Abstract
Targeting fibroblast-like synoviocyte (FLS) migration and invasion-mediated bone erosion is a promising clinical strategy for the treatment of rheumatoid arthritis (RA). Drug sensitivity testing is fundamental to this scheme. We designed a microfluidic chip-based, cell co-cultured platform to mimic RA FLS-mediated bone erosion and perform drug-sensitive assay. Human synovium SW982 cells were cultured in the central channel and migrated to flow through matrigel-coated side channels towards cell culture chamber where RANKL-stimulated osteoclastic RAW264.7 and osteogenic medium (OS)-stimulated bone marrow mesenchymal stem cells (BMSC) were cultured in the microfluidic chip device, mimicking FLS migration and invasion-mediated bone erosion in RA. These SW982 cells showed different migration potentials to osteoclasts and BMSC. The migration of SW982 cells with high expression of cadherin-11 was more potent when SW982 cells were connected with the co-culture of RAW264.7 and BMSC. Simultaneously, in the co-cultured chamber, tartrate-resistant acid phosphatase (TRAP) activity of RANKL-stimulated RAW264.7 cells was enhanced, but alkaline phosphatase (ALP) activity was decreased in comparison with mono-cultured chamber. Furthermore, it was confirmed that celastrol, a positive drug for the treatment of RA, inhibited SW982 cell migration as well as TRAP activity in the cell-cultured microfluidic chips. Thus, the migration and invasion to bone-related cells was reconstituted on the microfluidic model. It may provide an effective anti-RA drug screen model for targeting FLS migration-mediated bone erosion.
Highlights
Rheumatoid arthritis (RA) is a chronic systemic auto-immune disease, characterized by joint synovitis
The microfluidic model was composed of two layers: one layer of glass substrate and another layer of PDMS membrane, which is widely used in microfluidic platforms for biological research because of its good biocompatibility and gas permeability
Compared with RANKL or osteogenic medium (OS) stimulation group, the migrated number of fibroblast-like synoviocytes (FLS) and the migrated extend increased when FLS were co-cultured with bone marrow mesenchymal stem cells (BMSC), osteoclastic RAW264.7 cells or BMSC plus RAW264.7 cells
Summary
Rheumatoid arthritis (RA) is a chronic systemic auto-immune disease, characterized by joint synovitis. Bone erosion is a secondary factor in RA, bone erosions by FLS-mediated synovitis has become a central element in the diagnosis, treatment and monitoring of RA [6]. Understanding the mechanisms that define the formation of bone erosions requires insight into the interaction of FLS with osteoclasts and osteoblasts [7]. Most assays target only FLS or bone cells, which is extremely disparate from RA conditions in vivo. Even though some assays can select efficacious drugs, most fail to target both FLS-mediated synovitis and bone erosion.
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