Fracture repair requires TrkA signaling by skeletal sensory nerves

Journal of Clinical Investigation, Journal Year: 2019, Volume and Issue: 129(12), P. 5137 - 5150

Published: Oct. 21, 2019

Bone is richly innervated by nerve growth factor–responsive (NGF-responsive) tropomyosin receptor kinase A–expressing (TrKa-expressing) sensory fibers, which are required for osteochondral progenitor expansion during mammalian skeletal development. Aside from pain sensation, little known regarding the role of innervation in bone repair. Here, we characterized reinnervation tissue following experimental ulnar stress fracture and assessed impact loss TrkA signaling this process. Sequential histological data obtained reporter mice subjected to demonstrated a marked upregulation NGF expression periosteal stromal progenitors fracture-associated macrophages. Sprouting arborization CGRP+TrkA+ fibers within reactive periosteum NGF-enriched cellular domains were evident at time points preceding vascularization, ossification, mineralization. Temporal inhibition catalytic activity administration 1NMPP1 TrkAF592A significantly reduced numbers blunted revascularization, delayed ossification callus. We observed similar deficiencies regrowth healing mouse model peripheral neuropathy induced paclitaxel treatment. Together, our studies demonstrate an essential repair implicate nerves as important upstream mediator

Language: Английский

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NGF-TrkA signaling in sensory nerves is required for skeletal adaptation to mechanical loads in mice

Proceedings of the National Academy of Sciences, Journal Year: 2017, Volume and Issue: 114(18)

Published: April 17, 2017

Significance Peripheral sensory nerves expressing TrkA, the high-affinity receptor for NGF, densely innervate surfaces of long bones, a privileged location regulation biomechanical signaling. In this study, we used several genetically engineered mouse models to examine role NGF-TrkA signaling in skeletal adaptation mechanical loads. Our results support model which signals up-regulate expression NGF osteoblasts on bone surface that, turn, activates TrkA nerves, leading release osteogenic cues that modulate osteocytic Wnt/β-catenin and formation.

Language: Английский

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Use of human neuroblastoma SH-SY5Y cells to evaluate glyphosate-induced effects on oxidative stress, neuronal development and cell death signaling pathways

Environment International, Journal Year: 2019, Volume and Issue: 135, P. 105414 - 105414

Published: Dec. 23, 2019

Glyphosate-containing herbicides are the most used agrochemicals in world. Their indiscriminate application raises some concerns regarding possible health and environmental hazards. In this study, we investigated human neuroblastoma cell line SH-SY5Y if oxidative stress, altered neurodevelopment death pathways involved response to glyphosate its metabolite aminomethylphosphonic acid (AMPA) exposures. MTT LDH assays were carried out assess AMPA cytotoxicity. Lipid peroxides measured as malondialdehyde (MDA), nitric oxide (NO) reactive oxygen species (ROS) production, caspase-Glo 3/7 activity evaluated. The neuroprotective role of melatonin (MEL), Trolox, N-acetylcysteine (NAC) Sylibin against glyphosate- AMPA-induced stress was examined. Glyphosate effects on neuronal development related gene transcriptions, expression profiling by Real-Time PCR array also investigated. (5 mM) (10 induced a significant increase MDA levels, NO ROS production caspase activity. exposure up-regulation Wnt3a, Wnt5a, Wnt7a, CAMK2A, CAMK2B down-regulation GAP43 TUBB3 mRNA normal neural development. relation pathways, 84 genes examined cells greater than 2-fold change observed for APAF1, BAX, BCL2, CASP3, CASP7, CASP9, SYCP2, TNF, TP53, CTSB, NFκB1, PIK3C3, SNCA, SQSTMT, HSPBAP1 KCNIPI These data can help define neurotoxic mechanisms AMPA. Our results demonstrated that cytotoxic development, via apoptotic, autophagy necrotic confirmed becomes concern. This study demonstrates could be considered an vitro system pesticide screening.

Language: Английский

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Glucose, glycolysis, and neurodegenerative diseases

Journal of Cellular Physiology, Journal Year: 2020, Volume and Issue: 235(11), P. 7653 - 7662

Published: April 2, 2020

Abstract Prolonged survival of a typical postmitotic neuron hinges on balance between multiple processes, among these are sustenance ATP production and protection against reactive oxygen species. In neuropathological conditions, mitochondrial defects often lead to both drop in levels, as well increase species from inefficient electron transport processes NADPH‐oxidases activities. The former resulted the phenomenon compensatory aerobic glycolysis. latter stretches capacity cell's redox buffering capacity, may damages key enzymes involved energy metabolism. Several recent reports have indicated that enhancing glucose availability uptake, increasing glycolytic flux via pharmacological or genetic manipulation enzymes, could be protective animal models several major neurodegenerative diseases, including Parkinson's disease, Huntington's Amyotrophic lateral sclerosis. Activation canonical Wnt signaling, which improves disease symptoms mouse Alzheimer's also appears work an elevation enhance Here, I discuss findings possible underlying mechanisms how uptake glycolysis neuroprotective. Increased would help alleviate deficiency, ATP's hydrotropic effect solubility clearance toxic aggregates prevalent many diseases. Furthermore, channeling into Pentose Phosphate Pathway cell.

Language: Английский

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Parkinson's disease, aging and adult neurogenesis: Wnt/β‐catenin signalling as the key to unlock the mystery of endogenous brain repair

Aging Cell, Journal Year: 2020, Volume and Issue: 19(3)

Published: Feb. 12, 2020

Abstract A common hallmark of age‐dependent neurodegenerative diseases is an impairment adult neurogenesis. Wingless‐type mouse mammary tumor virus integration site (Wnt)/β‐catenin (WβC) signalling a vital pathway for dopaminergic (DAergic) neurogenesis and essential system during embryonic development aging, the most critical risk factor Parkinson's disease (PD). To date, there no known cause or cure PD. Here we focus on potential to reawaken impaired neurogenic niches rejuvenate repair aged PD brain. Specifically, highlight WβC ‐ in plasticity subventricular zone (SVZ), largest germinal region mature brain innervated by nigrostriatal DAergic terminals, mesencephalic aqueduct‐periventricular (Aq‐PVR) Wnt‐sensitive niche, which proximity SNpc harbors neural stem progenitor cells (NSCs) with potential. The cytosolic accumulation β‐catenin, enters nucleus associates T cell factor/lymphoid enhancer binding (TCF/LEF) transcription factors, leading Wnt target genes. Here, underscore dynamic interplay between innervation astroglial‐derived factors regulating WβC‐dependent key genes orchestrating NSC proliferation, survival, migration differentiation. Aging, inflammation oxidative stress synergize neurotoxin exposure “turning off” switch via down‐regulation nuclear erythroid‐2‐related 2/Wnt‐regulated signalosome, player maintenance antioxidant self‐defense mechanisms homeostasis. Harnessing WβC‐signalling can thus restore neurogenesis, microenvironment, promote neurorescue regeneration.

Language: Английский

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