A possible contribution of endothelial CCN 1 downregulation due to Fli1 deficiency to the development of digital ulcers in systemic sclerosis

CCN 1 is a pleiotropic molecule involved in angiogenesis and postnatal vasculogenesis, both of which are impaired in systemic sclerosis ( SS c). To elucidate the potential role of CCN 1 in the development of SS c, we investigated CCN 1 expression in the lesional skin of SS c patients and SS c animal models and the clinical correlation of serum CCN 1 levels. CCN 1 expression was markedly decreased in dermal small blood vessels of SS c patients compared with those of healthy controls, while comparable between normal and SS c dermal fibroblasts. Transcription factor Fli1, whose deficiency due to epigenetic suppression is implicated in the pathogenesis of SS c, occupied the CCN 1 promoter and gene silencing of Fli1 resulted in the reduction of CCN 1 expression in human dermal microvascular endothelial cells. Consistently, CCN 1 expression was suppressed uniformly and remarkably in dermal blood vessels of Fli1 +/− mice and partially in those of endothelial cell‐specific Fli1 knockout mice. Furthermore, serum CCN 1 levels were significantly decreased in SS c patients with previous and current history of digital ulcers as compared to those without. Collectively, these results suggest that endothelial CCN 1 downregulation at least partially due to Fli1 deficiency may contribute to the development of digital ulcers in SS c patients. This study further supports the idea that epigenetic downregulation of Fli1 is a potential predisposing factor in the pathogenesis of SS c.