Differential expression of the small inducible cytokines GRO alpha and GRO beta by synovial fibroblasts in chronic arthritis: possible role in growth regulation

Abstract

Synovial pannus represents a hypertrophic and locally invasive connective tissue response to chronic inflammation that accounts in large part for the periarticular destruction of rheumatoid arthritis. Synovial fibroblasts cultured from rheumatoid synovia have been found to display an increased rate of proliferation and the constitutive expression of collagenases, growth factors, and inflammatory cytokines. The existence in rheumatoid synovium of both a pro-inflammatory state and growth dysregulation led us to investigate the expression by synovial fibroblasts of the closely homologous cytokines GRO alpha (gro/MGSA), GRO beta (MIP-2 alpha), and GRO gamma (MIP-2 beta). These cytokines are released by a variety of cell types and display overlapping growth regulatory and pro-inflammatory activities. In contrast to expectations, the majority of synovial fibroblast cell lines derived from osteoarthritic or non-inflammatory synovia showed a relative increase in the constitutive expression of GRO alpha and GRO beta when compared to synovial fibroblasts obtained from rheumatoid synovia. Considered together with evidence that GRO alpha is a growth regulator that modulates the expression of metalloproteinase activity, these findings provide evidence for a differential pathway of cytokine activation that may downregulate the proliferative and erosive response to chronic arthritis.