Abstract
ABSTRACTLevels 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.
Highlights
Transthyretin (TTR)-related amyloidosis is the most common form of hereditary autosomic dominant systemic amyloidoses; TTR point mutations lead to the extracellular deposition of amyloidogenic species in different tissues (Benson and Kincaid, 2007)
Disease Models & Mechanisms (2017) 10, 1253-1260 doi:10.1242/dmm.028571 (AD), matrix metalloproteases (MMPs)-14 was found overexpressed in brain (Yamada et al, 1995), which was later corroborated by studies using a transgenic mouse model where MMP-14 was found in reactive astrocytes, in regions with fibrillar amyloid deposits (Liao and Van Nostrand, 2010)
Overexpression of MMP-14 correlates with TTR non-fibrillar deposition in the nerve of a Familial amyloidotic polyneuropathy (FAP) mouse model We started by analyzing MMP-14 expression in sciatic nerve from 6-month-old Hsf/V30M mice (Hsf-1-deficient mice transgenic for human TTR V30M, in the Sv/129 and endogenous Ttr-null background) by both immunohistochemistry (IHC) and quantitative real-time polymerase chain reaction
Summary
Transthyretin (TTR)-related amyloidosis is the most common form of hereditary autosomic dominant systemic amyloidoses; TTR point mutations lead to the extracellular deposition of amyloidogenic species in different tissues (Benson and Kincaid, 2007). The mechanisms leading to TTR deposition comprise an alteration in the conformational stability of the homotetrameric form, followed by the deposition of unfolded monomers, aggregates or amyloid fibers (Quintas et al, 2001), the mechanisms mediating cytotoxicity in FAP are not completely understood Several molecular pathways, such as oxidative stress, apoptosis, the heat-shock response and extracellular matrix remodeling, have been implicated in the pathogenesis of FAP (Saraiva et al, 2012). The disclosure of novel mechanisms and disease modifying agents underlying nerve degeneration is essential to understand disease progression In this regard, work on high-throughput gene arrays has shown that matrix metalloproteinase-9 (MMP-9) was increased in FAP and is able to in vitro degrade TTR aggregates and fibrils (Sousa et al, 2005). MMP-9 is transcriptionally upregulated by NF-κB, a transcription factor that is activated in FAP nerves
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