Causal associations between gut microbiota and synovitis-tenosynovitis: a two-sample Mendelian randomization study.

Background: Increasing evidence indicates that gut microbiota dysbiosis is related to synovitis and tenosynovitis. Nonetheless, whether these associations are causal is currently unknown. Objectives: A two-sample Mendelian randomization (MR) study was performed to reveal the causality of gut microbiota with synovitis and tenosynovitis. Methods: The summary statistical data from a large-scale genome-wide association study (GWAS) were applied as the basis for a two-sample MR analysis. The causal effect was estimated using inverse variance weighted (IVW), weighted median, simple mode, MR-Egger, and weighted mode methods, of which IVW was the important method. Meanwhile, the pleiotropy and heterogeneity were detected and measured using MR-Egger regression, Cochran's Q statistics, funnel plots, and MR pleiotropy residual sum and outlier (MR-PRESSO) methods. Results: The IVW technique demonstrated that genetically predicted five genera, namely Gordonibacter [odds ratio (OR) = 0.999, 95% confidence interval (CI): (0.9977, 0.9998), p = 0.019], Paraprevotella [OR = 0.999, 95% CI: (0.9971, 0.9999), p = 0.036], Lachnoclostridium [OR = 0.998, 95% CI: (0.9954, 0.9999), p = 0.041], RuminococcaceaeUCG003 [OR = 0.997, 95% CI: (0.9955, 0.9994), p = 0.011], and FamilyXIIIAD3011group [OR = 0.997, 95% CI: (0.9954, 0.9992), p = 0.006] were negatively correlated with the risk of synovitis and tenosynovitis, while two other genera, namely Ruminococcustorquesgroup [OR = 1.003, 95% CI: (1.0004, 1.0049), p = 0.019] and Parabacteroides [OR = 1.003, 95% CI: (1.0002, 1.0052), p = 0.035] were positively associated with synovitis and tenosynovitis risk. In addition, the data of sensitivity analyses demonstrated that there were no outliers, horizontal pleiotropy, or heterogeneity in the causal relationship of the above-mentioned gut microbiota on synovitis and tenosynovitis (p > 0.05). Conclusion: The results of the study suggested that the gut microbiota was causally involved in synovitis and tenosynovitis and identified specific bacterial taxa that affect synovitis and tenosynovitis, which provide new insights into the pathogenesis underlying the development of synovitis and tenosynovitis mediated by gut microbiota.

Tetramethylpyrazine alleviates hypoxia-induced proliferation, migration, and inflammatory response of fibroblast-like synoviocytes via inhibiting the HIF-1α- circCDC42BPB pathway.

OBJECTIVES: Rheumatoid arthritis (RA) is a chronic inflammatory joint disease, which might trigger cartilage, bone damage, and disability. Recent studies have suggested that Tetramethylpyrazine (TMP), an alkaloid monomer isolated from the rhizome of the traditional herbal medicine Ligusticum wallichii Franch, exerts a broad spectrum of pharmacological properties, containing anti-inflammatory. This study aimed to analyze the role and underlying mechanism of TMP in RA. METHODS: Under Hypoxia condition, RA-Fibroblast-like synoviocyte (FLS) were treated with TMP at different doses. Cell viability, proliferation, cell cycle progression, and migration were detected using Cell Counting Kit-8 (CCK-8) assay, 5-ethynyl-2'-deoxyuridine (EdU) assay, flow cytometry assay, wound healing assay, and transwell assay. Cyclin D1, Proliferating cell nuclear antigen (PCNA), Matrix metalloproteinase-2 (MMP2), MMP9, and hypoxia-inducible factor-1α (HIF-1α) protein levels were measured using western blot assay. Interleukin-6 (IL-6) and IL-8 were evaluated using ELISA. Circular RNA (circRNA) hsa_circ_0005178 (circCDC42BPB), CDC42BPB, and HIF-1α expression were determined using real-time quantitative polymerase chain reaction (RT-qPCR). Binding between HIF-1α and CDC42BPB promoter was predicted by JASPAR and verified using dual-luciferase reporter and Chromatin immunoprecipitation (ChIP) assays. RESULTS: TMP might hinder FLS proliferation, cycle progression, migration, and inflammatory response under hypoxic conditions. CircCDC42BPB expression was increased in RA patients and RA-FLSs treated with hypoxia, while its level was obviously reduced in RA-FLSs treated with hypoxia and TMP. TMP might abolish hypoxia-induced circCDC42BPB expression. Upregulation of circCDC42BPB might partially overturn the repression of TMP on hypoxia-caused RA-FLS damage. TMP might regulate circCDC42BPB level via HIF-1α in RA-FLSs under hypoxic conditions. CONCLUSION: TMP might block RA-FLS injury partly via regulating the HIF-1α- circCDC42BPB pathway, providing a promising therapeutic target for RA.

HIGHLIGHTS: • TMP suppressed hypoxia-induced RA-FLS growth and inflammatory response.• TMP might repress circCDC42BPB expression in RA-FLSs under hypoxic conditions.• TMP might inhibit HIF-1α-induced circCDC42BPB transcription under hypoxic conditions.

Comparative efficacy and safety of statins for osteoporosis: a study protocol for a systematic review and network meta-analysis.

INTRODUCTION: Osteoporosis (OP) is a prevalent skeletal disease with high mortality and morbidity, followed by acute and chronic back pain, severe spinal deformity and dysfunction. First-line drugs for OP work through antiresorptive or anabolic mechanisms. Although with good efficacy, these drugs still have certain limitations in clinical application due to delivery routes, medication cycles and cost issues. Nowadays, statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) appear to be potentially promising drugs for OP. Despite the controversy, previous studies have shown the efficacy of statins in treating OP. Other studies have further indicated that the therapeutic effect of OP in statin-treated patients is dose dependent. However, scientists have not yet reached a consensus on the use of statins for the treatment or which statin to choose first. This study aims to review the literature, ascertaining the relative efficacy and safety of statins for patients with OP using a Bayesian network meta-analysis. METHODS AND ANALYSIS: We will systematically search the following databases: MEDLINE, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure, Wanfang Database, China Science and Technology Journal Database, Chinese BioMedical Literature Database and preprint servers to include randomised controlled trials that compare different statins for treating OP. Primary outcomes are the incidence of overall fractures and bone mineral density changes. Secondary outcomes contain adverse effects and bone turnover markers. All items of this review will comply with the Cochrane Handbook, and the quality of evidence will be evaluated by Grading of Recommendations Assessment, Development and Evaluation. A traditional pairwise meta-analysis and the Bayesian network meta-analysis will be performed to compare the efficacy of different statins. ETHICS AND DISSEMINATION: Ethical approval is not required since this is a protocol study for meta-analyses. Results will be submitted to a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42021242619. SEARCH DATES: From database inception to February 2022.