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

Abstract

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 (TGFbeta and connective tissue growth factor (CTGF) and their relationship with cardiovascular disease in RA. The TSP1/TGFbeta/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. TGFbeta is activated by TSP1 through a non-enzymatic mechanism and is constitutively overexpressed by synovial fibroblasts from RA patients. Activation of TGFbeta 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/TGFbeta/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.

Angiogenesis and vasculogenesis in rheumatoid arthritis

“…Furthermore, there is an interaction between FGF-2, tissue-infiltrating leukocytes and proinflammatory chemokines during inflammatory neovascularization [42]. There is also cross-talk between TGF-b and CTGF in arthritis and angiogenesis [41].…”

“…Thrombospondin-1 (TSP1) is an angiostatic extracellular matrix component naturally produced within the RA synovium [10,41,50]. A TSP-1-TGF-b-CTGF axis has been identified.…”

“…This axis may play a role in atherogenesis, RA, as well as RA-associated cardiovascular disease. TSP-1 activates TGF-b that leads to a further up-regulation of CTGF [41]. TSP-1, TGF-b and CTGF have all been implicated in inflammatory synovitis and angiogenesis [10,41,51,52].…”

Disturbed Flow Promotes Arterial Stiffening Through Thrombospondin-1

“…Importantly this pathway can be modified by pharmacologically inhibiting TSP-1 binding to LAF via peptide inhibitors (e.g. LSKL) 16, 17 . TSP-1 has also been implicated in dysregulation of blood flow, impaired vessel dilation and increased vascular tone 18, 19 .…”

Connective Tissue Disorders and Cardiovascular Complications: The Indomitable Role of Transforming Growth Factor-Beta Signaling

“…Scleroderma (a disease of excessive fibrosis of vessels, organs and particularly the skin) severity has been correlated with levels of TGF-β, a potent regulator of ECM deposition [118]. Rheumatoid arthritis patients have elevated plasma thrombospondin-1 and TGF-β; the former activates TGF-β and the latter induces the expression of connective tissue growth factor (CTGF), which has been associated with atherosclerosis, a process occurring prematurely in RA [119, 120]. Recent evidence has identified a role for TGF-β in suppressing immune function directly and stimulating T cell conversion to a suppression phenotype [121].…”