Function and Regulation of the Transmembrane Glycoprotein Podoplanin in Inflammatory Bone Destruction in Rheumatoid Arthritis

类风湿性关节炎（RA）是一种慢性全身性炎症性疾病，其特征是关节结构的进行性丧失。膜结合糖蛋白podoplanin （PDPN）在ra -滑膜成纤维细胞（RA-FLS）亚型中被炎症细胞因子TNFalpha、IL-1 β和tgf - β上调，在ra -滑膜中RA-FLS与血小板微粒之间的通讯中起重要作用，促进炎症过程。唯一已知的PDPN受体是clc -2，一种c型凝集素受体，在血小板、炎性树突状细胞和巨噬细胞中高度表达，并负责ra - fls -血小板相互作用。基于我对关节炎小鼠骨细胞中PDPN表达和破骨细胞中clc -2表达的初步结果，我想解决PDPN如何参与成骨细胞/骨细胞-破骨细胞的通讯，从而如何影响RA的发病机制的问题。特别是，我想关注的假设是，在关节炎关节中，PDPN和clc -2在骨细胞或成骨细胞与破骨细胞之间的直接细胞-细胞相互作用与破骨细胞骨吸收增强导致骨质流失加剧有关。为了研究PDPN在破坏性关节炎发展过程中的功能重要性，我们将在PDPN缺陷小鼠中建立K/BxN血清转移诱导关节炎模型。此外，PDPN调控的体外研究以及破骨细胞与成骨细胞和骨细胞共培养的功能研究将为RA期间骨破坏的机制提供新的见解，并有助于开发新的治疗方法。

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease characterised by progressive loss of the joint structure. The membrane-bound glycoprotein podoplanin (PDPN) is upregulated in subtypes of RA-synovial fibroblasts (RA-FLS) by the inflammatory cytokines TNFalpha, IL-1 beta and TGF-beta and plays an important role in the communication between RA-FLS and platelet microparticles in the RA-synovium, promoting inflammatory processes. The only known receptor for PDPN is CLEC-2, a c-type lectin receptor, which is highly expressed by platelets, inflammatory dendritic cells and macrophages and is responsible for RA-FLS-platelet interaction. Based on my preliminary results about the expression of PDPN in osteocytes and CLEC-2 expression in osteoclasts of arthritic mice, I would like to address the question of how PDPN is involved in osteoblast/osteocyte-osteoclast communication and thus how it affects the pathogenesis of RA. In particular, I want to focus on the hypothesis that a direct cell-cell interaction between osteocytes or osteoblasts and osteoclasts by PDPN and CLEC-2 in arthritic joints is associated with enhanced bone resorption by osteoclasts leading to enhanced bone loss. To investigate the functional importance of PDPN during the development of a destructive arthritis, the K/BxN serum transfer-induced arthritis model will be performed in PDPN deficient mice. Additionally, in vitro investigations on the regulation of PDPN as well as functional studies using co-cultures of primary osteoclasts with osteoblasts and osteocytes will provide new insights into the mechanisms of bone destruction during RA and will help to develop new therapeutic approaches.