Circulating Plasma Levels of Connective Tissue Growth Factor (CTGF) Are Elevated In Patients Afflicted with Rheumatoid Arthritis

Abstract 4320

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 are at an increased risk to develop cardiovascular diseases and the precise mechanism(s) of action remain obscure. This laboratory has proposed the existence of a pro-inflammatory axis in RA comprised by thrombospondin-1 (TSP1), transforming growth factor-beta (TGF-b) and CTGF. The present study evaluated plasma levels of TSP1, TGFb and CTGF in patients with RA by ELISA as well as specific cytokines and chemokines. CTGF plasma levels in RA patients (9.2 pg/ml mean, range 3.44–17.08) were found significantly increased (P<0.047) when compared to control subjects (mean 4.43 pg/ml, range 1.62–7.35). This is the first report in the medical literature documenting an augmented human plasma circulating levels of CTGF in RA. TSP1 circulating levels were found elevated in RA patients when compared to control subjects (mean 315 ng/ml vs. 25.4 ng/ml respectively, P<0.039). TGFb showed a trend for higher levels in patients with RA (10.1 ng/ml vs. 4.5 ng/m, P<0.095). The source CTGF in plasma could not be determined precisely but there is evidence of platelet activation in RA (Platelets 19:146, 2008), and TSP1 is the major content of the platelet a-granule (25%). CTGF can attract monocytes and both have been found co-localized in atherosclerotic plaques (Circulation 95, 831, 1997). IL-6 (P< 0.05), IL-12p70 (P<0.04), IP-10 (P<0.03) and MIP1b (P<0.016) were increased in the RA patients when compared to controls. Recent findings have placed platelet microparticles (Science 327; 580, 2010) as playing a major role (arsonists) in RA via monocytes and neutrophils. In summary, our results provide evidence that a pro-inflammatory axis is active in RA potentially contributing to cytokine changes as well as the cardiovascular disease associated with RA since TSP1 can induced IL-6 generation from monocytes and can activate inert TGFb on cell surfaces (fibroblasts and synoviocytes) with the subsequent up-regulation of CTGF. Disruption of the axis in experimental models of RA may prove to be an emerging therapeutic target in RA. Elucidation of the source of CTGF should provide as well key information for cell-targeting to prevent CTGF secretion into the blood milieu.