Rheumatoid synovial fibroblasts differentiate into distinct subsets in the presence of cytokines and cartilage

Background: We investigated two distinct synovial fibroblast (SF) populations 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.

Methods: SFs were cultured in vitro and phenotypic changes following stimulation with IL-1β, TNFα and TGFβ1 were examined. To examine the phenotype of SF in vivo a SCID human-mouse model of cartilage destruction was utilised.

Results: SF in the lining layer in rheumatoid arthritis expressed high levels of PDPN compared to the normal synovium whereas CD248 expression was restricted to sub-lining layer cells. TNF or IL1 stimulation in vitro resulted in an increased expression of PDPN. In contrast, stimulation with TGF induced CD248 expression. In the SCID human-mouse model, rheumatoid SF recapitulated the expression of PDPN and CD248. Fibroblasts adjacent to cartilage expressed PDPN, attached to, invaded and degraded cartilage. PDPN+ CD248- SFs preceded the appearance of PDPN^- CD248⁺ cells in contralateral implants.

Conclusions: We have identified two distinct SF populations identified by expression of either PDPN or CD248 and 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 attractive therapeutic target in RA.