Collagen XVIII/endostatin is essential for vision and retinal pigment epithelial function

Abstract

Age-related macular degeneration (ARMD) with abnormal deposit formation under the retinal pigment epithelium (RPE) is the major cause of blindness in the Western world. basal laminar deposits are found in early ARMD and are composed of excess basement membrane material produced by the RPE. Here, we demonstrate that mice lacking the basement membrane component collagen XVIII/endostatin have massive accumulation of sub-RPE deposits with striking similarities to basal laminar deposits, abnormal RPE, and age-dependent loss of vision. The progressive attenuation of visual function results from decreased retinal rhodopsin content as a consequence of abnormal vitamin A metabolism in the RPE. In addition, aged mutant mice show photoreceptor abnormalities and increased expression of glial fibrillary acidic protein in the neural retina. Our data demonstrate that collagen XVIII/ endostatin is essential for RPE function, and suggest an important role of this collagen in Bruch's membrane. Consistent with such a role, the ultrastructural organization of collagen XVIII/endostatin in basement membranes, including Bruch's membrane, shows that it is part of basement membrane molecular networks.

Regulation of cysteine cathepsin expression by oxidative stress in the retinal pigment epithelium/choroid of the mouse

“…Cathepsin B is now thought to be capable of releasing endostatin from collagen XVIII (Ferreras, et al, 2000, Zatterstrom, et al, 2000 and the presence of this collagen has also been demonstrated in Bruch's membrane in rat (Marneros, et al, 2004). There is also a study by Bhutto et al demonstrating that endostatin declines in AMD, yet collagen XVIII (non-endostatin portion) is similar in level (Bhutto, et al, 2004).…”

Immunological Disruption of Antiangiogenic Signals by Recruited Allospecific T Cells Leads to Corneal Allograft Rejection

“…Previous work demonstrated that endostatin is produced by most of the ocular structures, especially the cornea and conjunctiva, as a crucial mechanism to maintain the avascular environment of the eye (28,29). To determine whether endostatin also plays a role in preventing angiogenesis after transplantation and increased graft survival, we first measured endostatin production in protein ex-…”

“…Collagen XVIII is found in almost all ocular structures (i.e., the basement membranes [BMs] of the corneal and conjunctival epithelia, Descemet's membrane, the anterior border layer and posterior pigmented epithelium of the iris, the BMs of the pigmented and nonpigmented ciliary epithelia, the internal wall of Schlemm's canal and trabeculae, the ciliary and iris muscle cells, the BMs of the pigment epithelium of the retina, and the internal limiting membrane). Endostatin shows a corresponding pattern, but with additional expression in corneal and conjunctival epithelial cells (28,29). The constitutive presence of endostatin in corneas suggests that this molecule may play an important role in maintaining corneal avascularity and transparency.…”

Basement membranes and human disease

“…It is unlikely that these vascular defects underlie the progressive loss of vision in Knobloch syndrome patients and Col18a1 -/-animals (Marneros and Olsen 2005) as they do not affect retinal perfusion or function (Marneros et al 2004). A more likely explanation may be the accumulation of deposits between the retinal pigment epithelium and Bruch's membrane, which are also observed in age related macular degeneration, possibly due to BM defects in Bruch's membrane (Marneros et al 2004).…”

“…A more likely explanation may be the accumulation of deposits between the retinal pigment epithelium and Bruch's membrane, which are also observed in age related macular degeneration, possibly due to BM defects in Bruch's membrane (Marneros et al 2004). …”