR-486-5p could be served as a novel and promising biomarker for diagnosis and disease severity of knee OA.

TNF-α -857 and -1031 polymorphisms predict good therapeutic response to TNF-α blockers in Chinese Han patients with ankylosing spondylitis.

AIM: To evaluate whether polymorphisms at -857, -1031, -308 and -238 positions of the TNF-α gene influence response to TNF-α-blocker therapy in Chinese Han patients with ankylosing spondylitis. PATIENTS & METHODS: A total of 106 patients with ankylosing spondylitis were recruited and genotyped for -857, -1031, -308 and -238 TNF-α gene polymorphisms. In total, 32 received infliximab and 74 received a recombinant human TNF-α receptor II-IgG Fc fusion protein (rhTNFR-Fc). At the end of 12 weeks, patients were assessed using the Assessment of SpondyloArthritis International Society (ASAS) 20, 40, 50 and 70 criteria. RESULTS: Polymorphisms at -308 and -238 did not affect therapeutic response. The -857 C/C genotype (p = 0.0021) responded better to therapy. The -1031 T/T genotype (p = 0.0004) showed better outcome. CONCLUSION: In Chinese Han ankylosing spondylitis patients, polymorphisms at the -308 and -238 positions of the TNF-α gene are unable to predict TNF-α-blocker response; however, -857 C/C and -1031 T/T genotypes have the ability to predict good response.