Elevated CCN2 expression in scleroderma: a putative role for the TGFβ accessory receptors TGFβRIII and endoglin |
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Authors: | Alan M Holmes Markella Ponticos Xu Shi-wen Christopher P Denton David J Abraham |
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Institution: | (1) Centre for Rheumatology and Connective Tissue Diseases, UCL Medical School, Royal Free Campus, London, UK, NW3 2PF |
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Abstract: | The ability of TGFβ1 to act as a potent pro-fibrotic 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 TGFβ accessory receptor,
endoglin on Systemic Sclerosis (SSc) dermal fibroblasts. Here we sought to assess the cell surface expression of the TGFβ
receptor complex on SSc dermal fibroblasts (SDF), and investigate their role in maintaining the elevated expression of CCN2.
SDF exhibited elevated expression of the TGFβ accessory receptors betaglycan/TGFβRIII and endoglin, but not type I or type
II receptors. To determine the effect of altered receptor repertoire on TGFβ responses, we investigated the effect of exogenous
TGFβ on expression of two pro-fibrotic genes. SDF exhibited higher basal expression of COL1A2 and CCN2 compared to healthy
controls. TGFβ 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 TGFβ. Surprisingly basal expression was not affected by a pan-neutralizing TGFβ 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 TGFβ. TGFβRIII alone or in combination with endoglin was sufficient to enhance
basal CCN2 promoter activity. Thus TGFβ accessory receptors may play a significant role in the altered expression of fibrogenic
genes in SDF. |
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Keywords: | CCN2 TGFβRIII Endoglin TGFβ |
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