Extracellular matrix in the trabecular meshwork

Abstract

The extracellular matrix (ECM) of the trabecular meshwork (TM) is thought to be important in regulating intraocular pressure (IOP) in both normal and glaucomatous eyes. IOP is regulated primarily by a fluid resistance to aqueous humor outflow. However, neither the exact site nor the identity of the normal resistance to aqueous humor outflow has been established. Whether the site and nature of the increased outflow resistance, which is associated with open-angle glaucoma, is the same or different from the normal resistance is also unclear. The ECMs of the TM beams, juxtacanalicular region (JCT) and Schlemm's canal (SC) inner wall are comprised of fibrillar and non-fibrillar collagens, elastin-containing microfibrils, matricellular and structural organizing proteins, glycosaminoglycans (GAGs) and proteoglycans. Both basement membranes and stromal ECM are present in the TM beams and JCT region. Cell adhesion proteins, cell surface ECM receptors and associated binding proteins are also present in the beams, JCT and SC inner wall region. The outflow pathway ECM is relatively dynamic, undergoing constant turnover and remodeling. Regulated changes in enzymes responsible for ECM degradation and biosynthetic replacement are observed. IOP homeostasis, triggered by pressure changes or mechanical stretching of the TM, appears to involve ECM turnover. Several cytokines, growth factors and drugs, which affect the outflow resistance, change ECM component expression, mRNA alternative splicing, cellular cytoskeletal organization or all of these. Changes in ECM associated with open-angle glaucoma have been identified.

Fig. 1

Diagram of the outflow pathway and juxtacanalicular or cribriform region. The lower portion of the figure shows a stylized view of the TM and the upper inset shows an expanded view of the JCT region. The figure is modified from several sources.(Tripathi 1971, 1977; Grierson et al. 1978; Rohen et al. 1981; Rohen 1983; Grierson and Calthorpe 1989; Epstein and Rohen 1991; Maepea and Bill 1992; Lutjen-Drecoll 1999; Parc et al. 2000)

Fig. 2

Versican structural domains, binding sites and alternative splicing. Key shows versican domains, positions of GAG chain attachments and position of ADAMTS 1–4 cut site. Various ECM molecules bind to these domains as indicated. The four alternative splice forms of versican are shown binding to hyaluronan with a stabilizing interaction with link protein. (Diagram modified from (Wight 2002; Wu et al. 2005)

Fig. 3

Fibronectin repeat type I, II and III domains, binding sites and alternative splicing. RGD, synergy and IDAPS sequences bind α5β1 and α4β1 integrins. Alternative splicing domains EIIIB, EIIIA and V1, V2 and V3 of IIICS are inserted as indicated. V1, V2 and V2 produce additional heparin, α4β1 integrin and a zinc binding site. FN and assembly represent fibril formation sites.

Fig. 4

Type VI collagen chains, domain structure, binding domains and proposed microfibril organization.

Fig. 5

Type XII FACIT collagen domain structure, multimerization and binding domains.

Fig. 6

Structural domains of several SPARC family member expressed by outflow pathway cells.

Fig. 7

Thrombospondin family domain structures and binding sites. N- and C-terminal globe domains, a multimerization domain resembling the N-terminal region of type I procollagen and three types of thrombospondin (TSP) repeat domains are shown.

Fig. 8

Tenascin C domain structure, binding sites and alternative splicing. Heptad repeat hexamer assembly domain, EGF-like domains, type III fibronectin and fibrin globular domains are as indicated.