Abstract
BackgroundWe investigated two distinct synovial fibroblast populations that were located preferentially in the lining or sub-lining layers and defined by their expression of either podoplanin (PDPN) or CD248, and explored their ability to undergo self-assembly and transmigration in vivo.MethodsSynovial fibroblasts (SF) were cultured in vitro and phenotypic changes following stimulation with interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-β1 were examined. To examine the phenotype of SF in vivo, a severe combined immunodeficiency (SCID) human-mouse model of cartilage destruction was utilised.ResultsSF in the lining layer in rheumatoid arthritis (RA) expressed high levels of PDPN compared to the normal synovium, whereas CD248 expression was restricted to sub-lining layer cells. TNF-α or IL1 stimulation in vitro resulted in an increased expression of PDPN. In contrast, stimulation with TGF-β1 induced CD248 expression. In the SCID human-mouse model, rheumatoid SF recapitulated the expression of PDPN and CD248. Fibroblasts adjacent to cartilage expressed PDPN, and attached to, invaded, and degraded cartilage. PDPN+ CD248– SF preceded the appearance of PDPN– CD248+ cells in contralateral implants.ConclusionsWe have identified two distinct SF populations identified by expression of either PDPN or CD248 which are located within different anatomical compartments of the inflamed synovial membrane. These markers discriminate between SF subsets with distinct biological properties. As PDPN-expressing cells are associated with early fibroblast migration and cartilage erosion in vivo, we propose that PDPN-expressing cells may be an attractive therapeutic target in RA.
Highlights
We investigated two distinct synovial fibroblast populations that were located preferentially in the lining or sub-lining layers and defined by their expression of either podoplanin (PDPN) or CD248, and explored their ability to undergo self-assembly and transmigration in vivo
PDPN was mainly expressed by Synovial fibroblasts (SF) in the lining layer whereas CD248 was predominantly expressed by fibroblasts in the sub-lining layer (Fig. 1a)
High-magnification confocal images of rheumatoid synovium in the lining versus sub-lining layer confirmed that CD248 expression was found in association with other known sub-lining layer markers such as CD90, while PDPN expression was found in association with the lining layer markers vascular cell adhesion molecule (VCAM)-1 and protein disulfide isomerase (PDI) (Fig. 1c)
Summary
We investigated two distinct synovial fibroblast populations that were located preferentially in the lining or sub-lining layers and defined by their expression of either podoplanin (PDPN) or CD248, and explored their ability to undergo self-assembly and transmigration in vivo. Rheumatoid arthritis (RA) is characterised by the formation of a hyperplastic and invasive synovium, comprised of an expanded synovial fibroblast population with infiltration of inflammatory cells [1]. Synovial fibroblasts (SF) are key mediators of joint destruction and disease persistence [2, 3]. Despite their fundamental importance, Fibroblasts within the synovium are a heterogeneous cell population with distinct anatomical and functional phenotypes [1]. SF undergo epigenetic changes, assume a stable, activated phenotype, and are capable of invading and destroying articular cartilage [1, 5]. Rheumatoid but not normal SF are capable of vascular transmigration from their site of primary origin to distant cartilage sites where they attach and invade cartilage [6, 7].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
