Platelet-Derived Growth Factor: A Key Factor in the Pathogenesis of Graves' Ophthalmopathy and Potential Target for Treatment

Abstract

Activation of orbital fibroblasts resulting in excessive proliferation, cytokine and hyaluronan production and differentiation into adipocytes, is a main determinant of orbital tissue inflammation and tissue expansion in Graves' ophthalmopathy (GO). During the last years we have shown that the platelet-derived growth factor (PDGF) isoforms PDGF-AA, PDGF-AB and PDGF-BB are increased in orbital tissue from GO patients with active and inactive disease. These PDGF isoforms exhibit the capacity to stimulate proliferation, hyaluronan and cytokine/chemokine production by orbital fibroblasts. Moreover, PDGF-AB and PDGF-BB increase thyroid stimulating hormone receptor (TSHR) expression by orbital fibroblasts, which enhances the orbital fibroblast activating capacity of the THSR stimulatory autoantibodies present in Graves' disease (GD) patients. Of these PDGF isoforms PDGF-BB exhibits the strongest orbital fibroblast activating effects, which is likely related to its ability to bind both the PDGF-receptor (PDGF-R)α and PDGF-Rβ chains. Thus the PDGF-system fulfills important roles in orbital fibroblast activation in both active and inactive GO, which supports a therapeutic rationale for blocking PDGF signaling in GO. Tyrosine kinase inhibitors (TKIs) may be candidates to target PDGF signaling. Of several TKIs tested dasatinib exhibited the highest potency to block PDGF-R signaling in orbital fibroblasts and may represent a promising compound for the treatment of GO as it was effective at low dosage and is associated with less side effects compared to imatinib mesylate and nilotinib. In this review the contribution of PDGF to the pathophysiology of GO as well as therapeutic approaches to target this PDGF-system will be addressed.

Platelet-Derived Growth Factor-BB Enhances Adipogenesis in Orbital Fibroblasts

“…However, alternative approaches to interfere with PDGF signaling in GO can be thought of, for instance via PDGF-neutralization with specific neutralizing antibodies or soluble receptor molecules, or blockage of the PDGF-receptor with neutralizing antibodies or dominant negative ligands. 1 In summary, we report that PDGF-BB enhances adipogenesis by orbital fibroblasts exposed to a proadipogenic culture environment. Therefore, PDGF-BB can be expected to contribute to the orbital adipose tissue expansion in GO.…”

“…In most patients the adipose/connective tissue and extraocular muscle volumes increase, while in some patients either adipose/connective tissue expansion or extraocular muscle enlargement may predominate. 1 Activation of orbital fibroblasts by inflammatory cytokines and lipids, growth factors, and stimulatory autoantibodies against the thyrotropin receptor (TSHR), and possibly the insulin-like growth factor-1 receptor is the central hallmark of GO's pathogenesis. 1 The activated orbital fibroblasts produce cytokines and chemokines that are involved in the recruitment, activation, and differentiation of immune cells.…”

“…1 Activation of orbital fibroblasts by inflammatory cytokines and lipids, growth factors, and stimulatory autoantibodies against the thyrotropin receptor (TSHR), and possibly the insulin-like growth factor-1 receptor is the central hallmark of GO's pathogenesis. 1 The activated orbital fibroblasts produce cytokines and chemokines that are involved in the recruitment, activation, and differentiation of immune cells. 2,3 In addition, the orbital fibroblasts display increased proliferative activity, produce excess amounts of glycosaminoglycans (especially hyaluronan), and differentiate into mature adipocytes.…”

“…2,3 In addition, the orbital fibroblasts display increased proliferative activity, produce excess amounts of glycosaminoglycans (especially hyaluronan), and differentiate into mature adipocytes. 1 Together, these processes contribute to orbital tissue volume expansion within the noncompliant space-limited bony orbit, which causes typical clinical features, including upper eyelid retraction, edema, erythema of the periorbital tissues and conjunctivae, and proptosis. 1 Previously we found that orbital tissue from GO patients contains increased levels of platelet-derived growth factor (PDGF)-BB, a growth factor that is important in developmental and healing processes, while excessive amounts are associated with diseases characterized by pathologic tissue remodeling.…”

“…1 Previously we found that orbital tissue from GO patients contains increased levels of platelet-derived growth factor (PDGF)-BB, a growth factor that is important in developmental and healing processes, while excessive amounts are associated with diseases characterized by pathologic tissue remodeling. 1 cytokines by orbital fibroblasts. 7 These data implicate that PDGF-BB may represent an important pathologic growth factor in GO where it regulates orbital inflammation, proliferation of fibroblasts, and hyaluronan production.…”