Abstract
Retinitis pigmentosa (RP), an inherited retinal degenerative disease, is characterized by a progressive loss of rod photoreceptors followed by loss of cone photoreceptors. Previously, when tissue inhibitor of metalloproteinase 1 (TIMP1), a key extracellular matrix (ECM) regulator that binds to and inhibits activation of Matrix metallopeptidase 9 (MMP9) was intravitreal injected into eyes of a transgenic rhodopsin rat model of RP, S334ter-line3, we discovered cone outer segments are partially protected. In parallel, we reported that a specific MMP9 and MMP2 inhibitor, SB-3CT, interferes with mechanisms leading to rod photoreceptor cell death in an MMP9 dependent manner. Here, we extend our initial rat studies to examine the potential of TIMP1 as a treatment in retinal degeneration by investigating neuroprotective effects in a classic mouse retinal degeneration model, rdPde6b-/- (rd1). The results clearly demonstrate that intravitreal injections of TIMP1 produce extended protection to delay rod photoreceptor cell death. The mean total number of rods in whole-mount retinas was significantly greater in TIMP-treated rd1 retinas (postnatal (P) 30, P35 (P<0.0001) and P45 (P<0.05) than in saline-treated rd1 retinas. In contrast, SB-3CT did not delay rod cell death, leading us to further investigate alternative pathways that do not involve MMPs. In addition to inducing phosphorylated ERK1/2, TIMP1 significantly reduces BAX activity and delays attenuation of the outer nuclear layer (ONL). Physiological responses using scotopic electroretinograms (ERG) reveal b-wave amplitudes from TIMP1-treated retinas are significantly greater than from saline-treated rd1 retinas (P<0.05). In later degenerative stages of rd1 retinas, photopic b-wave amplitudes from TIMP1-treated rd1 retinas are significantly larger than from saline-treated rd1 retinas (P<0.05). Our findings demonstrate that TIMP1 delays photoreceptor cell death. Furthermore, this study provides new insights into how TIMP1 works in the mouse animal model of RP.
Highlights
The cell-extracellular matrix (ECM) interaction influences cell survival by regulating gene expression, differentiation, and growth [1]
Our results demonstrate that TIMP1-mediated rod survival is MMP9-independent, at least in part, works through an ERK survival pathway in mouse rdPde6b-/- retina
In our previous report [38], we observed that up-regulation of MMP9 in S334ter-line3 retinas is associated with rod death and SB-3CT, a specific inhibitor of MMP2 and MMP9, dramatically inhibits up-regulated MMP9 expression by interfering with mechanisms that lead to MMP9-dependent apoptosis
Summary
The cell-extracellular matrix (ECM) interaction influences cell survival by regulating gene expression, differentiation, and growth [1]. The C-terminal domain of TIMPs activates cell survival in an MMP-independent manner through cell-signaling pathways [20, 21, 29]. TIMP1, through its C-terminal domain, has been linked to regulation of specific cell-signaling pathways to promote cellular growth and inhibit apoptosis [15, 16, 30, 31]. TIMP1 inhibition of apoptosis in various cells involves focal adhesion kinase (FAK) and mitogen-activated protein kinase (MAPK)-mediated cell survival signaling via cell surface receptors, CD63 and 1 integrin [27, 28], rather than regulation of cell interactions with ECM through MMP inhibitory activity [32, 33]
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