TGF-β regulates nerve growth factor expression in a mouse intervertebral disc injury model

Abstract Background Intervertebral disc (IVD) degeneration is a major cause of low back pain (LBP). Following disc injury, nerve growth factor (NGF) concentrations rise in IVDs, and anti-NGF therapy has been shown to attenuate LBP in humans. Increased levels of tumor necrosis factor-α (TNF-α) and transforming growth factor-β (TGF-β) in degenerative IVDs and in in vitro studies suggest that these factors promote NGF production. However, whether these factors regulate NGF in vivo remains unclear. Thus, we studied NGF regulation in a mouse model of IVD injury. Methods After inducing IVD injury, we examined mRNA levels of Tnfa, Tgfb, and Ngf in IVDs from control and IVD-injured mice across 7 days. To do this, we used magnetic cell separation to isolate CD11b ( +) (macrophage-rich) and CD11b (-) (IVD cell-rich) cell fractions from injured IVDs. To study the effect of TNF-α on Ngf expression, we examined Ngf expression in injured IVDs from C57BL/6 J and Tnfa-knockout (KO) mice (C57BL/6 J background). To study the effect of TGF-β on Ngf expression, C57/BL6J mice were given an intraperitoneal injection of either the TGF-β inhibitor SB431542 or DMSO solution (vehicle) one and two days before harvesting IVDs. Results mRNA expression of Tnfa, Tgfb, and Ngf was significantly increased in injured IVDs. Tnfa was predominantly expressed in the CD11b ( +) fraction, and Tgfb in the CD11b (-) fraction. Ngf expression was comparable between CD11b ( +) and CD11b (-) fractions, and between wild-type and Tnfa-KO mice at post-injury day (PID) 1, 3, and 7. SB431542 suppressed TGF-β-mediated Ngf expression and NGF production in vitro. Further, administration of SB431542 significantly reduced Ngf expression in IVDs such that levels were below those observed in vehicle-treated animals at PID3 and PID7. Conclusion A TGF-β inhibitor reduced Ngf expression in a mouse model of IVD injury, suggesting that TGF-β may regulate NGF expression in vivo.

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Gangliosides potentiate in vivo and in vitro effects of nerve growth factor on central cholinergic neurons.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.86.6.2056 ◽

1989 ◽

Vol 86 (6) ◽

pp. 2056-2060 ◽

Cited By ~ 102

Author(s):

A. C. Cuello ◽

L. Garofalo ◽

R. L. Kenigsberg ◽

D. Maysinger

Keyword(s):

Nerve Growth Factor ◽

Growth Factor ◽

Cholinergic Neurons ◽

Nerve Growth ◽

In Vitro Effects

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Cartilage injury regulates nerve growth factor (NGF) in vitro and in vivo and drives painful behaviour in murine OA

Osteoarthritis and Cartilage ◽

10.1016/j.joca.2014.02.084 ◽

2014 ◽

Vol 22 ◽

pp. S35

Author(s):

C. Driscoll ◽

A. Chanalaris ◽

C. Knight ◽

C. Gentry ◽

S. Bevan ◽

...

Keyword(s):

Nerve Growth Factor ◽

Growth Factor ◽

Cartilage Injury ◽

Nerve Growth

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The in vitro effect of the nerve growth factor on chick embryo spinal ganglia—a light-microscopic evaluation

Development ◽

10.1242/dev.24.2.381 ◽

1970 ◽

Vol 24 (2) ◽

pp. 381-392

Author(s):

Peddrick Weis

Keyword(s):

Nerve Growth Factor ◽

Growth Factor ◽

Chick Embryo ◽

Culture Period ◽

Spinal Ganglia ◽

Nerve Growth ◽

Microscopic Evaluation ◽

Vitro Effect

The effect of the nerve growth factor (NGF) on chick embryo spinal ganglia was studied in the hanging-drop bioassay system by comparison with parallel development in vivo. The well-differentiated ventrolateral neuroblasts, which in vivo increase 1·33 times in size during the culture period, did not increase in size at all in vitro. Only 65–72% survived to the end of the culture period regardless of the NGF concentration. The less-differentiated mediodorsal (M-D) neuroblasts, which in vivo increase 1·31 times in size during the culture period, were found to increase equally in vitro if sufficient NGF was present. Such a quantity was greater than that which evoked maximum outgrowth of neurites. Survival of M-D neuroblasts was also related to NGF concentration but did not equal the in vivo condition even at the highest concentration. The hyperchromatic type of degeneration prevented by high NGF concentrations is that which results in vivo from insufficient peripheral field. From this and other reports it would appear that the response to NGF seen in vitro is due only to the M-D neuroblasts, and that all biochemical and cytological observations which have been reported would therefore represent conditions within those cells only.

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Multiple myeloma increases nerve growth factor and other pain-related markers through interactions with the bone microenvironment

Scientific Reports ◽

10.1038/s41598-019-50591-5 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 3

Author(s):

Sam W. Z. Olechnowicz ◽

Megan M. Weivoda ◽

Seint T. Lwin ◽

Szi K. Leung ◽

Sarah Gooding ◽

...

Keyword(s):

Multiple Myeloma ◽

Nerve Growth Factor ◽

Growth Factor ◽

Cell Activation ◽

Cellular Interactions ◽

Bone Microenvironment ◽

Related Factors ◽

Nerve Growth ◽

Tnf Α

Abstract Interactions between multiple myeloma (MM) and bone marrow (BM) are well documented to support tumour growth, yet the cellular mechanisms underlying pain in MM are poorly understood. We have used in vivo murine models of MM to show significant induction of nerve growth factor (NGF) by the tumour-bearing bone microenvironment, alongside other known pain-related characteristics such as spinal glial cell activation and reduced locomotion. NGF was not expressed by MM cells, yet bone stromal cells such as osteoblasts expressed and upregulated NGF when cultured with MM cells, or MM-related factors such as TNF-α. Adiponectin is a known MM-suppressive BM-derived factor, and we show that TNF-α-mediated NGF induction is suppressed by adiponectin-directed therapeutics such as AdipoRON and L-4F, as well as NF-κB signalling inhibitor BMS-345541. Our study reveals a further mechanism by which cellular interactions within the tumour-bone microenvironment contribute to disease, by promoting pain-related properties, and suggests a novel direction for analgesic development.

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In Vitro and in Vivo Methods for Evaluating Actions of Cytokines on Nerve Growth Factor Production in Central Nervous System

Methods in Neurosciences - Neurobiology of Cytokines ◽

10.1016/s1043-9471(13)70008-9 ◽

1993 ◽

pp. 37-60 ◽

Cited By ~ 6

Author(s):

Dan Lindholm ◽

Bastian Hengerer ◽

Eero Ċastrén

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Nerve Growth Factor ◽

Growth Factor ◽

Nerve Growth ◽

Factor Production ◽

Growth Factor Production

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MicroRNA-98 reduces nerve growth factor expression in nicotine-induced airway remodeling

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.012019 ◽

2020 ◽

Vol 295 (52) ◽

pp. 18051-18064

Author(s):

Cherry Wongtrakool ◽

Junsuk Ko ◽

Andrew J. Jang ◽

Kora Grooms ◽

Sarah Chang ◽

...

Keyword(s):

Nerve Growth Factor ◽

Growth Factor ◽

Airway Remodeling ◽

Luciferase Reporter ◽

Mouse Lung ◽

Luciferase Expression ◽

Nerve Growth ◽

Pparγ Agonist

Evolving evidence suggests that nicotine may contribute to impaired asthma control by stimulating expression of nerve growth factor (NGF), a neurotrophin associated with airway remodeling and airway hyperresponsiveness. We explored the hypothesis that nicotine increases NGF by reducing lung fibroblast (LF) microRNA-98 (miR-98) and PPARγ levels, thus promoting airway remodeling. Levels of NGF, miR-98, PPARγ, fibronectin 1 (FN1), endothelin-1 (EDN1, herein referred to as ET-1), and collagen (COL1A1 and COL3A1) were measured in human LFs isolated from smoking donors, in mouse primary LFs exposed to nicotine (50 μg/ml), and in whole lung homogenates from mice chronically exposed to nicotine (100 μg/ml) in the drinking water. In selected studies, these pathways were manipulated in LFs with miR-98 inhibitor (anti-miR-98), miR-98 overexpression (miR-98 mimic), or the PPARγ agonist rosiglitazone. Compared with unexposed controls, nicotine increased NGF, FN1, ET-1, COL1A1, and COL3A1 expression in human and mouse LFs and mouse lung homogenates. In contrast, nicotine reduced miR-98 levels in LFs in vitro and in lung homogenates in vivo. Treatment with anti-miR-98 alone was sufficient to recapitulate increases in NGF, FN1, and ET-1, whereas treatment with a miR-98 mimic significantly suppressed luciferase expression in cells transfected with a luciferase reporter linked to the putative seed sequence in the NGF 3′UTR and also abrogated nicotine-induced increases in NGF, FN1, and ET-1 in LFs. Similarly, rosiglitazone increased miR-98 and reversed nicotine-induced increases in NGF, FN1, and ET-1. Taken together, these findings demonstrate that nicotine-induced increases in NGF and other markers of airway remodeling are negatively regulated by miR-98.

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Involvement of a metalloprotease in low-affinity nerve growth factor receptor truncation: inhibition of truncation in vitro and in vivo

Journal of Neuroscience ◽

10.1523/jneurosci.13-06-02405.1993 ◽

1993 ◽

Vol 13 (6) ◽

pp. 2405-2414 ◽

Cited By ~ 33

Author(s):

PS DiStefano ◽

DM Chelsea ◽

CM Schick ◽

JF McKelvy

Keyword(s):

Nerve Growth Factor ◽

Growth Factor ◽

Growth Factor Receptor ◽

Nerve Growth Factor Receptor ◽

Nerve Growth

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Rescue of α-SNS Sodium Channel Expression in Small Dorsal Root Ganglion Neurons After Axotomy by Nerve Growth Factor In Vivo

Journal of Neurophysiology ◽

10.1152/jn.1998.79.5.2668 ◽

1998 ◽

Vol 79 (5) ◽

pp. 2668-2676 ◽

Cited By ~ 125

Author(s):

S. D. Dib-Hajj ◽

J. A. Black ◽

T. R. Cummins ◽

A. M. Kenney ◽

J. D. Kocsis ◽

...

Keyword(s):

Nerve Growth Factor ◽

Growth Factor ◽

Dorsal Root Ganglion ◽

Sodium Channel ◽

Dorsal Root ◽

Sodium Current ◽

Mrna Levels ◽

Drg Neurons ◽

Nerve Growth

Dib-Hajj, S. D., J. A. Black, T. R. Cummins, A. M. Kenney, J. D. Kocsis, and S. G. Waxman. Rescue of α-SNS sodium channel expression in small dorsal root ganglion neurons after axotomy by nerve growth factor in vivo. J. Neurophysiol. 79: 2668–2676, 1998. Small (18–25 μm diam) dorsal root ganglion (DRG) neurons are known to express high levels of tetrodotoxin-resistant (TTX-R) sodium current and the mRNA for the α-SNS sodium channel, which encodes a TTX-R channel when expressed in oocytes. These neurons also preferentially express the high affinity receptor for nerve growth factor (NGF), TrkA. Levels of TTX-R sodium current and of α-SNS mRNA are reduced in these cells after axotomy. To determine whether NGF participates in the regulation of TTX-R current and α-SNS mRNA in small DRG neurons in vivo, we axotomized small lumbar DRG neurons by sciatic nerve transection and administered NGF or Ringer solution to the proximal nerve stump using osmotic pumps. Ten to 12 days after pump implant, whole cell patch-clamp recording demonstrated that TTX-R current density was decreased in Ringer-treated axotomized neurons (154 ± 45 pA/pF; mean ± SE) compared with nonaxotomized control neurons (865 ± 123 pA/pF) and was restored partially toward control levels in NGF-treated axotomized neurons (465 ± 78 pA/pF). The V 1/2 for steady-state activation and inactivation of TTX-R currents were similar in control, Ringer- and NGF-treated axotomized neurons. Reverse transcription polymerase chain reaction revealed an upregulation of α-SNS mRNA levels in NGF-treated compared with Ringer-treated axotomized DRG. In situ hybridization showed that α-SNS mRNA levels were decreased significantly in small Ringer-treated axotomized DRG neurons in vivo and also in small DRG neurons that were dissociated and maintained in vitro, so as to correspond to the patch-clamp conditions. NGF-treated axotomized neurons had a significant increase in α-SNS mRNA expression, compared with Ringer-treated axotomized cells. These results show that the administration of exogenous NGF in vivo, to the proximal nerve stump of the transected sciatic nerve, results in an upregulation of TTX-R sodium current and of α-SNS mRNA levels in small DRG neurons. Retrogradely transported NGF thus appears to participate in the control of excitability in these cells via actions that include the regulation of sodium channel gene expression in vivo.

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