Deficiency of sorting nexin 10 prevents bone erosion in collagen-induced mouse arthritis through promoting NFATc1 degradation
Deficiency of sorting nexin 10 prevents bone erosion in collagen-induced mouse arthritis through promoting NFATc1 degradation
复制标题
排序 nexin 10 的缺陷通过促进 NFATc1 降解来防止胶原诱导的小鼠关节炎中的骨侵蚀
DOI：
10.1136/annrheumdis-2014-207134
复制
发表时间：
2016-06-01
影响因子：
27.4
通讯作者：
Shen, Xiaoyan
中科院分区：
文献类型：
--
作者：
Zhou, Chun;You, Yan;Shen, Xiaoyan
目的破骨细胞分化和活化引起的类风湿关节炎关节周围及软骨下骨侵蚀是诊断、治疗和监测类风湿关节炎的重要指标。SNX家族成员之一的SNX 10参与了内体细胞的分选，在恶性骨硬化症中发挥重要的临床作用。本文研究了SNX 10在胶原诱导性关节炎（CIA）小鼠骨破坏中的作用及其确切机制。方法通过在雄性SNX 10 −/−小鼠和野生型同窝小鼠中诱导CIA小鼠模型来评估SNX 10在骨破坏中的作用。在由来自野生型和SNX 10 −/−小鼠的骨髓单个核细胞的核因子κB配体的受体激活剂诱导的破骨细胞中探索了机制。结果SNX 10基因敲除可抑制CIA小鼠骨丢失和关节破坏，降低血清TNF-α、IL-1β和抗胶原IgG 2α抗体水平。SNX 10缺乏并不阻断破骨细胞的生成，但通过干扰肌动蛋白带的形成，显著损害破骨细胞的成熟和骨吸收功能。SNX 10-/-破骨细胞中TRAP、CtsK和MMP 9的产生受到显著抑制，并通过SNX 10过表达部分恢复。我们进一步证明了NFATc 1的降解在SNX 10 −/−破骨细胞中加速，导致整联蛋白β3-Src-PYK 2信号传导的抑制。结论SNX 10在破骨细胞功能中的重要作用及其新机制，为SNX 10作为抗类风湿关节炎免疫炎症和骨侵蚀的新靶点提供了实验依据。
Objective Periarticular and subchondral bone erosion in rheumatoid arthritis caused by osteoclast differentiation and activation is a critical index for diagnosis, therapy and monitoring of the disease. Sorting nexin (SNX) 10, a member of the SNX family which functions in regulation of endosomal sorting, has been implicated to play an important clinical role in malignant osteopetrosis. Here we studied the roles and precise mechanisms of SNX10 in the bone destruction of collagen-induced arthritis (CIA) mice. Methods The role of SNX10 in bone destruction was evaluated by a CIA mice model which was induced in male SNX10−/− mice and wild type littermates. The mechanism was explored in osteoclasts induced by receptor activator of nuclear factor κB ligand from bone marrow mononuclear cells of wild type and SNX10−/− mice. Results SNX10 knockout prevented bone loss and joint destruction in CIA mice with reduced serum levels of TNF-α, interleukin 1β and anticollagen IgG 2α antibody. SNX10 deficiency did not block osteoclastogenesis, but significantly impaired osteoclast maturation and bone-resorption function by disturbing the formation of actin belt. The production of TRAP, CtsK and MMP9 in SNX10−/− osteoclasts was significantly inhibited, and partially restored by SNX10 overexpression. We further demonstrated that the degradation of NFATc1 was accelerated in SNX10−/− osteoclasts causing an inhibition of integrin β3-Src-PYK2 signalling. Conclusions Our study discloses a crucial role and novel mechanism for SNX10 in osteoclast function, and provides evidence for SNX10 as a promising novel therapeutic target for suppression of immune inflammation and bone erosion in rheumatoid arthritis.