Mithramycin reduces expression of fibro-proliferative mRNAs in human gingival fibroblasts.

Fibrosis is characterized by loss of normal structure and function of a tissue or organ resulting from excessive fibroblast proliferation and extracellular matrix production. Currently, there is no efficient treatment for fibrosis. Herein, we test effects of the drug mithramycin, which targets the Sp1 family of transcription factors, on mRNA expression by human gingival fibroblasts. Mithramycin reduced expression of connective tissue growth factor and type I collagen mRNAs. Microarray profiling revealed that mithramycin selectively blocked expression of cell proliferation and transforming growth factor-beta (TGF-ß) signalling clusters. These microarray data were validated using real-time polymerase chain reaction and western blot analyses. Mithramycin suppressed expression of key profibrotic TGF-ß signalling mediators, Smad3 and p300, as well as cell proliferation. Taken together, these data suggest that the Sp1 family of transcription factors may contribute to expression of fibrogenic genes in human gingival fibroblasts; drugs targeting the Sp1 family may be beneficial in treatment of fibro-proliferative diseases.

Corticosteroids and glaucoma risk.

Corticosteroids (glucocorticoids), used frequently as potent anti-inflammatory agents, increase the risk of glaucoma by raising the intraocular pressure (IOP) when administered exogenously (topically, periocularly or systemically) and in certain conditions of increased endogenous production (e.g. Cushing's syndrome). Approximately 18 to 36% of the general population are corticosteroid responders. This response is increased to 46 to 92% in patients with primary open-angle glaucoma (POAG). Patients over 40 years of age and with certain systemic diseases (e.g. diabetes mellitus, high myopia) as well as relatives of patients with POAG are more vulnerable to corticosteroid-induced glaucoma. The association of corticosteroid-induced ocular hypertension in other conditions which are considered as risk factors for glaucoma (racial origins, hypertension, migraine, vasospasm) is likely but not fully established. The proposed mechanism of corticosteroid-induced glaucoma includes morphological and functional changes in the trabecular meshwork system and is similar to the pathogenesis of POAG. Trabecular cells exposed to corticosteroids in vitro show endoreplication of nuclei, an increase in cell size and excessive production of an approximately 56kD glycoprotein, identified as myocilin and transcribed by the GLC1A gene. Induction of ocular hypertension after corticosteroid administration depends on the specific drug, the dose, the frequency of administration and the corticosteroid responsiveness of the patient. The risk of corticosteroid-induced glaucoma can be minimised with judicious use of corticosteroids, as well as education of patients and medical practitioners. New treatment modalities include modified steroids and nonsteroidal anti-inflammatory agents that will have less effect on the elevation of IOP.