**1. Introduction**

Sorsby's fundus dystrophy (SFD) is a dominantly inherited, degenerative disease of the macula that is characterized by bilateral loss of central vision as a consequence of choroidal neovascularization (CNV) [1–6]. Specific mutations in the tissue inhibitor of metalloproteinase 3 (*TIMP3*) gene involving exon 5, exon 1 or the intron 4-exon 5 boundary have been shown to be causative [7–14]. In comparative studies using TIMP3 deficient mice, S179C-TIMP3 transgenic mice and in vitro culture experiments we have determined that TIMP3 partially inhibits angiogenesis by blocking the binding of vascular endothelial growth factor (VEGF) to VEGF Receptor 2 (VEGFR2). We have also demonstrated that the S179C-TIMP3 mutant protein induces angiogenesis via VEGF and fibroblast growth factor 2 (FGF-2) [15–21].

TIMP3 is produced constitutively by the retinal pigment epithelium (RPE) and choroidal endothelial cells [2,20]. It is a normal component of Bruch's membrane [22] and binds to sulfated glycosaminoglycans of the extracellular matrix (ECM) [23,24]. Hyaluronan (HA) is a large glycosaminoglycan that is a significant component of peri-cellular and extracellular matrices. HA is essential for numerous physiological functions that are dependent on its chain size and its interactions with various effector proteins and receptors [25]. HA has been implicated in the regulation of neovascularization and endothelial barrier function [26]. While studies have demonstrated that signaling via HA and its cell surface receptor CD44 accentuates CNV in mice using a laser-induced model [27], the exact molecular mechanism by which HA regulates tissue remodeling and neovascularization is unknown.

We have recently reported that RPE cells expressing mutant TIMP3 secrete increased amounts of FGF-2 [28] and that this contributes to increased angiogenesis. FGF-2 has been shown to be important in tumor angiogenesis, but its role in CNV has been less well studied. The most direct evidence for a role of FGF-2 in CNV comes from studies in which Flk1-Cre or Tie2-Cre mediated deletions of FGF receptor 1 (FGFR1) and FGF receptor 2 (FGFR2) in endothelial cells resulted in reduced laser-induced CNV in mice [29]. Extracellular matrix components such as heparan sulfate proteoglycans (HSPGs) bind and regulate the activity of growth factors such as FGF-2 [30] and have a critical role in the regulation of neovascularization [31]. In addition, the observation that activation of the FGFR-STAT3 pathway can induce a hyaluronan-rich microenvironment that can affect tumor growth [32] led us to test the hypothesis that in addition to VEGF, FGF-2 and hyaluronan also have critical roles in the increased neovascularization induced by mutant TIMP3 in Sorsby's fundus dystrophy.
