Endoplasmic Reticulum Stress Inhibited The Growth Of Fibroblast Like Synovicytes From Patients With Rheumatoid Arthritis

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease characterized by hyperplasia and invasive growth of synovial lining cells, and further destruction of joint tissues, cartilage subchondral bone. Although various cell types are involved in RA pathogenesis, synovial cells, especially fibroblast-like synoviocytes (FLS), play a role in inflammation and joint destruction. Unfolded proteins and other conditions affecting endoplasmic reticulum (ER) homeostasis cause ER stress. The articular inflammatory milieu of RA can elicit endoplasmic reticulum stress, therefore high ER stress status is a characteristic of FLS. To elucidate FLS response to ER stress, FLS from synovial tissue of RA patient were isolated, cultured and characterized. We isolated homogeneous fibroblast-like synoviocytes because most of them expressed highly CD90/Thy-1 and CD106/VCAM-1, two cell surface markers of FLS identified by immunofluorescence by FCS. Furthermore, FLS proliferation stimulated by two drugs inducing ER stress was determined by MTS assay. We found that both drugs inducing ER stress can inhibit significantly FLS growth. ER stress induced G2/M arrest in FLS mediated by significantly decreased expression of Cyclin B1 and slightly elevated level of CDK inhibitory protein p27. These results suggested that the abnormal expression of cell cycle regulatory proteins in FLS is mainly responsible for G2/M arrest.We successfully isolated and cultured FLS, which is a basis for further study of signaling pathway in FLS and its involvement in the pathogenesis of RA. In addition, we found that ER stress can inhibit proliferation, and induce cell cycle arrest in G2/M phase in FLS. This discovery provides a theoretical basis for drug design targeting ER stress pathway for effective RA treatment.