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Ramez I. Haddadin, Dong-Jin Oh, E. H. Sage, Douglas J. Rhee; Dexamethasone Administration Decreases SPARC Expression in Human Trabecular Meshwork and Increases IOP in SPARC-null Mice. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5920.
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SPARC is a matricellular protein associated with profibrotic states that is located within a known primary open-angle glaucoma (POAG) locus, 5q22.1-q32 (GLC1M). SPARC-null mice exhibit a 15-20% lower intraocular pressure (IOP). Steroid-induced glaucoma and POAG both result from increased outflow resistance. SPARC may be part of the pathophysiology of steroid-induced glaucoma as well. We studied the effect of dexamethasone (DEX) on the IOP of SPARC-null (KO) and wild-type (WT) mice as well as on SPARC protein and mRNA levels in vitro.
Five to six week-old WT and KO mice were fed ad lib and given drinking water containing 10 mg/L of dexamethasone sodium phosphate. IOPs were measured with the TonoLab tonometer prior to starting treatment, weekly during treatment, and 4 days after stopping treatment. We also incubated trabecular meshwork (TM) and ciliary body smooth muscle (CBSM) cells with DEX for 1, 3, and 7 days. Expression of SPARC mRNA, cell/extracellular matrix (ECM)-bound protein, and soluble protein secreted into the culture media were measured by real-time RT-PCR, western blotting, and ELISA, respectively.
Average IOP measurements of WT mice treated with DEX and control were 21.3, 22.4, 24.5, 19.7, 20.7, 19.5 mm Hg; and 21.2, 20.5, 22.7, 19.6, 19.4, 18.9 mm Hg at 0, 1, 2, 3, 4, and 4.5 weeks, respectively (n=22, 20; p>0.05 at all time points). Average IOP measurements of SPARC-null mice treated with DEX and control were 17.7, 19.6, 20.8, 20.5, 19.2, 18.5 mm Hg; and 16.9, 16.4, 17.8, 17.9, 16.9, 17.9 mm Hg at 0, 1, 2, 3, 4, and 4.5 weeks, respectively (n=20, 18; p<0.05 at 1, 2, 3 and 4 weeks). KO mice exhibited proportionally greater peak elevations in IOP at 1 week (19.2% versus 9.7%). Compared to control-treated TM cells, cells incubated with DEX showed a significant decrease in SPARC mRNA levels at 3- and 7-days, by 0.323- and 0.372-fold, respectively (p <0.05). Cell/ECM-bound SPARC protein in TM cells was decreased at 1-, 3-, and 7-days, by 30.8, 20.1, and 17.6% (p <0.05). Soluble, secreted SPARC protein was unchanged at all time points. CBSM cells exhibited no significant changes in SPARC mRNA, or protein levels.
Administration of DEX resulted in statistically significant IOP elevations in SPARC-null mice but not in WT mice. Incubation with DEX lowered cell/ECM-bound SPARC protein and mRNA levels in TM but not CBSM cells. SPARC may play a counter-regulatory role in steroid-induced glaucoma.
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