SPHK1调控RA滑膜细胞侵袭和关节破坏的作用及机制

The pathogenesis of rheumatoid arthritis is not clearly understood, fibroblast-like synoviotyces, exhibiting the characteritics of maligant cells, play a pivotal role in the destructive process of joints. Our data show that SPHK1 is expressed by RA-FLS and that knockdown of SPHK1 inhibits the human RA-FLS invasion by down-regulating the PI3K/AKT activation and MMPs production in vitro. However, the role of SPHK1 in joint destruction of in RA has never been explored. And this prompt us to hypothesize that SPHK1 may control the aggressive behaviour of RA-FLS and lead to bone destruction. In the present study, we will validate SPHK1 can modulate fibroblast-like synoviotyces invasion through PI3K/AKT/NF-κB signaling pathway and the expression of MMPs synthesis by construction of Lentivirus vector with TNF-αand IL-1βstimulating RA-FLS in vitro. Furthermore, we will discuss the relationship between the signal pathway of SPHK1/PI3K/AKT/NF-κB/MMPs and the fibroblast-like synoviotyces invasion and cartilage destruction by collagen antibody-induced arthritis and severe combined immunodeficient (SCID)-human anthritis cartilage mouse animal model in vivo.This study will send the vitality from sphingosine kinase 1 this new viewpoint foundation for clarifing the role and mechanism of synovial invasion and joint destruction, revealing the mystery of the rheumatoid arthritis pathogenesis, providing a new new drug targets or clues for the prevention and treatment of rheumatoid arthritis.

类风湿关节炎（RA）病因及发病机制不明确，成纤维样滑膜细胞（FLS）具有“类肿瘤细胞样”的侵袭性，是RA关节破坏的根源。我们前期研究发现，RA-FLS表达鞘氨醇激酶1（SPHK1），小RNA干扰SPHK1，抑制PI3K/AKT/MMPs通路活性和RA-FLS侵袭能力，但SPHK1是否参与RA关节破坏尚不清楚。为此，我们提出假说，SPHK1参与RA-FLS侵袭并导致关节破坏。为验证这一假说，本研究拟通过构建慢病毒SPHK1过表达载体，TNF-α和IL-1β等刺激RA-FLS，从细胞水平验证SPHK1调控RA-FLS侵袭；并在动物水平进一步探讨SPHK1/PI3K/AKT/NF-κB/MMPs通路与胶原诱导关节炎（CIA）大鼠和SCID小鼠嵌合体模型滑膜侵袭和软骨破坏的关系，旨在阐明SPHK1调控RA滑膜细胞侵袭和关节破坏的分子机制，破解RA发病的奥秘，为RA的防治提供新的药物靶点或线索。