Role of DDR2 in synovial cell invasion: implications for rheumatoid arthritis
File(s)
Author(s)
Majkowska, Iwona
Type
Thesis
Abstract
A hallmark of rheumatoid arthritis (RA) is cartilage erosion by pannus — an inflamed, hyperplastic and highly invasive synovial tissue. Cartilage degradation is primarily mediated by invading synovial fibroblasts. At the cartilage invasion front of the pannus, these cells destroy the tissue, leading to the permanent loss of joint structure and function. It has been shown that membrane type 1 metalloproteinase (MT1-MMP) plays a key role in promoting RA synovial fibroblast invasion into the cartilage. However little is known about regulatory mechanisms of MT1-MMP in RA synovial fibroblasts.
MT1-MMP is highly upregulated in RA synovium, but mechanisms regulating its expression are not well understood. Interestingly, several reports show high MT1-MMP levels in fibroblasts at the pannus-cartilage junction. In addition, MT1- MMP expression and activity in cultured cells can be induced by collagen. We hypothesised that cartilage, more specifically cartilage collagen, induces MT1-MMP activity in the pannus. In this study, I have confirmed that both collagen and cartilage induce MT1-MMP activity and expression in RA synovial fibroblasts. To understand mechanisms of collagen signalling I have also investigated the role of collagen receptors, namely integrins and discoidin domain receptor 2 (DDR2), in MT1-MMP activation. Knockdown of DDR2, but not collagen-binding integrins, resulted in decreased MT1-MMP activity and expression upon collagen stimulation. DDR2 knockdown also inhibited MT1-MMP-dependent collagen degradation and invasion by RA synovial fibroblasts.
Analysis of DDR2 binding to intact or telopeptide-devoid collagens indicates that collagen structure might influence cell signalling. Furthermore, activation of MT1-MMP by cartilage, which is also mediated by DDR2, is enhanced by removal of proteoglycans. In summary, I have demonstrated that cartilage signalling through collagen receptor DDR2 induces MT1-MMP activity in RA synovial fibroblasts.
MT1-MMP is highly upregulated in RA synovium, but mechanisms regulating its expression are not well understood. Interestingly, several reports show high MT1-MMP levels in fibroblasts at the pannus-cartilage junction. In addition, MT1- MMP expression and activity in cultured cells can be induced by collagen. We hypothesised that cartilage, more specifically cartilage collagen, induces MT1-MMP activity in the pannus. In this study, I have confirmed that both collagen and cartilage induce MT1-MMP activity and expression in RA synovial fibroblasts. To understand mechanisms of collagen signalling I have also investigated the role of collagen receptors, namely integrins and discoidin domain receptor 2 (DDR2), in MT1-MMP activation. Knockdown of DDR2, but not collagen-binding integrins, resulted in decreased MT1-MMP activity and expression upon collagen stimulation. DDR2 knockdown also inhibited MT1-MMP-dependent collagen degradation and invasion by RA synovial fibroblasts.
Analysis of DDR2 binding to intact or telopeptide-devoid collagens indicates that collagen structure might influence cell signalling. Furthermore, activation of MT1-MMP by cartilage, which is also mediated by DDR2, is enhanced by removal of proteoglycans. In summary, I have demonstrated that cartilage signalling through collagen receptor DDR2 induces MT1-MMP activity in RA synovial fibroblasts.
Version
Open Access
Date Issued
2014-06
Date Awarded
2014-10
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Itoh, Yoshifumi
Publisher Department
Department of Medicine
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)