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

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

BMC Musculoskeletal Disorders ◽

10.1186/s12891-021-04509-w ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Yuji Yokozeki ◽

Kentaro Uchida ◽

Ayumu Kawakubo ◽

Mitsufumi Nakawaki ◽

Tadashi Okubo ◽

...

Keyword(s):

Nerve Growth Factor ◽

Growth Factor ◽

Mouse Model ◽

Intervertebral Disc ◽

Mrna Levels ◽

Nerve Growth ◽

Tnf Α ◽

Disc Injury

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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The effect of nerve growth factor and its antibody on mast cells in vivo

Journal of Neuroimmunology ◽

10.1016/0165-5728(88)90129-4 ◽

1988 ◽

Vol 18 (1) ◽

pp. 1-12 ◽

Cited By ~ 57

Author(s):

L ALOE

Keyword(s):

Nerve Growth Factor ◽

Growth Factor ◽

Mast Cells ◽

Nerve Growth

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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 Biology of Nerve Growth Factor in Vivo

Neurobiology of Amino Acids, Peptides and Trophic Factors ◽

10.1007/978-1-4613-1721-0_7 ◽

1988 ◽

pp. 101-114 ◽

Cited By ~ 4

Author(s):

Eugene M. Johnson ◽

Pamela T. Manning ◽

Christine Wilcox

Keyword(s):

Nerve Growth Factor ◽

Growth Factor ◽

Nerve Growth

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Antihypernociceptive and Neuroprotective Effects of the Aqueous and Methanol Stem-Bark Extracts of Nauclea pobeguinii (Rubiaceae) on STZ-Induced Diabetic Neuropathic Pain

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/6637584 ◽

2021 ◽

Vol 2021 ◽

pp. 1-17

Author(s):

Eric Gonzal Tsafack ◽

Marius Mbiantcha ◽

Gilbert Ateufack ◽

Stephanie Flore Djuichou Nguemnang ◽

William Nana Yousseu ◽

...

Keyword(s):

Body Weight ◽

Nerve Growth Factor ◽

Growth Factor ◽

Sciatic Nerve ◽

Diabetic Neuropathy ◽

Stem Bark ◽

Nerve Growth ◽

Methanol Extracts ◽

Tnf Α ◽

Nauclea Pobeguinii

The greatest common and devastating complication of diabetes is painful neuropathy that can cause hyperalgesia and allodynia. It can disturb psychosocial functioning by increasing levels of anxiety and depression. This work was designed to evaluate the antihyperalgesic, antidepressant, and anxiolytic-like effects of the aqueous and methanol extracts of Nauclea pobeguinii stem-bark in diabetic neuropathy induced by streptozotocin in mice. Diabetic neuropathy was induced in mice by the intraperitoneal administration of 200 mg/kg streptozotocin (STZ) to provoke hyperglycemia. Nauclea pobeguinii aqueous and methanol extracts at the doses of 150 and 300 mg/kg were administered by oral route, and their effects were evaluated on antihyperalgesic activity (Von Frey filaments, hot plate, acetone, and formalin tests), blood glucose levels, body weight, serum, sciatic nerve proinflammatory cytokines (TNF-α, IL-1β, and IL-6) and sciatic nerve growth factor (IGF and NGF) rates, depression (open field test, forced swimming test, tail suspension test), and anxiety (elevated plus maze, light-dark box test, social interaction). Oral administration of Nauclea pobeguinii stem-bark aqueous and methanol extracts (150 and 300 mg/kg) produced antihyperalgesic, antidepressant, and anxiolytic-like effects in STZ-induced diabetic neuropathic mice. Extracts also triggered a decrease in glycaemia and increased body weight in treated animals. They also significantly ( p <0.001) reduced tumour necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and IL-6 and significantly ( p <0.001) increased nerve growth factor (NGF) and insulin-like growth factor (IGF) in sciatic nerves. The results of this study confirmed that Nauclea pobeguinii aqueous and methanol extracts possess antihyperalgesic, antidepressant, and anxiolytic activities and could be beneficial therapeutic agents.

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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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