Current understanding of osteoarthritis pathogenesis and relevant new approaches

Osteoarthritis(OA)is the most common degenerative joint disease that causes painful swelling and permanent damage to the joints in the body.The molecular mechanisms of OA are currently unknown.OA is a heterogeneous disease that affects the entire joint,and multiple tissues are altered during OA development.To better understand the pathological mechanisms of OA,new approaches,methods,and techniques need to be used to understand OA pathogenesis.In this review,we first focus on the epigenetic regulation of OA,with a particular focus on DNA methylation,histone modification,and microRNA regulation,followed by a summary of several key mediators in OA-associated pain.We then introduce several innovative techniques that have been and will continue to be used in the fields of OA and OA-associated pain,such as CRISPR,scRNA sequencing,and lineage tracing.Next,we discuss the timely updates concerning cell death regulation in OA pathology,including pyroptosis,ferroptosis,and autophagy,as well as their individual roles in OA and potential molecular targets in treating OA.Finally,our review highlights new directions on the role of the synovial lymphatic system in OA.An improved understanding of OA pathogenesis will aid in the development of more specific and effective therapeutic interventions for OA.

MicroRNA immunobiology: when microRNA chemists meet immunologists

Although interdisciplinary research has been heralded as the engine of basic discovery for decades,many in the immunology community have been taken back by the recent marriage between microRNA(miRNA)and immunology.MicroRNAs were first discovered by Ambros and colleagues in 1993.1 They are small untranslated RNAs,highly conserved between different eukaryotic species.2–5 They are encoded by specific genes in the genome,which are controlled at the transcriptional level in a manner similar to protein-encoding genes.2 Following the synthesis of the primary miRNA by RNA polymerase Ⅱ or Ⅲ,nuclear processing by the enzyme Drosha produces a primary miRNA transcript which can be shuttled into the cytoplasm2 Final production of the mature miRNA species requires further cytoplasmic processing by an RNase Ⅲ enzyme called Dicer,producing a 19-to 24-base pair product,capable of being incorporated into the RNA-induced silencing complex.The RNA-induced silencing complex,in turn,is able to use the‘seed sequence’of the miRNA to recognize complementary mRNAtranscripts for degradation or translational silencing.To date,more than 800 human miRNAs have been identified,regulating an estimated 50%of all human genes.Each miRNA appears to regulate the expression of tens to hundreds of genes,thereby functioning as‘master-switches’that regulate and coordinate multiple cellular pathways in important processes such as embryonic development and oncogenesis,as well as cellular growth and proliferation.

抗PD-1治疗相关肝损伤的组织学模式

背景:Nivolumab和pembrolizumab是两种PD-1受体阻断性单克隆抗体,已成功用于多种晚期恶性肿瘤的治疗。抗PD-1治疗诱发的肝脏毒性的组织学变化尚未被深入研究,因此,本研究旨在评估这一组织学模式。方法:回顾性分析来自5个医疗中心(佛罗里达大学医学院、芝加哥大学Pritzker医学院、Loyola大学医学中心、耶鲁大学医学院、杜克大学医学中心)的8例接受Nivolumab或pembrolizumab治疗的晚期恶性肿瘤患者。这些患者既往均无肝病史,病毒性肝炎检测均为阴性。结果:抗PD-1治疗后,8例患者中有7例出现轻中度的胃肠道症状,如腹痛、疲乏、恶心、呕吐及黄疸。所有患者肝脏化学检测指标均显著升高。6例患者的肝损伤表现为急性小叶性肝炎,另外2例不同的损伤模式分别为脂肪性肝炎合并轻度胆汁淤积和急性胆汁淤积性损伤。无一例出现自身免疫性肝炎的典型特征。所有患者在中止抗PD-1治疗并予以免疫抑制治疗后,肝功能均恢复正常。结论:本研究结果显示,在抗PD-1治疗前对肝功能异常者进行筛选并在治疗期间定期监测肝功能指标,有助于预防严重肝损伤的发生。PD-1抑制剂并不会导致自身免疫性肝炎,而仅仅是引起免疫介导的急性非特异性肝炎。对于部分肝损伤患者,只要中止抗PD-1治疗即可,不必采用类固醇治疗。