Involvement of PDGF in fibrosis and scleroderma: recent insights from animal models and potential therapeutic opportunities

Abstract

Fibrosis is the principal characteristic of the autoimmune disease known as scleroderma or systemic sclerosis (SSc). Studies published within the last three years suggest central involvement of platelet-derived growth factors (PDGFs) in SSc-associated fibrosis. PDGFs may also be involved in SSc-associated autoimmunity and vasculopathy. The PDGF signaling pathway is well understood and PDGF receptors are expressed on collagen-secreting fibroblasts and on mesenchymal stem and/or progenitor cells that may affect SSc in profound and unexpected ways. Although much work remains before we fully understand how PDGFs are involved in SSc, there is much interest in using PDGF inhibitors as a therapeutic approach to SSc.

Fig. 1

Different involvement of PDGFRα and PDGFRβ in SSc pathogenesis. Injury and inflammation initiate secretion of PDGF isoforms that bind and activate their cognate PDGFRs. Some autoantibodies might also induce PDGFR signaling in SSc. Genetic mouse models of hyperresponsive PDGFR signaling reveal distinct consequences for each receptor. This leads to the prediction that the PDGFRα signaling pathway predominates in SSc fibrosis; PDGFRβ signaling, which is not sufficient to promote fibrosis, is likely to promote other hallmarks of SSc