MMP-14 overexpression correlates with the neurodegenerative process in familial amyloidotic polyneuropathy
Levels of matrix metalloproteases (MMPs) can be differentially regulated in response to injury or neurological diseases. For instance, it is known that selective and short-term inhibition of MMP-14, a membrane-type 1 MMP, accelerates axon regeneration. Because axon growth and regeneration is impaire...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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The Company of Biologists
2017-10-01
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| Series: | Disease Models & Mechanisms |
| Subjects: | |
| Online Access: | http://dmm.biologists.org/content/10/10/1253 |
| _version_ | 1818488354324348928 |
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| author | Diana Martins João Moreira Nádia Pereira Gonçalves Maria João Saraiva |
| author_facet | Diana Martins João Moreira Nádia Pereira Gonçalves Maria João Saraiva |
| author_sort | Diana Martins |
| collection | DOAJ |
| description | Levels of matrix metalloproteases (MMPs) can be differentially regulated in response to injury or neurological diseases. For instance, it is known that selective and short-term inhibition of MMP-14, a membrane-type 1 MMP, accelerates axon regeneration. Because axon growth and regeneration is impaired in familial amyloidotic polyneuropathy (FAP), a neurodegenerative disorder characterized by misfolding and deposition of mutant transthyretin (TTR) in the peripheral nervous system (PNS), we presently investigated the expression levels and the potential role for MMP-14 in this condition. By using cell culture studies, a mouse model of disease and human clinical samples, we observed that MMP-14: (i) is overexpressed in FAP nerves, correlating with TTR deposition; (ii) is upregulated in sciatic nerves from a preclinical transgenic mouse model, increasing with TTR deposition; (iii) levels in the PNS and plasma are rescued upon treatment of mice with anakinra or TTR siRNA, drugs acting over the IL-1 signaling pathway or TTR liver synthesis, respectively; (iv) increases in Schwann cells upon incubation with amyloid-like aggregates; and, finally, (v) is increased in plasma of FAP patients, correlating with disease progression. These results highlight the relevance of MMP-14 in the pathophysiology of FAP, suggesting not only a potential role for this molecule as a novel biomarker for therapy follow up, but also as a new potential therapeutic target. |
| first_indexed | 2024-12-10T16:50:01Z |
| format | Article |
| id | doaj.art-178da3dea7cb435380d42ac0e37521d3 |
| institution | Directory Open Access Journal |
| issn | 1754-8403 1754-8411 |
| language | English |
| last_indexed | 2024-12-10T16:50:01Z |
| publishDate | 2017-10-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-178da3dea7cb435380d42ac0e37521d32022-12-22T01:40:55ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112017-10-0110101253126010.1242/dmm.028571028571MMP-14 overexpression correlates with the neurodegenerative process in familial amyloidotic polyneuropathyDiana Martins0João Moreira1Nádia Pereira Gonçalves2Maria João Saraiva3 Instituto de Inovação e Investigação em Saúde (I3S), Universidade do Porto, R. Alfredo Allen 208, 4200-135 Porto, Portugal Instituto de Inovação e Investigação em Saúde (I3S), Universidade do Porto, R. Alfredo Allen 208, 4200-135 Porto, Portugal Instituto de Inovação e Investigação em Saúde (I3S), Universidade do Porto, R. Alfredo Allen 208, 4200-135 Porto, Portugal Instituto de Inovação e Investigação em Saúde (I3S), Universidade do Porto, R. Alfredo Allen 208, 4200-135 Porto, Portugal Levels of matrix metalloproteases (MMPs) can be differentially regulated in response to injury or neurological diseases. For instance, it is known that selective and short-term inhibition of MMP-14, a membrane-type 1 MMP, accelerates axon regeneration. Because axon growth and regeneration is impaired in familial amyloidotic polyneuropathy (FAP), a neurodegenerative disorder characterized by misfolding and deposition of mutant transthyretin (TTR) in the peripheral nervous system (PNS), we presently investigated the expression levels and the potential role for MMP-14 in this condition. By using cell culture studies, a mouse model of disease and human clinical samples, we observed that MMP-14: (i) is overexpressed in FAP nerves, correlating with TTR deposition; (ii) is upregulated in sciatic nerves from a preclinical transgenic mouse model, increasing with TTR deposition; (iii) levels in the PNS and plasma are rescued upon treatment of mice with anakinra or TTR siRNA, drugs acting over the IL-1 signaling pathway or TTR liver synthesis, respectively; (iv) increases in Schwann cells upon incubation with amyloid-like aggregates; and, finally, (v) is increased in plasma of FAP patients, correlating with disease progression. These results highlight the relevance of MMP-14 in the pathophysiology of FAP, suggesting not only a potential role for this molecule as a novel biomarker for therapy follow up, but also as a new potential therapeutic target.http://dmm.biologists.org/content/10/10/1253MMP-14Familial amyloidotic polyneuropathyNeurodegenerationNeuroinflammationPeripheral nervous system |
| spellingShingle | Diana Martins João Moreira Nádia Pereira Gonçalves Maria João Saraiva MMP-14 overexpression correlates with the neurodegenerative process in familial amyloidotic polyneuropathy Disease Models & Mechanisms MMP-14 Familial amyloidotic polyneuropathy Neurodegeneration Neuroinflammation Peripheral nervous system |
| title | MMP-14 overexpression correlates with the neurodegenerative process in familial amyloidotic polyneuropathy |
| title_full | MMP-14 overexpression correlates with the neurodegenerative process in familial amyloidotic polyneuropathy |
| title_fullStr | MMP-14 overexpression correlates with the neurodegenerative process in familial amyloidotic polyneuropathy |
| title_full_unstemmed | MMP-14 overexpression correlates with the neurodegenerative process in familial amyloidotic polyneuropathy |
| title_short | MMP-14 overexpression correlates with the neurodegenerative process in familial amyloidotic polyneuropathy |
| title_sort | mmp 14 overexpression correlates with the neurodegenerative process in familial amyloidotic polyneuropathy |
| topic | MMP-14 Familial amyloidotic polyneuropathy Neurodegeneration Neuroinflammation Peripheral nervous system |
| url | http://dmm.biologists.org/content/10/10/1253 |
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