Connective tissue growth factor (CTGF, CCN2) gene regulation derma patients which results in increased Sp1-dependent transcription (Fonseca et al. 2007). However, increased expression of CCN2 in cell-culture activated hepatic stellate cells is dependent on TGFβ (Leask et al. 2008). Intrigu- ingly, elective disruption of TβRII in mouse skin fibro- blasts increases constitutive expression CTGF/CCN2 (Denton et al. 2009). It remains to be established whether the rise in CCN2 expression in patients correlates with the increased expression of ET-1 or TGFβ. Overall, these data reveal that the regulation of CCN2 expression in fibrotic conditions is complex and is perhaps disease/organ specific. Inhibitors of CCN2 expression It has long been suggested that agents that inhibit CCN2 expression may be used as anti-fibrotic therapies (Blom et al. 2002). As discussed above, inhibitors of TGFβ or endothelin receptors may be used to reduce CCN2 expression in activated hepatic stellate cells or scleroderma fibroblasts, respectively (Leask et al. 2008; Shi-wen et al. 2007a). Moreover, prostaglandins [PGE(2)] and prostacy- clins (such as the synthetic prostacyclin Iloprost) can antagonize CCN2 expression, including in scleroderma fibroblasts (Ricupero et al. 1999; Stratton et al. 2001, 2002). It has been shown that 9-cis-retinoic acid reduced CCN2 expression in scleroderma fibroblasts, possibly through its ability to produce PGE(2) production (Xiao et al. 2008). Iloprost works, at least in part, by antagonizing MEK/ERK signaling (Stratton et al. 2002) and, indeed, the MEK inhibitor U0126 reduces CCN2 expression in response to TGFβ and ET-1 in fibroblasts as well as constitutive over-expression of CCN2 in the pancreatic cancer cell line PANC-1 (Pickles and Leask 2007). TNFα suppresses TGFβ-induced gene expression in fibroblasts but has no appreciable effect on the constitutive CCN2 expression in scleroderma fibroblasts (Abraham et al. 2000). Caffeine also reduces TGFβ-induced CCN2 expres- sion in hepatocytes by blocking Smad activation (Gressner et al. 2008; Leask 2008). Finally, it has been shown recently that the addition of the lipid second messenger C2- ceramide can also reduce TGFβ-induced CCN2 expression in human foreskin fibroblasts (Kennedy et al. 2008). CCN2 as a surrogate marker of fibroproliferative disease As discussed above, CCN2 is over-expressed in fibrotic disorders. Early studies examining the kinetics of CCN2 induction showed that, in the anti-Thy-1.1 antibody model of rat kidney fibrosis, CCN2 induction paralleled the progression of fibrogenesis and repair (Ito et al. 2001; 91 Table 1). Subsequent studies have established that CCN2 levels in biological fluids correlate with the levels of fibrosis in patient samples (Table 1). For example, urinary CCN2 levels appear at both stage nephropathy and appear to predict those patients who are destined for progressive glomerulosclerosis and end-stage renal disease (Riser et al. 2003). In addition, glomerular basement membrane thickness correlates with tubular and total CCN2 levels (Thomson et al. 2008) In particular, studies using an enzyme-linked immuno- sorbent assay (ELISA) to examining the appearance of amino-terminal fragments of CCN2 appear especially promising as potential diagnostic tools to show the severity of fibrosis. An ELISA detecting amino-terminal CCN2 appears to be superior to ELISAs detecting full-length of carboxy-terminal CCN2 as the latter moieties of CCN2 bind the cell surface and are internalized through the heparin- and integrin-binding carboxy-terminal domain of CCN2. The advantage of these ELISAs is that CCN2 can be readily detected in body fluids (e.g., urine, blood, blister fluid). Amino-terminal CCN2 ELISAs may be especially useful in diagnosing fibrosis associated with diabetes or, alternatively, in clinical trials testing the efficacy of anti- fibrotic compounds. For example, in type 1 diabetic patients with incipient and overt diabetic nephropathy, the magnitude of urinary amino-terminal excretion relates to the severity of diabetic nephropathy (Gilbert et al. 2003). Similarly, NH2-terminal CCN2 is also increased in the vitreous of patients with active progressive diabetic proliferative vitreoretinopathy, suggesting that it represents a surrogate marker of fibrosis in the disorder (Hinton et al. 2002). Indeed, plasma CCN2 levels contribute significantly to prediction of end-stage renal disease and mortality in patients with type 1 diabetic nephropathy (Nguyen et al. 2008). Such a diagnostic tool may not merely be limited to diabetes. N-terminal CCN2 levels in plasma and dermal interstitial fluid correlated with severity of skin disease of Table 1 CCN2 levels as a surrogate marker of fibrosis: Diseases in which CCN2 levels, detected by ELISA, correlate with severity of fibrosis Hepatic fibrosis in biliary atresia Pulmonary fibrosis in scleroderma diabetic nephropathy proliferative vitreoretinopathy skin fibrosis in scleroderma Kidney allograft fibrosis liver fibrosis chronic viral hepatitis Fibrotic carcinoid tumors diabetic retinopathy End-stage renal disease myocardial fibrosis (Tamatani et al. 1998) (Sato et al. 2000) (Gilbert et al. 2003) (Hinton et al. 2002). (Dziadzio et al. 2005) (Cheng et al 2006) (Gressner et al. 2006) (Gressner et al. 2006) (Kidd et al 2007) (Kuiper et al 2008) (Nguyen et al. 2006) (Koitabashi et al. 2008)