Decorin treatment for reversing trabecular meshwork fibrosis in open-angle glaucoma

In this perspective, we discuss the use of an anti-fibrotic agent Decorin to treat established fibrosis associated with glaucoma originally published by Hill et al. (2015). Glaucoma describes a group of progressive optic neuropathies that have the potential to cause irreversible blindness, for which it is recognized that a main risk factor is raised intraocular pressure (IOP). Currently, there is no precise explanation of why high IOP causes retinal ganglion cell (RGC) death. Factors contributing to IOP-related RGC death include compromised retrograde axonal transport of target derived neurotrophic factors, leading to activation of apoptosis and mitochondrial dysfunction after the biomechanical and ischemic insult of optic nerve head compression. In open-angle glaucoma (OAG), increases in IOP occur when aqueous humour (AqH) outflow through the trabecular meshwork (TM) is reduced, usually as a result of progressive abnormalities in TM cellularity and extracellular matrix (ECM) levels culminating in TM fibrosis (Prendes et al., 2013). These cellular and ECM changes (which includes upregulation of collagen IV, laminin, and fibronectin) in the TM, together with altered TM cell contractility, result in TM dysfunction and ultimately loss of the tightly controlled AqH outflow. Currently, treatments for glaucoma are symptomatic and focus on the use of drugs formulated as eye drops to lower IOP either by reducing AqH production or increasing AqH outflow through non-TM pathways. Alternatively, surgical insertion of shunts through the TM can drain AqH directly to the exterior of the eye, although these often become blocked. For some patients it seems that primary open-angle glaucoma is a fibroproliferative condition and no current treatment addresses the TM fibrosis that is the predominant underlying causes of TM dysregulation. The mechanisms that lead to TM dysfunction in OAG are multifactorial and may relate to dysregulated ocular inflammation since pathologically high levels of the pro-inflammatory cytokine transforming growth factor β (TGF-β) within the AqH and TM have been implicated. For example, some OAG patients have elevated levels of TGF-β1 and/ or TGF-β2 in their AqH compared to age-matched patients with other forms of glaucoma (e.g., primary angle closure glaucoma and uveitis-associated secondary glaucoma) and with cataracts (Prendes et al., 2013). Other studies have shown that it is the TGF-β2 isoform that is significantly elevated in eyes with primary OAG compared with non-glaucomatous eyes, and have shown elevated TGF-β1 and TGF-β3 isoforms in pseudoexfoliative glaucoma and in primary angle closure glaucoma (Prendes et al., 2013). TGF-β1 and TGF-β2 are known potent fibrogenic factors and, at pathologically high levels in the eye, can induce the overexpression of ECM proteins that lead to TM dysfunctions (Prendes et al., 2013). TGF-βs also prevent the breakdown of ECM by inhibiting matrix metalloproteinases (MMP) (Ahmed et al. 2014), creating a pro-fibrotic microenvironment within the TM. TGF-β is directly implicated in the pathogenesis of ocular hypertension since: (1) infusion of TGF-β2 for 14 days in an anterior eye segment perfusion culture model significantly increased IOP (Battacharya et al., 2009); (2) adenoviral gene delivery of human TGF-β2 into the anterior segment to the rodent eye reduced AqH outflow and increased IOP (Shepard et al., 2010); and (3) TGF-β1 gene delivery by adenovirus to the anterior segment of the rat eye increased IOP (Robertson et al., 2010). Thus, treatment of the TM in OAG with a TGF-β antagonist may help to ablate TM fibrogenesis, thereby perturbing the progression of OAG pathology. The matrikine Decorin is a small leucine-rich proteoglycan that regulates cell proliferation, survival and differentiation by antagonizing a panel of growth factors and/or their receptors, including TGF-β, epidermal growth factor, vascular endothelial growth factor, hepatocyte growth factor and insulin-like growth factor-1. Decorin also ‘decorates’ collagen, interfering with collagen fibrillogenesis and stabilizing collagen fibres. In addition, Decorin enhances matrix metalloproteinases (MMP) activity by increasing levels of tissue plasminogen activator (tPA), thus enabling plasmin-dependent activation of MMP by cleavage of plasminogen to plasmin, and reducing levels of PAI-1 and tissue inhibitors of MMPs, further facilitating MMP activation. The fibrolytic actions of Decorin have been harnessed to attenuate the progression of tissue damage in other fibroproliferative pathologies, including juvenile communicating hydrocephalus (Botfield et al., 2013) and spinal cord injury (Ahmed et al., 2014), making Decorin an ideal candidate for treating TM fibrosis and progressive RGC loss in glaucoma.