15-Lipoxygenase-1 in osteoblasts promotes TGF-β1 expression via inhibiting autophagy in human osteoarthritis.
成骨细胞中 15-Lipoxygenase-1 通过抑制人骨关节炎中自噬促进tgf-β 1 的表达。
- 作者列表："Wan Y","Lv Y","Li L","Yin Z
BACKGROUND:15-Lipoxygenase-1 (15-LOX-1) belongs to the lipoxygenase family involved in the inflammatory response and pathological process of various diseases, including osteoarthritis (OA). The overexpression of TGF-β1 in osteoblasts leads to abnormal changes in subchondral bone structure, eventually causing OA. However, the pathogenesis of the disease is poorly defined, and the interaction between 15-LOX-1 and TGF-β1 in osteoblasts has not been evaluated in OA. In this study, the role of 15-LOX-1 in subchondral bone osteoblasts in OA was evaluated. METHOD:15-LOX-1 expression in osteoblasts of the subchondral bone of patients with OA was measured by immunohistochemistry, qRT-PCR, and western blotting. Osteoblasts extracted from the subchondral bone of OA were transfected with 15-LOX-1 siRNA and an overexpression vector. The eﬀ ;ect of 15-LOX-1 on the expression of TGF-β1 in OA osteoblasts was assessed by qRT-PCR and western blotting. The effect of 15-LOX-1 on autophagy via AMPK pathway in OA osteoblasts was evaluated by qRT-PCR, western blotting, and transmission electron microscopy. RESULTS:The expression levels of 15-LOX-1 and TGF-β1 were higher in OA subchondral bone osteoblast than that in non-OA subchondral bone. 15-LOX-1, which downregulated autophagy by inhibiting AMPK following the activation of mTORC1, upregulated the osteoblast expression of TGF-β1. Treatment with autophagy inhibitors significantly increased the expression levels of TGF-β1 in osteoblasts. CONCLUSION:In the present study, our findings suggested that 15-Lipoxygenase-1 in Osteoblasts Promotes TGF-β1 expression via inhibiting autophagy in human Osteoarthritis. These novel results suggested that 15-Lipoxygenase-1 expressed by subchondral bone osteoblasts might be a promising therapeutic target in human OA.
背景: 1 5-脂氧合酶-1 (1 5-LOX-1) 属于脂氧合酶家族，参与多种疾病的炎症反应和病理过程，包括骨关节炎 (OA)。成骨细胞中tgf-β 1 的过度表达导致软骨下骨结构的异常改变，最终引起OA。然而，该病的发病机制尚不明确，1 5-LOX-1 和TGF-β 1 在成骨细胞中的相互作用尚未在OA中得到评价。本研究评价了 1 5-LOX-1 在OA软骨下骨成骨细胞中的作用。 方法: 采用免疫组织化学、qRT-PCR和western blotting检测OA患者软骨下骨成骨细胞中 1 5-LOX-1 的表达。用 1 5-LOX-1 siRNA和过表达载体转染从OA软骨下骨中提取的成骨细胞。通过qRT-PCR和western blotting评估 1 5-LOX-1 对OA成骨细胞TGF-β 1 表达的影响。通过qRT-PCR、western blotting和透射电镜评价 1 5-LOX-1 通过AMPK通路对OA成骨细胞自噬的影响。 结果: 1 5-LOX-1 和TGF-β 1 在OA软骨下骨成骨细胞中的表达水平高于非OA软骨下骨。1 5-LOX-1 通过抑制mTORC 1 激活后的AMPK下调自噬，上调TGF-β 1 的成骨细胞表达。自噬抑制剂治疗可显著增加成骨细胞中tgf-β 1 的表达水平。 结论: 在本研究中，我们的研究结果表明成骨细胞中的 15-Lipoxygenase-1 通过抑制人骨关节炎中的自噬促进tgf-β 1 的表达。提示软骨下骨成骨细胞表达的 15-Lipoxygenase-1 有望成为治疗OA的新靶点。
METHODS:OBJECTIVE:Patients with immune-mediated inflammatory diseases such as rheumatoid arthritis or systemic lupus erythematosus are at increased risk of cardiovascular disease. However, the cardiovascular risk of patients with primary Sjögren's syndrome (SS) remains poorly studied. We aimed to investigate the association between primary SS and cardiovascular morbidity and mortality. METHODS:We performed a systematic review of articles in Medline and the Cochrane Library and recent abstracts from US and European meetings, searching for reports of randomized controlled studies of cardiovascular morbidity and cardiovascular mortality in primary SS. The relative risk (RR) values for cardiovascular morbidity and mortality associated with primary SS were collected and pooled in a meta-analysis with a random-effects model by using Review Manager (Cochrane collaboration). RESULTS:The literature search revealed 484 articles and abstracts of interest; 14 studies (67,124 patients with primary SS) were included in the meta-analysis. With primary SS versus control populations, the risk was significantly increased for coronary morbidity (RR 1.34 [95% confidence interval (95% CI) 1.06-1.38]; P = 0.01), cerebrovascular morbidity (RR 1.46 [95% CI 1.43-1.49]; P < 0.00001), heart failure rate (odds ratio 2.54 [95% CI 1.30-4.97]; P < 0.007), and thromboembolic morbidity (RR 1.78 [95% CI 1.41-2.25]; P < 0.00001), with no statistically significant increased risk of cardiovascular mortality (RR 1.48 [95% CI 0.77-2.85]; P = 0.24). CONCLUSION:This meta-analysis demonstrates that primary SS is associated with increased cardiovascular morbidity, which suggests that these patients should be screened for cardiovascular comorbidities and considered for preventive interventions, in a multidisciplinary approach with cardiologists.
METHODS:OBJECTIVE:We aimed to evaluate the comparative risk of hospitalized infection among patients with rheumatoid arthritis (RA) who initiated abatacept versus a tumor necrosis factor inhibitor (TNFi). METHODS:Using claims data from Truven MarketScan database (2006-2015), we identified patients with RA ages ≥18 years with ≥2 RA diagnoses who initiated treatment with abatacept or a TNFi. The primary outcome was a composite end point of any hospitalized infection. Secondary outcomes included bacterial infection, herpes zoster, and infections affecting different organ systems. We performed 1:1 propensity score (PS) matching between the groups in order to control for baseline confounders. We estimated incidence rates (IRs) and hazard ratios (HRs) with 95% confidence intervals (95% CIs) for hospitalized infection. RESULTS:We identified 11,248 PS-matched pairs of patients who initiated treatment with abatacept and TNFi with a median age of 56 years (83% were women). The IR per 1,000 person-years for any hospitalized infection was 37 among patients who initiated treatment with abatacept and 47 in those who initiated treatment with TNFi. The HR for the risk of any hospitalized infection associated with abatacept versus TNFi was 0.78 (95% CI 0.64-0.95) and remained lower when compared to infliximab (HR 0.63 [95% CI 0.47-0.85]), while no significant difference was seen when compared to adalimumab and etanercept. The risk of secondary outcomes was lower for abatacept for pulmonary infections, and similar to TNFi for the remaining outcomes. CONCLUSION:In this large cohort of patients with RA who initiated treatment with abatacept or TNFi as a first- or second-line biologic agent, we found a lower risk of hospitalized infection after initiating abatacept versus TNFi, which was driven mostly by infliximab.
METHODS:OBJECTIVE:Reducing pain is one of the main health priorities for children and young people with juvenile idiopathic arthritis (JIA); however, some studies indicate that pain is not routinely assessed in this patient group. The aim of this study was to explore health care professionals' (HCPs) beliefs about the role of pain and the prioritization of its assessment in children and young people with JIA. METHODS:Semi-structured interviews were conducted with HCPs who manage children and young people with JIA in the UK (including consultant and trainee pediatric rheumatologists, nurses, physical therapists, and occupational therapists). Data were analyzed qualitatively following a framework analysis approach. RESULTS:Twenty-one HCPs participated. Analyses of the data identified 6 themes, including lack of training and low confidence in pain assessment, reluctance to engage in pain discussions, low prioritization of pain assessment, specific beliefs about the nature of pain in JIA, treatment of pain in JIA, and undervaluing pain reports. Assessment of pain symptoms was regarded as a low priority and some HCPs actively avoided conversations about pain. CONCLUSION:These findings indicate that the assessment of pain in children and young people with JIA may be limited by knowledge, skills, and attitudinal factors. HCPs' accounts of their beliefs about pain in JIA and their low prioritization of pain in clinical practice suggest that a shift in perceptions about pain management may be helpful for professionals managing children and young people with this condition.