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Cheryl Mae Craft, Jung-a Shin, Yun Sung Eom, Wan-Qing Yu, Andrew J. Vargas, Ruqayyah A. Malik, Erika Baral, Eun-Jin Lee; Tissue Inhibitor of Metalloproteinase 1 Enhances Cell Survival in a Matrix Metalloproteinase Dependent Mechanism in the Rhodopsin S334ter-line 3 Retinitis Pigmentosa Model. Invest. Ophthalmol. Vis. Sci. 2016;57(12):1169.
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© ARVO (1962-2015); The Authors (2016-present)
Retinitis Pigmentosa (RP) leads to inherited retinal blindness with a loss of rods then cones. In a transgenic rat retina RP model, rhodopsin S334ter-line3, rods die in “hot spots (clusters)” and create holes in the rod mosaic resulting in cone ring formation.1 Homogeneity of cone mosaic is restored and cone outer segments are protected at later stages with Tissue Inhibitor of Metalloproteinase 1 (TIMP-1), a key extracellular matrix (ECM) regulator that binds to and inhibits Matrix Metalloproteinase (MMP)-9 activation.2-3 In the current study, the impact of TIMP-1 and MMP9 inhibition specificity using SB-3CT on rod death during various phases of S334ter-line3 rat were investigated.
Timed intravitreal injections of TIMP-1 or MMP9 inhibitor, SB-3CT, or saline to RP retinas at postnatal day (P) 30, 45, and 60, followed by processing of frozen retinas for immunohistochemistry of retinal tissue slices or whole mounts with photoreceptor specific antibodies (1D4, rhodopsin; M- and S-opsin)3 to investigate the impact of TIMP-1 or SB3-CT on rod survival using statistical methods to quantify the homogeneity and cluster-of-rod death structures.
Our results indicated that TIMP-1 and SB-3CT dramatically changed cone mosaic in similar manner in RP retina compared to saline. Simultaneously, they disrupted clustering-related cell death of rods in RP retinas to gain homogeneity. Lastly, the mean number of rods in 1mm2 was significantly larger in TIMP-1 injected RP retinas (7,399±1,237 at P30, 3,014±349 at P45 & 233±116 at P60) than age matched saline injected RP retinas (5,029±1,144 at P30, 499±160 at P45 & 20±9 at P60). The results were similar to SB-3CT injected RP retina. These results indicate that TIMP-1 interferes and delays rod death with in a MMP9-dependent manner.
TIMP-1 disrupts cluster rod death to prevent cone ring formation and slows rod cell death in a MMP9-dependent mechanism in the S344ter-line3 RP. Furthermore, novel insights are revealed on the pathway of how TIMP-1 promotes the survival of retinal photoreceptors. This approach may provide a potential therapeutic strategy using MMP9 inhibitors to slow photoreceptor loss and progression of RP.1 Lee et al., 2011. " Glia 59(7): 1107-1117.2Ji et al., 2015. IOVS 56(1): 352-364.3Shin et al., 2015. Exp Eye Res 140: 41-52.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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