Matricellular Proteins in the Trabecular Meshwork: Review and Update

Abstract

Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide, and intraocular pressure (IOP) is an important modifiable risk factor. IOP is a function of aqueous humor production and aqueous humor outflow, and it is thought that prolonged IOP elevation leads to optic nerve damage over time. Within the trabecular meshwork (TM), the eye's primary drainage system for aqueous humor, matricellular proteins generally allow cells to modulate their attachments with and alter the characteristics of their surrounding extracellular matrix (ECM). It is now well established that ECM turnover in the TM affects outflow facility, and matricellular proteins are emerging as significant players in IOP regulation. The formalized study of matricellular proteins in TM has gained increased attention. Secreted protein acidic and rich in cysteine (SPARC), myocilin, connective tissue growth factor (CTGF), and thrombospondin-1 and -2 (TSP-1 and -2) have been localized to the TM, and a growing body of evidence suggests that these matricellular proteins play an important role in IOP regulation and possibly the pathophysiology of POAG. As evidence continues to emerge, these proteins are now seen as potential therapeutic targets. Further study is warranted to assess their utility in treating glaucoma in humans.

A Comparison of Gene Expression Profiles between Glucocorticoid Responder and Non-Responder Bovine Trabecular Meshwork Cells Using RNA Sequencing

“…Naschberger et al showed that SPARCL1 contributes to tumor endothelial cell quiescence [61]. In POAG TM, Rhee and colleagues found that SPARC plays a role in IOP regulation and TM pathology [62]. Although we found a DEX-induced down-regulation of SPARCL1 in responders, it may indicate a remodeling of the TM.…”

Extracellular matrix in the trabecular meshwork: Intraocular pressure regulation and dysregulation in glaucoma

“…Mouse models targeting matricellular genes, including SPARC, thrombospondins-1 and −2, tenascins-C and –X, hevin and osteopontin, have been investigated (Chatterjee et al, 2014; Chowdhury et al, 2011; Haddadin et al, 2009; Haddadin et al, 2012; Kang et al, 2011; Keller et al, 2013). Of these, gene knockout of SPARC and both thrombospondins significantly lowered IOP in mice, while ablation of the other genes had minimal effects on IOP.…”

Life under pressure: The role of ocular cribriform cells in preventing glaucoma

“…(Acott and Kelley, 2008; Vranka et al, 2015a, 2015b) For instance, the matricellular proteins shown altered in glaucoma specimens include SPARC, myocilin, CTGF, TSP-1, and -2. (Chatterjee et al, 2014) Changes in these and other proteins can be observed following treatment of cultured cells with stretching, dexamethasone, or TGF-beta stimuli. For example, increased expression of fibronectin, tenascin C, Versican, CD 44, syndecan, periostin, TSP-2, VCAM-1, GLA protein, and MMP-2 have been observed in response to stretch.…”

“…Several details presented are striking such as origin, ultrastructural findings, cellular behaviors in culture and functional relationship with the surrounding ECM. They also are remarkably alike in terms of the type and protein components of their basement membrane and ECM, which are altered in glaucoma (Acott and Kelley, 2008; Chatterjee et al, 2014; Kirwan et al, 2009, 2005b, 2004; Liton et al, 2006; Rehnberg et al, 1987; Steely et al, 2000; Wallace and O’Brien, 2016). …”