Metalloproteinases mediate diabetes-induced retinal neuropathy and vasculopathy.

Matrix metalloproteinases (MMPs) and related metalloproteinases with a disintegrin domain (ADAMs) have become interesting probes and targets in eye diseases, including diabetic retinopathy. We here summarize recent data about MMPs and ADAMs in retinopathies. Retinal diseases range from rare genetic afflictions to diabetic retinopathy, the latter of which is reaching epidemic proportions. MMPs and ADAMs play roles in normal eye development and in disease states, not only in local proteolysis but also signaling functions mediated by specific protein domains, interacting with cell surface receptors. In proliferative diabetic retinopathy, inflammation, hypoxia-induced vascular endothelial growth factor and oxidative stress collectively stimulate the production, activation and signaling functions of pro-MMP-9. This leads to angiogenesis, destruction of neuroprotective prominin-1, loss of photoreceptors and blood-retina barrier breakdown. Biological inhibition of proteolysis and control of signaling functions are executed by the tissue inhibitors of metalloproteases (TIMPs). Angiogenic, inflammatory and fibrotic reactions, in which MMPs, ADAMs and TIMPs are involved, co-determine common eye diseases. Therefore, visions about the use of these proteases as biomarkers and as targets for therapeutic inhibitors, including small molecule inhibitors and monoclonal antibodies, may lead to breakthroughs in tissue regeneration, maintenance of photoreceptors and neuroprotection.