The Orbital Fibroblast: A Key Player and Target for Therapy in Graves’ Ophthalmopathy

Abstract

Orbital fibroblasts play a key role in the pathogenesis of Graves' ophthalmopathy (GO). We discuss some major aspects by which orbital fibroblasts contribute to GO and the important role of PDGF-BB herein. Finally, we propose the orbital fibroblast, and especially the PDGF system acting on orbital fibroblasts, as an important therapeutic target in GO.

Orbit-Infiltrating Mast Cells, Monocytes, and Macrophages Produce PDGF Isoforms that Orchestrate Orbital Fibroblast Activation in Graves' Ophthalmopathy

“…Excessive production of hyaluronan and IL-6 by orbital fibroblasts and enhanced orbital fibroblast proliferation are key events in the pathophysiology of GO (8,14,15,17). Therefore, we examined how these processes are affected by PDGF-AA, PDGF-AB, and PDGF-BB.…”

“…Cytokines and growth factors activate orbital fibroblasts to produce inflammatory mediators to proliferate and to secrete the glycosaminoglycan hyaluronan (4 -7). Consequently, orbital fibroblast activation is recognized as a main determinant of orbital tissue expansion and the resultant eye ball protrusion in GO (1,8). Nevertheless, the cellular origins of cytokines and growth factors and the relative contribution of these factors to orbital fibroblast activation in GO thus far remain largely unknown.…”

L’ophtalmopathie thyroïdienne à l’heure de l’European Group On Graves Orbitopathy (EUGOGO)

“…L'activation du R-IGF1, fortement exprimé sur les fibroblastes orbitaires et co-localisé avec le R-TSH, participerait à la production de GAG, à la sécrétion par ces fibroblastes de chémoattractants et de TGF-b [9,11,13]. À côté de la participation cellulaire avec initialement une réponse de type Th1, le fibroblaste orbitaire joue un rôle majeur [14]. Son activation conduit, outre à sa prolifération, aux événements suivants : production de protéines immunomodulatrices (cytokines, protéine RANTES, IL16, PGE2) responsable d'une autoactivation et d'un recrutement de cellules immunocompé-tentes comme les lymphocytes T et B et les mastocytes ;…”

Whole orbital tissue culture identifies imatinib mesylate and adalimumab as potential therapeutics for Graves' ophthalmopathy

“…Graves' ophthalmopathy (GO) is an inflammatory fibro-proliferative disease of the orbit that is characterised by inflammation and excessive orbital fibroblast proliferation and extracellular matrix production (especially hyaluronan), which together cause orbital tissue expansion and proptosis 9 10. Besides autoantibodies against the thyroid-stimulating hormone receptor and the insulin-like growth factor-1 receptor, also cytokines, including TNF-α and interleukin (IL)-6, as well as growth factors, such as PDGF, play a role in the pathophysiology of GO 9 11 12.…”