The Axis of Thrombospondin-1, Transforming Growth Factor Beta and Connective Tissue Growth Factor: An Emerging Therapeutic Target in Rheumatoid Arthritis

Biologic therapy for rheumatoid arthritis (RA) targets specific molecules that mediate and sustain the clinical manifestations of this complex illness. Compared with the general population, patients with RA die prematurely, in part due to associated cardiovascular disease. Even though the mechanisms by which premature atherosclerosis develops in RA is unknown, chronic inflammation may play a major role. This review connects current knowledge of the pathophysiology of RA with data available in the literature related to thrombospondin-1 (TSP1), transforming growth factor beta (TGFβ) and connective tissue growth factor (CTGF) and their relationship with cardiovascular disease in RA. The TSP1/TGFβ/CTGF axis may contribute in the pro-inflammatory and pro-atherogenic state in patients affected with RA. In fact, increased TSP1 plasma levels are found in patients of RA. TGFβ is activated by TSP1 through a non-enzymatic mechanism and is constitutively overexpressed by synovial fibroblasts from RA patients. Activation of TGFβ pathway in synovial fibroblasts and other cells including neutrophils leads to downstream upregulation of CTGF. Overexpression of CTGF is associated with angiogenesis, fibrosis, atherosclerotic blood vessels and erosive arthritis lesions. Recent RA therapies emphasize the need for aggressive control of the activity of the disease to prevent premature atherosclerosis in RA patients. The complexity and heterogeneity of RA as judged by response to a wide spectrum of treatments mandates the elucidation of unknown pro-inflammatory pathways playing a major role in this disease. The TSP1/TGFβ/CTFG axis represents one of these pro-inflammatory pathways that may result in the development of promising therapeutic strategies to prevent chronic inflammation and thus premature atherosclerosis in RA.