Identification of a novel chemokine-dependent molecular mechanism underlying rheumatoid arthritis-associated autoantibody-mediated bone loss.
Identification of a novel chemokine-dependent molecular mechanism underlying rheumatoid arthritis-associated autoantibody-mediated bone loss.
复制标题
DOI：
10.1136/annrheumdis-2015-208093
复制
发表时间：
2016-04
影响因子：
27.4
通讯作者：
Catrina AI
中科院分区：
文献类型：
--
作者：
Krishnamurthy A;Joshua V;Haj Hensvold A;Jin T;Sun M;Vivar N;Ytterberg AJ;Engström M;Fernandes-Cerqueira C;Amara K;Magnusson M;Wigerblad G;Kato J;Jiménez-Andrade JM;Tyson K;Rapecki S;Lundberg K;Catrina SB;Jakobsson PJ;Svensson C;Malmström V;Klareskog L;Wähämaa H;Catrina AI
风湿性关节炎（RA）特异性抗瓜氨酸蛋白/肽抗体（ACPA）出现在疾病发作之前，并与骨破坏有关。我们的目的是剖析ACPAs在破骨细胞（OC）激活中的作用，并确定在这一过程中的关键细胞介质。从RA患者的关节液和外周血中分离ACPA。从RA患者的单个SF B细胞中分离出单克隆ACPA。OC是由血细胞前体在有或没有ACPA的情况下开发的。我们通过免疫组织化学和流式细胞仪微珠阵列分析了瓜氨酸化靶点和肽基精氨酸脱亚胺酶（PAD）的表达。在OC培养物中检测抗白细胞介素（IL）-8中和抗体和泛PAD抑制剂的作用。将单克隆ACPAs注射到小鼠体内，并在用瑞帕瑞辛阻断CXCR 1/2之前和之后通过显微CT分析骨结构。PAD的瓜氨酸蛋白对OC分化至关重要。多克隆ACPA通过PAD依赖性IL-8介导的自分泌环增强OC分化，该自分泌环被IL-8中和完全消除。一些，但不是全部，人单克隆ACPA衍生自RA患者的单个SF B细胞，并表现出不同的表位特异性，促进OC在细胞培养物中的分化。将单克隆ACPAs转移到小鼠中诱导骨丢失，其被IL-8拮抗剂瑞帕瑞辛完全逆转。我们对瓜氨酸和PAD酶在OC分化和ACPA诱导的OC活化过程中的关键作用提供了新的见解。我们的研究结果表明，IL 8依赖OC激活可能构成了ACPA阳性RA关节特异性炎症启动的早期事件。
Rheumatoid arthritis (RA)-specific anti-citrullinated protein/peptide antibodies (ACPAs) appear before disease onset and are associated with bone destruction. We aimed to dissect the role of ACPAs in osteoclast (OC) activation and to identify key cellular mediators in this process. Polyclonal ACPA were isolated from the synovial fluid (SF) and peripheral blood of patients with RA. Monoclonal ACPAs were isolated from single SF B-cells of patients with RA. OCs were developed from blood cell precursors with or without ACPAs. We analysed expression of citrullinated targets and peptidylarginine deiminases (PAD) enzymes by immunohistochemistry and cell supernatants by cytometric bead array. The effect of an anti-interleukin (IL)-8 neutralising antibody and a pan-PAD inhibitor was tested in the OC cultures. Monoclonal ACPAs were injected into mice and bone structure was analysed by micro-CT before and after CXCR1/2 blocking with reparixin. Protein citrullination by PADs is essential for OC differentiation. Polyclonal ACPAs enhance OC differentiation through a PAD-dependent IL-8-mediated autocrine loop that is completely abolished by IL-8 neutralisation. Some, but not all, human monoclonal ACPAs derived from single SF B-cells of patients with RA and exhibiting distinct epitope specificities promote OC differentiation in cell cultures. Transfer of the monoclonal ACPAs into mice induced bone loss that was completely reversed by the IL-8 antagonist reparixin. We provide novel insights into the key role of citrullination and PAD enzymes during OC differentiation and ACPA-induced OC activation. Our findings suggest that IL8-dependent OC activation may constitute an early event in the initiation of the joint specific inflammation in ACPA-positive RA.