PDGF/PDGFR: A Possible Molecular Target in Scleroderma Fibrosis

Abstract

Systemic sclerosis (SSc) is a clinically heterogeneous disorder of the connective tissue characterized by vascular alterations, immune/inflammatory manifestations, and organ fibrosis. SSc pathogenesis is complex and still poorly understood. Therefore, effective therapies are lacking and remain nonspecific and limited to disease symptoms. In the last few years, many molecular and cellular mediators of SSc fibrosis have been described, providing new potential options for targeted therapies. In this review: (i) we focused on the PDGF/PDGFR pathway as key signaling molecules in the development of tissue fibrosis; (ii) we highlighted the possible role of stimulatory anti-PDGFRα autoantibodies in the pathogenesis of SSc; (iii) we reported the most promising PDGF/PDGFR targeting therapies.

Keywords: PDGF receptor (PDGFR); PDGF/PDGFR targeting therapy; anti-PDGFR autoantibodies; fibrosis; platelet-derived growth factor (PDGF); scleroderma (SSc); systemic sclerosis (SSc).

Figure 1

Distinct epitopes of stimulatory and non-stimulatory anti-PDGFRα autoantibodies. Left cartoon: the interaction of stimulatory autoantibody cloned from memory B cells of a scleroderma patient and the discontinuous, conformational epitope identified on the extracellular PDGFRα domain induces the intracellular signaling activation and collagen gene overexpression. The identification of this binding region of PDGFRα provides a possible target for new therapeutic strategies to block excessive collagen synthesis under pathologic conditions such as SSc. Right cartoon: binding of non-stimulatory autoantibodies cloned from memory B cells of the same scleroderma patient to a single linear epitope of extracellular PDGFRα domain does not induce receptor dimerization/activation. This non-agonistic autoantibody could reflect the natural autoimmunity, already observed in many healthy individuals, without any clear role in physiology or disease.

Figure 2

Molecular modeling of the V_HPAM–V_κ16F4 (light blue)/PDGFRα (gold) complex. The identification of the five immunoglobulin-like (Ig) domains in the extracellular segment (D1–D5) and the binding area (in pink surface) of the PDGF-B/PDGFRα complex are reported.