Antagonistic effect of the matricellular signaling protein CCN3 on TGF-beta- and Wnt-mediated fibrillinogenesis in systemic sclerosis and Marfan syndrome.

Abnormal fibrillinogenesis is associated with connective tissue disorders (CTDs), including Marfan syndrome (MFS), systemic sclerosis (SSc) and Tight-skin (Tsk) mice. We have previously shown that TGF-beta and Wnt stimulate fibrillin-1 assembly and that fibrillin-1 and the developmental regulator CCN3 are both highly increased in Tsk skin. We investigated the role of CCN3 in abnormal fibrillinogenesis in Tsk mice, MFS, and SSc. Smad3 deletion in Tsk mice decreased CCN3 overexpression, suggesting that TGF-beta mediates at least part of the effect of Tsk fibrillin on CCN3 which is consistent with a synergistic effect of TGF-beta and Wnt in vitro on CCN3 expression. Disruption of fibrillin-1 assembly by MFS fibrillin decreased CCN3 expression and skin from patients with early diffuse SSc showed a strong correlation between increased CCN3 and fibrillin-1 expression, suggesting that CCN3 regulation by fibrillin-1 extends to these CTDs. Diffuse SSc skin and sera also showed evidence of increased Wnt activity, implicating a Wnt stimulus behind this correlation. CCN3 overexpression markedly repressed fibrillin-1 assembly and also blocked other TGFbeta- and Wnt-regulated profibrotic gene expression. Together, these data indicate that CCN3 counter-regulates positive signals from TGF-beta and Wnt for fibrillin fibrillogenesis and profibrotic gene expression.