Elevated CCN2 expression in scleroderma: a putative role for the TGFβ accessory receptors TGFβRIII and endoglin

The ability of TGF beta 1 to act as a potent profibrotic mediator is well established, potently inducing the expression of fibrogenic genes including type I collagen (COL1A2) and CCN2. Previously we have shown elevated expression of the TGF beta accessory receptor, endoglin on Systemic Sclerosis (SSc) dermal fibroblasts. Here we sought to assess the cell surface expression of the TGF beta receptor complex on SSc dermal fibroblasts (SDF), and investigate their role in maintaining the elevated expression of CCN2. SDF exhibited elevated expression of the TGF beta accessory receptors betaglycan/TGF beta RIII and endoglin, but not type I or type II receptors. To determine the effect of altered receptor repertoire on TGF beta responses, we investigated the effect of exogenous TGF beta on expression of two pro-fibrotic genes. SDF exhibited higher basal expression of COL1A2 and CCN2 compared to healthy controls. TGF beta induced a marked increase in the expression of these genes in normal dermal fibroblasts, whereas SDF exhibited only a modest increase. We next sought to determine if higher basal expression in SDF was a result of autocrine expression of TGF beta. Surprisingly basal expression was not affected by a pan-neutralizing TGF beta antibody. To explore if altered accessory receptor expression alone could account for these changes, we determined their effects on CCN2 promoter activity. Endoglin inhibited CCN2 promoter activity in response to TGF beta. TGF beta RIII alone or in combination with endoglin was sufficient to enhance basal CCN2 promoter activity. Thus TGF beta accessory receptors may play a significant role in the altered expression of fibrogenic genes in SDF.