Background/Purpose: It is generally known that members of the TGF-β superfamily are involved in the regulation of connective tissue biology in systemic sclerosis (SSc). Growth differentiation factor 15 is a distant member of this TGF-β family. We aimed to evaluate the role of GDF15 in SSc-pathogenesis.

Methods:   A longitudinal prospective cohort of SSc patients was screened for GDF15 serum levels by ELISA and associations with disease activity and tissue damage were analyzed. Moreover, in vitro stimulation experiments were performed in lung fibroblasts. The role of GDF15 in fibrosis development in vivo was evaluated by performing the bleomycin lung fibrosis model in GDF15 deficient mice.

Results: Baseline serum samples from a prospective cohort of 119 patients were screened for GDF15 levels. An increase in GDF15 levels was observed in patients classified as limited SSc, limited cutaneous SSc and diffuse SSc. Moreover, baseline GDF15 serum levels highly correlated with disease activity, extent of organ involvement, particularly clinical symptoms of lung fibrosis including impact on lung function in prospective follow up. This was also mimicked in the bleomycin mouse model of SSc. Here, bleomycin exposed animals displayed elevated expression levels of GDF15 in lung tissue. Isolated lung fibroblast of GDF15 deficient mice showed reduced induction of IL6 and CCL2 upon bleomycin stimulation compared to wild-type littermates. Surprisingly, no differences in fibrosis development were observed between wild-type and GDF15 deficient animals.

Conclusion: An intriguing profile of GDF15 serum levels was found in SSc patients. GDF15 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.

Figure 1: GDF15 serum levels are elevated in SSc patients. Panel A: An elevated level of GDF15 was detected in SSc patients (1367 pg/ml; n=119) compared to healthy controls (390,9 pg/ml; n=29), p<0,001.  Panel B: An increase is observed in GDF15 serum levels of patients suffering from dcSSc (p=0,008, ANOVA).

Figure 2: In vitro and in vivo experimental induction of fibrosis results in elevated GDF15 gene expression. Panel A: Bleomycin treated animals show elevated expression of GDF15 in lung tissue Panel B: Stimulation of lung fibroblasts from WT (solid line) and HZ (dashed line) with bleomycin resulted in an increased GDF15 expression compared to non-stimulated controls.