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Non-invasive In Vivo Fluorescence Optical Imaging of Inflammatory MMP Activity Using an Activatable Fluorescent Imaging Agent
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MMP Inhibition Preserves Integrin Ligation and FAK Activation to Induce Survival and Regeneration in RGCs Following
Philippe M D'Onofrio1,2, Alireza P Shabanzadeh1,3, Brian K Choi1,2
1Division of Anatomy, Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
Investigative Ophthalmology & Visual Science
|February 12, 2019
Summary
Matrix metalloproteinases (MMPs) degrade extracellular matrix (ECM), harming retinal ganglion cells (RGCs). Inhibiting MMPs and activating focal adhesion kinase (FAK) promotes RGC survival and axon regeneration after optic nerve injury.
Area of Science:
- Neuroscience
- Cell Biology
- Ophthalmology
Background:
- Integrin-extracellular matrix (ECM) interactions are critical for retinal ganglion cell (RGC) survival.
- Optic nerve injury triggers matrix metalloproteinases (MMPs) that degrade the ECM, disrupting integrin signaling and causing RGC death.
Purpose of the Study:
- To investigate the roles of MMPs, integrins, and focal adhesion kinase (FAK) in RGC survival and axon regeneration following optic nerve injury.
- To elucidate the molecular mechanisms underlying RGC death and potential therapeutic targets.
Main Methods:
- Optic nerve transection and crush models were used to study RGC survival and regeneration.
- MMP activity, FAK activation, and integrin ligation were assessed using Western blot and immunohistochemistry.
- RGC survival and axon regeneration were quantified via microscopy and cell counting.
Main Results:
- MMP-9 expression significantly increased in RGCs post-injury.
- Inhibition of MMPs (pan-MMP, MMP-2/-9, MMP-3) markedly enhanced RGC survival and axon regeneration.
- FAK activation was crucial; FAK inhibition reduced RGC survival, while FAK activation promoted it, even with MMP activity present.
- Direct integrin ligation also improved RGC survival.
Conclusions:
- ECM-integrin ligation is a key pathway promoting RGC survival and axon regeneration.
- FAK activation mediates the neuroprotective effects of ECM-integrin interactions.
- Targeting MMPs and enhancing FAK activation represent promising therapeutic strategies for optic nerve injury.
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