Unraveling the in vivo role of MMP-2 and MT1-MMP in mammalian axonal regeneration
Het herstellen van het centraal zenuwstelsel,
vandaag en morgen
De ziekte van Alzheimer, de ziekte van Parkinson, de ziekte van Huntington, multiple sclerose, glaucoom, het zijn maar enkele van de meer dan 600 neurodegeneratieve aandoeningen waarbij na verloop van tijd zenuwcellen afsterven. Dit laatste is onomkeerbaar en leidt tot symptomen als dementie, slikproblemen, bewegings-, loop-, of spraakstoornissen. Wat is nu de exacte oorzaak waardoor het centraal zenuwstelsel (CZS) van de mens zich niet spontaan kan herstellen? Rond deze vraag gebeurt heel wat onderzoek waaronder deze studie die specifiek de focus legt op matrix metalloproteinases (MMP’s), meer bepaald MMP-2 en MT1-MMP. Dit zijn eiwitten die een invloed kunnen hebben op de capaciteit om axonen (uitlopers van de zenuwcellen) in het CZS te regenereren.
Het belang van neurobiologisch onderzoek!
Neurodegeneratieve aandoeningen vormen een uitdaging voor de gezondheidszorg. Enerzijds blijft de vraag: ‘Wat is de oorzaak van neurodegeneratieve ziekten?’ onbeantwoord. Op een paar uitzonderingen na is de oorzaak van degeneratie van zenuwcellen bij deze ziekten niet gekend en zijn er nog geen geneesmiddelen of behandelingen die het ziekteproces kunnen vertragen of verhinderen. Momenteel zijn er enkel therapieën beschikbaar die de symptomen (tijdelijk) kunnen verlichten, zonder de vooruitgang van de ziekte te stoppen. Anderzijds komen deze aandoeningen meestal voor op latere leeftijd en treffen, met de toenemende vergrijzing, een steeds groter wordende groep mensen. De Wereldgezondheidsorganisatie voorspelt dat in 2040 neurodegeneratieve aandoeningen, kanker zullen inhalen en de tweede belangrijkste doodsoorzaak zullen worden na hart- en vaatziekten. Daarom is fundamenteel neurobiologisch onderzoek, dat de ziektemechanismen probeert te ontrafelen en gevonden inzichten vertaalt naar nieuwe behandelingen voor deze aandoeningen, van zeer groot belang.
Regeneratiemogelijkheid
In de embryonale en postnatale fase van de ontwikkeling van zoogdieren kan regeneratie van beschadigde zenuwbanen optreden in het CZS. Volwassen zoogdieren verliezen echter deze capaciteit. Na beschadiging, treedt er een beperkte periode van axonuitgroei op, maar zonder verlenging, wat uiteindelijk leidt tot axonale degeneratie en celdood. Wat stopt het axonale regeneratieproces? Welke factoren ontbreken ten opzichte van het embryo? Onderzoek naar deze mechanismen kan nieuwe inzichten leveren in hoe regeneratie in het CZS van volwassen zoogdieren kan geïnduceerd worden.
Hulp uit ‘onverwachte’ hoek
Ondanks intensieve onderzoeksinspanningen blijft de volledige regeneratie van axonen en het functioneel herstel van het beschadigde CZS van zoogdieren een uitdaging. Dit maakt het zoeken naar nieuwe moleculen die betrokken zijn bij het herstellen van axonen onmisbaar. Het gebruik van de oogzenuw als een model voor axonale regeneratie in het CZS, heeft aanzienlijke vooruitgang geboekt in het identificeren van de oorzaken van de beperkte regeneratie in het CZS van volwassen zoogdieren. Een belangrijk modelorganisme in neurobiologisch onderzoek is de muis. Het feit dat het genoom van de muis 95% gelijkenis vertoont met dat van de mens maakt deze nieuwe inzichten bijzonder vertaalbaar naar humane ziekten. Daarenboven zijn er al heel wat onderzoeksmethodes in de muis geoptimaliseerd. De oogzenuw wordt vaak gebruikt in het onderzoek naar axonale regeneratie in het CZS. Hierbij worden de muizen onderworpen aan het RONC (regenerative optic nerve crush) model waarbij eerst de oogzenuw beschadigd wordt gevolgd door inductie van regeneratie in het CZS.
MMP’s als oplossing?
In dit project wordt gezocht naar de rol van MMP’s als regeneratie-inducerende moleculen. MMP’s kennen vele functies en worden vergeleken met het Chinese concept, yin en yang. Enerzijds zijn ze van essentieel belang voor de ontwikkeling en het behoud van het CZS, anderzijds wordt een MMP overmaat vaak geassocieerd met neurologische ziektebeelden. MMP activiteit moet dus gebalanceerd zijn. Uit recente ex vivo (experimenten op weefsel in een externe omgeving) studies blijkt dat MMP-2 en MT1-MMP een positieve rol spelen in het ontwikkelen en herstellen van axonen. Een volgende stap is om deze data te bevestigen in vivo (experimenten op weefsel binnen het lichaam) via het gebruik van het RONC model.
De knock-out van MMP-2 of MT1-MMP
Zorgt de aanwezigheid van MMP-2 of MT1-MMP voor een betere regeneratie van de axonen na het beschadigen van de oogzenuw? Om deze vraag te beantwoorden, wordt onderzocht of het uitschakelen van het Mmp‑2 of het Mt1-mmp gen een effect heeft op de axonale regeneratie in de oogzenuw van volwassen muizen. De axonale regeneratie in muizen waarvan het Mmp‑2 of het Mt1-mmp gen al dan niet uitgeschakeld is, wordt vergeleken op verschillende afstanden na beschadiging.
Na analyse van de onderzoeksresultaten wordt vastgesteld dat er significant minder regeneratie zichtbaar is bij muizen waar het gen voor MMP-2 uitgeschakeld is (Mmp-2-/- muizen) ten opzichte van muizen waar het gen voor MMP-2 niet uitgeschakeld is (wild-type muizen). Het aantal regenererende axonen in Mmp-2-/- muizen is, op elke afstand gemeten, tussen 40-50% lager dan in wild-type muizen (figuur bijlage). Er zijn minder en kortere axonen in Mmp-2-/- muizen. MMP-2 is dus noodzakelijk voor succesvolle regeneratie van axonen in de oogzenuw.
Het uitschakelen van het Mt1-mmp gen vertoont een trend naar een verminderde regeneratie in het CZS hoewel deze resultaten niet statistisch significant zijn. Daarnaast heeft MT1-MMP een subtieler effect op de regeneratie dan MMP-2.
Er kan geconcludeerd worden dat MMP-2, en mogelijk ook MT1-MMP, een belangrijke rol spelen bij het induceren van regeneratie na beschadiging van het CZS in volwassen zoogdieren.
En nu?
Samengevat, de huidige in vivo studie levert het bewijs voor de betrokkenheid van MMP-2 en MT1-MMP in axonale regeneratie wat overeenkomt met eerdere ex vivo studies.
De huidige studie maakt gebruik van genetisch gemanipuleerde muizen. Verder onderzoek kan gebruikmaken van farmacologische methodes zoals het toedienen van extra MMP’s of van MMP inhibitoren. Het uiteindelijke doel van dit fundamenteel onderzoek is inzicht te verwerven in de moleculen en hun werkingsmechanismen die een invloed hebben op de regeneratie van de axonen. Op lange termijn kan dit leiden tot de identificatie van nieuwe, MMP-gebaseerde benaderingen voor het induceren van axonale regeneratie en, meer algemeen, herstel van het CZS. De nieuwe inzichten kunnen bijdragen tot het ontwikkelen van behandelingen voor o.a. de ziekte van Alzheimer, de ziekte van Parkinson, de ziekte van Huntington, multiple sclerose, glaucoom en andere neurodegeneratieve aandoeningen.
‘Neurology takes us right to the heart of the question of who we are’
Vilayanur S. Ramachandran
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