Grem1 is a key regulator of synovial hyperplasia in rheumatoid arthrit…
Eun-Jin Han, Sussanna Choi, Daehee Hwang, sungyong you and Wan-uk Kim
Fibroblast like synoviocyte plays critical roles is the major cell in the inflammatory processes of Rheumatoid arthritis. We attempted to identify a key regulator that can drive aggressive phenotypes of RA FLS. For this, we performed an integrative transcriptome data analysis using three datasets from independent RA studies, a panel of normal tissues, and NCI60 cancer cell line panel. Through the analysis, we identified Gremlin (GREM1), which is robustly up-regulated in RA and predominantly expressed in FLS. GREM1 is identified as bone morphogenetic proteins antagonist and is known to bind BMPs. To investigate potential roles of GREM1 in RA, we first examined the level of GREM1 expression in synovial tissues, synovial fluid (SF) and FLS from RA. Immunohistochemistry and ELISA revealed up-regulation of GREM1 protein in RA compared to OA. Proinflammatory cytokines also induced the expression of GREM1 in RA FLS and their expressions were significantly correlated with GREM1 expression in RA SF. We next investigated cellular functions of GREM1 using RA FLS. GREM1 deficieny by siRNA elicited significant suppression of FLS proliferation, migration and invasion. In contrast, stimulation with rhGREM1 to RA FLS increased cell survival and invasion. Furthermore, we found that GREM1 activates AKT1 and MAPK signaling cascade, as well as antagonizes BMP2. This study demonstrated that GREM1 is a key regulator responsible for synovial hyperplasia and FLS migration.