Modulation of extracellular matrix turnover in the trabecular meshwork.
Intraocular pressure (IOP) is the most critical risk factor for primary open angle glaucoma (POAG). In most cases of POAG, IOP is increased because of an abnormally high aqueous humor outflow resistance in the juxtacanalicular region of the trabecular meshwork. A distinct structural change in the trabecular meshwork of patients with POAG is the increase in fibrillar extracellular matrix in the juxtacanalicular region of the trabecular meshwork. Our knowledge on the molecular factors that govern turnover of the extracellular matrix in the trabecular meshwork has increased considerably in recent years. It has become clear that quality and quantity of the extracellular matrix in the trabecular meshwork are regulated by several signaling molecules that interact with each other to promote its synthesis, degradation, or extracellular modification. Transforming growth factor-beta1 and beta2 (TGF-beta1 and TGF-beta2) which derive from the aqueous humor or may be locally expressed induce in cultured trabecular meshwork cells the expression of a variety of extracellular matrix molecules. The action of TGF-betas very likely requires local activation by thrombospondin-1 and is partly mediated by its downstream mediator connective tissue growth factor, both of which are constitutively expressed in the trabecular meshwork. Bone morphogenetic proteins (BMP)-7 and -4 effectively antagonize the effects of TGF-beta2 on matrix deposition. The antagonizing effects of BMP-7 are mediated in trabecular meshwork cells through Smad7. Smad7 is a key molecular switch to inhibit TGF-beta2 signaling in the trabecular meshwork.
Fuchshofer
Rudolf
R
Institute of Human Anatomy and Embryology, University of Regensburg, Regensburg, Germany. rudolf.fuchshofer@vkl.uni-regensburg.de
Tamm
Ernst R
ER
D019485:Bone Morphogenetic Proteins / Q000502:physiology; D055513:Connective Tissue Growth Factor / Q000502:physiology; D005109:Extracellular Matrix / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D007429:Intraocular Pressure / Q000502:physiology; D051906:Smad7 Protein / Q000502:physiology; D019700:Thrombospondin 1 / Q000502:physiology; D014129:Trabecular Meshwork / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000502:physiology
D019485:Bone Morphogenetic Proteins; C497806:SMAD7 protein, human; D051906:Smad7 Protein; D019700:Thrombospondin 1; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor