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

Abstract

ObjectiveTransforming growth factor β 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.MethodsA 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 GDF‐15–deficient mice.ResultsGDF‐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.ConclusionAn 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.

Growth Differentiation Factor 15 Predicts Chronic Liver Disease Severity

“…Regarding studies of the relationships between GDF-15 and fibrosis, when Lambrecht et al 21. measured the serum GDF-15 concentration in 119 patients with systemic sclerosis, disease activity and organ involvement showed a strong relationship; in particular, more severe fibrosis in the liver showed a higher GDF-15 concentration.…”

Interstitial lung disease in systemic sclerosis: where do we stand?

“…A meta-analysis of 26 studies identified male sex, disease extent on HRCT, presence of honeycombing, elevated Krebs von den Lungen (KL-6) values and increased alveolar epithelial permeability as predictors of both mortality and ILD progression in unadjusted analysis, while disease extent on the HRCT scan was the only variable that independently predicted both mortality and ILD progression [39]. Recently, a loss of density on capillaroscopy was shown to be associated with worse FVC and DLCO [40] and biomarkers that correlate with the severity of fibrosis have been proposed: elevated levels of chitinase [41], tenascin C [42], growth differentiation protein 15 [43], cartilage oligomeric matrix protein, alveolar epithelial cell antigen, KL-6 [44] and the chemokine CXCL4 [45]. Serum IL-6 predicted early disease progression and IL-6 values >767 pg·mL −1 were predictive of risk of death within the first 30 months in patients with mild SSc-ILD [46].…”

Biomarkers in connective tissue diseases

“…GDF-15 levels strongly correlate with a modified Rodnan severity score for skin involvement and negatively correlate with FVC and DLCO. 94, 95 Levels of GDF-15 are increased in SSc patients with ILD compared to other SSc patients, and higher levels of GDF-15 at baseline were predictive of worse lung disease severity scores at 30 months of follow-up. Therefore, GDF-15 may be a prognostic marker for lung function.…”