Alexander G. Marneros

Lack of collagen XVIII/endostatin results in eye abnormalities

Mice lacking collagen XVIII and its proteolytically derived product endostatin show delayed regression of blood vessels in the vitreous along the surface of the retina after birth and lack of or abnormal outgrowth of retinal vessels. This suggests that collagen XVIII/endostatin is critical for normal blood vessel formation in the eye. All basement membranes in wild‐type eyes, except Descemets membrane, showed immunogold labeling with antibodies against collagen XVIII. Labeling at sites where collagen fibrils in the vitreous are connected with the inner limiting membrane and separation of the vitreal matrix from the inner limiting membrane in mutant mice indicate that collagen XVIII is important for anchoring vitreal collagen fibrils to the inner limiting membrane. The findings provide an explanation for high myopia, vitreoretinal degeneration and retinal detachment seen in patients with Knobloch syndrome caused by loss‐of‐function mutations in collagen XVIII.

Vascular Endothelial Growth Factor Expression in the Retinal Pigment Epithelium Is Essential for Choriocapillaris Development and Visual Function

The choroid in the eye provides vascular support for the retinal pigment epithelium (RPE) and the photoreceptors. Vascular endothelial growth factor (VEGF) derived from the RPE has been implicated in the physiological regulation of the choroidal vasculature, and overexpression of VEGF in this epithelium has been considered an important factor in the pathogenesis of choroidal neovascularization in age-related macular degeneration. Here, we demonstrate that RPE-derived VEGF is essential for choriocapillaris development. Conditional inactivation of VEGF expression in the RPE (in VEGFrpe-/- mice) results in the absence of choriocapillaris, occurrence of microphthalmia, and the loss of visual function. Severe abnormalities of RPE cells are already observed when VEGF expression in the RPE is only reduced (in VEGFrpe+/- mice), despite the formation of choroidal vessels at these VEGF levels. Finally, using Hif1arpe-/- mice we demonstrate that these roles of VEGF are not dependent on hypoxia-inducible factor-1alpha-mediated transcriptional regulation of VEGF expression in the RPE. Thus, hypoxia-inducible factor-1alpha-independent expression of VEGF is essential for choroid development.

The role of collagen-derived proteolytic fragments in angiogenesis.

Basement membrane molecules and fragments derived from them are regulators of biological activities such as cell growth, differentiation and migration. This review describes proteolytically derived fragments from the non-collagenous (NC1) domain at the C-terminus of the basement membrane collagens type IV, XV and XVIII, which have been implicated as regulators of angiogenesis. Endostatin is an endogenous collagen XVIII/NC1 derivative, inhibiting endothelial cell proliferation and migration in vitro and tumor-growth in vivo. A homologous NC1 domain fragment of type XV collagen has anti-angiogenic activity as well. Furthermore, NC1 domain fragments of the most abundant basement membrane collagen, type IV collagen, have been shown to inhibit induced vessel growth.

Physiological role of collagen XVIII and endostatin

Collagen XVIII is a component of basement membranes (BMs) with the structural properties of both a collagen and a proteoglycan. Proteolytic cleavage within its C‐terminal domain releases a fragment, endostatin, which has been reported to have anti‐angiogenesis effects. Molecular studies demonstrated binding of the endostatin domain to heparan sulfate and to BM components like laminin and perlecan, but the functional role of these interactions in vivo remains unknown. Insights into the physiological function of collagen XVIII/endostatin have recently been obtained through the identification of inactivating mutations in the human collagen XVIII/endostatin gene (COL18A1) in patients with Knobloch syndrome, characterized by age‐dependent vitreoretinal degeneration and occipital encephalocele. That collagen XVIII/endostatin has an essential role in ocular development and the maintenance of visual function is further demonstrated by the ocular abnormalities seen in mice lacking collagen XVIII/endostatin. Age‐dependent loss of vision in these mutant mice is associated with pathological accumulation of deposits under the retinal pigment epithelium, as seen in early stages of age‐related macular degeneration in humans. In addition, recent evidence suggests that lack of collagen XVIII/endostatin predisposes to hydrocephalus formation. These recent findings demonstrate an important role for collagen XVIII/endostatin in cell‐matrix interactions in certain tissues that may be compensated for in other tissues expressing this collagen.—Marneros, A. G., Olsen, B. R. Physiological role of collagen XVIII and endostatin. FASEB J. 19, 716–728 (2005)

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

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 Bruchs membrane. Consistent with such a role, the ultrastructural organization of collagen XVIII/endostatin in basement membranes, including Bruchs membrane, shows that it is part of basement membrane molecular networks.

Keloids – clinical diagnosis, pathogenesis, and treatment options

Keloids are defined as excessive scar tissue formation extending beyond the area of the original skin injury and occurring in predisposed individuals. They are considered to be a result of abnormal wound healing. The pathogenetic mechanisms that cause keloids remain unknown. Experiments with cells derived from keloid tissue revealed a number of abnormalities in cellular functions, such as in proliferation, apoptosis, or expression of growth factors and extracellular matrix proteins. Furthermore, several studies have reported altered keratinocyte‐fibroblast interactions in keloids. Despite the diverse pathological changes in cellular functions and expression profiles of cells derived from keloid tissue, recent genetic studies have provided evidence that single genes may act as major regulators of keloid formation. We provide an overview of the pathogenetic mechanisms of keloid formation in the context of their clinical characteristics and current therapeutic approaches.

Long-term outcome of schizoaffective and schizophrenic disorders: a comparative study

SummaryThe long-term outcome of 72 schizoaffective and 97 schizophrenic patients with a mean duration of illness of 25.6 years and 19.6 years respectively was investigated. The outcome was assessed using the WHO Disability Assessment Schedule (WHO/DAS), the Psychological Impairment Rating Schedule (PIRS) (also developed by the WHO), the Global Assessment Scale (GAS), and the Bonn Psychopathological Criteria of Outcome. The outcome of schizoaffective disorders was found to differ from that of schizophrenia in several ways: (a) schizoaffectives achieve a full remission significantly more frequently than schizophrenics (50% vs 10%); (b) the development of so-called characteristic schizophrenic residua is the exception in schizoaffective disorders, but is frequent in schizophrenia; (c) disability, psychological impairment and disturbances of the level of functioning are not only significantly less frequent in schizoaffective disorders but are also less intense than in the schizophrenic group. The factors influencing the outcome of the two disorders are different (see part 11), as are the social consequences (part III).

Stability of diagnoses in affective, schizoaffective and schizophrenic disorders

SummaryThe present study investigated the syndrome shift during the course of disease in 355 patients with functional psychoses. The mean observation time was 25.2 years. Every episode was diagnosed cross-sectionally as schizophrenic, melancholic, manic, manic-depressive mixed, schizodepressive, schizomanic or schizomanic-depressive mixed. With regard to the whole course, 148 patients fulfilled the diagnostic criteria of schizophrenic, 106 of affective and 101 of schizoaffective disorders. Patients with a schizophrenic initial episode showed the greatest stability: 90% had no other type of episode. The majority of patients who suffered a melancholic initial episode remained unipolar melancholics or developed manic symptomatology, and only a few suffered schizoaffective or schizophrenic episodes. Patients with a manic symptomatology at the beginning had a very unstable and changeable course. The stability of patients with initial schizodepressive episodes lay between that of patients with melancholic initial episodes and that of those with manic initial episodes. The findings demonstrate the relevance of longitudinal considerations in making the final diagnosis.

Psychopathological and social status of patients with affective, schizophrenic and schizoaffective disorders after long-term course.

A total of 106 affective, 101 schizoaffective and 148 schizophrenic disorders were investigated after a long‐term course of illness (mean follow‐up period 25.1 years), employing narrow definitions and using reliable international instruments of evaluation. In addition, the social consequences of the illness were evaluated (upward and downward social and occupational drift, premature retirement and achievement of the expected social development). Considering all aspects of outcome, schizophrenic patients (narrow defined, slightly modified DSM‐III criteria) had persistent alterations in several aspects of social life, communication and cognitive functions, in some cases to a very high degree. Although the outcome of affective disorders is not always favourable, it is significantly more favourable than that of schizophrenia. Schizoaffective disorders occupy a position between affective and schizophrenic disorders regarding outcome, but with more similarities to that of affective than to that of schizophrenic disorders.

Endogenous endostatin inhibits choroidal neovascularization

Endostatin, a fragment of the basement membrane component collagen XVIII, exhibits antian‐ giogenic properties in vitro and in vivo when high doses are administered. It is not known whether endogenous endostatin at physiological levels has a protective role as an inhibitor of pathological angiogenesis, such as choroidal neovascularization (CNV) in age‐related macular degeneration. Using a laser injury model, we induced CNV in mice lacking collagen XVIII/endosta‐ tin and in control mice. CNV lesions in mutant mice were ~ 3‐fold larger than in control mice and showed increased vascular leakage. These differences were independent of age‐related changes at the choroid‐ retina interface. Ultrastructural analysis of the choroidal vasculature in mutant mice excluded morphological vascular abnormalities as a cause for the larger CNV lesions. When recombinant endostatin was administered to collagen XVIII/endostatin‐deficient mice, CNV lesions were similar to those seen in control mice. In control mice treated with recombinant endostatin, CNV lesions were almost undetectable. These findings demonstrate that endogenous endostatin is an inhibitor of induced angiogenesis and that administration of endostatin potently inhibits CNV growth and vascular leakage. Endostatin may have a regulatory role in the pathogenesis of CNV and could be used therapeutically to inhibit growth and leakage of CNV lesions.— Marneros, A. G., She, H., Zambarakji, H., Hashizume, H., Connolly, E. J., Kim, I., Gragoudas, E. S., Miller, J. W., Olsen, B. R. Endogenous endostatin inhibits choroidal neovascularization. FASEB J. 21, 3809–3818 (2007)