The role of WAVE Complex in osteoclast-mediated bone destruction in experimental arthritis

WAVE 复合物在破骨细胞介导的实验性关节炎骨质破坏中的作用

• 批准号: 456073691
• 负责人: Dr. Berno Dankbar, Ph.D.
• 金额: --
• 依托单位: Helmholtz-Zentrum für Infektionsforschung (HZI)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/456073691?language=en
• 关键词: role; WAVE; Complex; osteoclast; mediated

Migration, adhesion as well as endo- and exocytosis all critically depend on dynamic reorganization of the actin cytoskeleton, potentially involving actin nucleators like Arp2/3-complex and its activators such as WAVE-complex. In order to investigate the role of WAVE-complex in the hematopoietic system, we have generated mice in which the gene encoding the only hematopoietic-specific subu-nit of WAVE-complex, Hem1, is deleted. By 3 months of age, Hem1-/- mice display lymphopenia, anaemia and extramedullary myelopoiesis, suffer from systemic inflammation and die prematurely. In addition, our preliminary results demonstrate that Hem1-/- mice have developed an aberrant bone-phenotype. Whereas the formation both in vitro and in vivo of Hem1-deficient osteoclasts seems to be promoted, their ability to degrade bone matrix is impaired. Based on these findings, combined with the observation that there is an increase in expression of Hem1 in chronic destructive arthritis, we want to study how Hem1 mediates osteoclast differentiation and bone destruktion and whether it plays a role in rheumatoid arthritis (RA) pathogenesis. In particular, we want to follow the hypothesis that the increased expression of Hem1 in arthritic joints is associated with bone destruction during chronic inflammatory arthritis. Moreover, we want to determine to which extent the loss of Hem1 specifically in osteoclasts or in macrophages affects arthritis development in mice. For this pur-pose, we will induce arthritis in total, macrophage-specific and osteoclast-specific Hem1-/- mice by crossing them into hTNFtg mice, that develop a TNFalpha-dependent arthritis, or by K/BxN serum transfer and analyse the development and severity of disease (e.g. inflammation, synovial hyper-plasia, bone erosion) by morphometric, histological and immunohistochemical methods. Further-more, the putative inhibitory effect of Hem1 on osteoclast differentiation and/or osteoclast cell-fusion will be examined. This project will provide new insights into the mechanisms of inflammatory bone destruction and facilitate the development of novel treatment strategies for chronic inflammatory disorders, particularly RA.

迁移、粘附以及胞内分泌和胞外分泌都严重依赖于肌动蛋白细胞骨架的动态重组，可能涉及肌动蛋白成核物如arp2 /3复合物及其激活物如wave复合物。为了研究WAVE-complex在造血系统中的作用，我们产生了编码WAVE-complex唯一造血特异性亚基Hem1的基因缺失的小鼠。到3个月大时，Hem1-/-小鼠表现出淋巴细胞减少、贫血和髓外骨髓增生，出现全身性炎症并过早死亡。此外，我们的初步结果表明，Hem1-/-小鼠已经发展出异常的骨表型。尽管体外和体内缺乏hem1的破骨细胞的形成似乎得到了促进，但它们降解骨基质的能力却受到了损害。基于这些发现，结合观察到Hem1在慢性破坏性关节炎中表达增加，我们想研究Hem1如何介导破骨细胞分化和骨破坏，以及是否在类风湿关节炎（RA）发病过程中发挥作用。特别是，我们想要遵循这样的假设，即在慢性炎症性关节炎期间，关节炎关节中Hem1的表达增加与骨破坏有关。此外，我们想确定在破骨细胞或巨噬细胞中Hem1的特异性缺失在多大程度上影响小鼠关节炎的发展。为此，我们将通过将Hem1-/-小鼠与hTNFtg小鼠杂交，或通过K/BxN血清转移，在巨噬细胞特异性和破骨细胞特异性小鼠中诱导关节炎，hTNFtg小鼠发展为tnfalpha依赖性关节炎，并通过形态测量学，组织学和免疫组织化学方法分析疾病的发展和严重程度（例如炎症，滑膜增生，骨侵蚀）。此外，Hem1对破骨细胞分化和/或破骨细胞融合的抑制作用将被检验。该项目将为炎性骨破坏机制提供新的见解，并促进慢性炎性疾病，特别是RA的新治疗策略的发展。