Growth Differentiation Factor 15, a Marker of Lung Involvement in Systemic Sclerosis, Is Involved in Fibrosis Development but Is not Indispensable for Fibrosis Development

Objective. Transforming growth factor beta superfamily members are involved in the pathogenesis of systemic sclerosis (SSc). Growth differentiation factor 15 (GDF-15) is a distant member of this family. We undertook this study to evaluate the role of GDF-15 in SSc pathogenesis. Methods. A longitudinal prospective cohort of SSc patients was screened for serum GDF-15 levels using enzyme-linked immunosorbent assay, and associations with clinical data were analyzed. In vitro stimulation experiments were performed on lung fibroblasts. The role of GDF-15 in fibrosis development in vivo was evaluated in the bleomycin lung fibrosis model in GDF15-deficient mice. Results. GDF-15 was measured at baseline in serum samples from 119 SSc patients. An increase in GDF-15 levels was observed in patients classified as having no skin involvement, those with limited cutaneous SSc, and those with diffuse cutaneous SSc. Moreover, baseline serum GDF-15 levels correlated strongly with disease activity and extent of organ involvement, particularly clinical symptoms of lung fibrosis, including impact on lung function at prospective followup. This was mimicked in the bleomycin model of SSc, in which animals exposed to bleomycin had elevated expression levels of GDF-15 in lung tissue. Lung fibroblasts isolated from GDF-15-deficient mice showed reduced induction of interleukin-6 and CCL2 upon bleomycin stimulation. Surprisingly, no differences in fibrosis development were observed between wild-type and GDF-15-deficient animals. Conclusion. An intriguing profile of serum GDF-15 levels was found in SSc patients. GDF-15 expression is induced during fibrosis development and markedly correlates with lung function impairment in this disease. The protein may participate in fibrosis initiation, but is not indispensable in the course of fibrosis development in vivo.