Neuromedin U and Its Receptors: Structure, Function, and Physiological Roles

Brighton, Paul J.; Szekeres, Philip G.; Willars, Gary B.

doi:10.1124/pr.56.2.3

Cited by 248 publications

(237 citation statements)

References 123 publications

(258 reference statements)

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“…Two NMU receptors, NMUR1 (FM3) and NMUR2 (FM4) (Brighton et al, 2004), have similar affinity for NMU. It is interesting to note that these two receptors can affect different pathways that may lead to cancer cachexia.…”

Section: Discussionmentioning

confidence: 99%

“…Human NMU is synthesized as a 174-amino-acid precursor protein, undergoing C-terminal cleavage into a mature peptide of 25 amino acids. This peptide is found at highest levels in the gut and genitourinary system, and two receptors for it (NMUR1 and NMUR2) are preferentially expressed in either peripheral or central nervous system tissues (Brighton et al, 2004). NMU was initially characterized as causing smooth muscle contraction and increasing blood pressure and was also shown to regulate body weight, having an anorexigenic effect independent of the leptin signaling pathway (Hanada et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Neuromedin U is regulated by the metastasis suppressor RhoGDI2 and is a novel promoter of tumor formation, lung metastasis and cancer cachexia

McRoberts

Berr

et al. 2006

Oncogene

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Most deaths from urinary bladder cancer are owing to metastatic disease. A reduction in Rho GDP Dissociation Inhibitor 2 (RhoGDI2) protein has been associated with increased risk of metastasis in patients with locally advanced bladder cancer, whereas in animal models, RhoGDI2 reconstitution in cells without expression results in lung metastasis suppression. Recently, we noted an inverse correlation between tumor RhoGDI2 and Neuromedin U (NMU) expression, suggesting that NMU might be a target of the lung metastasis suppressor effect of RhoGDI2. Here we evaluated whether NMU is regulated by RhoGDI2 and is functionally important in tumor progression. We used small interfering RNA knockdown of endogenous RhoGDI2 in poorly tumorigenic and nonmetastatic human bladder cancer T24 cells and observed increased NMU RNA expression. Although NMU overexpression did not increase the monolayer growth of T24 or related T24T poorly metastatic human bladder cancer cells, it did augment anchorage-independent growth for the latter. Overexpression of NMU in T24 and T24T cells significantly promoted tumor formation of both cell lines in nude mice, but did not alter the growth rate of established tumors. Furthermore, NMU-overexpressing xenografts were associated with lower animal body weight than control tumors, indicating a possible role of NMU in cancer cachexia. NMU overexpression in T24T cells significantly enhanced their lung metastatic ability. Bioluminescent in vivo imaging revealed that lung metastases in T24T grew faster than the same tumors in the subcutaneous microenvironment. In conclusion, NMU is a RhoGDI2-regulated gene that appears important for tumorigenicity, lung metastasis and cancer cachexia, and thus a promising therapeutic target in cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Neuromedin U is regulated by the metastasis suppressor RhoGDI2 and is a novel promoter of tumor formation, lung metastasis and cancer cachexia

McRoberts

Berr

et al. 2006

Oncogene

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“…Inhibition of NPY or deletion of the NPY receptor gene increased trabecular bone mass and fracture healing [28]. Negative osteotropic effects have also been observed in neuromedin U, a neuropeptide synthesized in the hypothalamus, pituitary and small intestine [29]. Neuromedin U was reported to inhibit osteoblastic function [30].…”

Section: Bone Homeostasis Regulated By the Central Nervous Systemmentioning

confidence: 99%

Chronic Psychological Stress as a Risk Factor of Osteoporosis

Chen

Adachi

Hayashi

et al. 2015

J UOEH

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: Osteoporosis, the most common metabolic skeletal disease, is characterized by decreased bone mass and deteriorated bone quality, leading to increased fracture risk. With the aging of the population, osteoporotic fracture is an important public health issue. Organisms are constantly exposed to various stressful stimuli that affect physiological processes. Recent studies showed that chronic psychological stress is a risk factor for osteoporosis by various signaling pathways. The purpose of this article is to review the recent progress of the association between chronic psychological stress and osteoporosis. Increasing evidence confirms the physiological importance of the central nervous system, especially the hypothalamus, in the regulation of bone metabolism. Both animal and human studies indicate that chronic psychological stress induces a decrease of bone mass and deterioration of bone quality by influencing the hypothalamic-pituitary-adrenocortical (HPA) axis, sympathetic nervous system, and other endocrine, immune factors. Active mastication, proven to be an effective stress-coping behavior, can attenuate stress-induced neuroendocrine responses and ameliorate stress-induced bone loss. Therefore, active mastication may represent a useful approach in preventing and/or treating chronic stress-associated osteoporosis. We also discuss several potential mechanisms involved in the interaction between chronic stress, mastication and osteoporosis. Chronic stress activates the HPA axis and sympathetic nervous system, suppresses the secretion of gonadal hormone and growth hormone, and increases inflammatory cytokines, eventually leading to bone loss by inhibiting bone formation and stimulating bone resorption.

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“…One such discovery involved the actions of neuromedin U (NMU). NMU is a neuropeptide expressed in hypothalamic neurons and in the small intestine, and is regulated by sympathetic activation (Brighton et al 2004). However, it has also been shown to regulate bone mass.…”

Section: Involvement Of the Brainstem: Brain-derived Serotoninmentioning

confidence: 99%

Hypothalamic regulation of bone

Drießler

Baldock²

2010

Journal of Molecular Endocrinology

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On initial inspection, bone remodeling, the process whereby the skeleton adapts through time, appears to be relatively simple. Two cell types, the bone-forming osteoblasts and the bone-resorbing osteoclasts, interact to keep bone mass relatively stable throughout adult life. However, the complexity of the regulatory influences on these cells is continuing to expand our understanding of the intricacy of skeletal physiology and also the interactions between other organ systems and bone. One such example of the broadening of understanding in this field has occurred in the last decade with study of the central, neural regulation of bone mass. Initial studies of an adipose-derived hormone, leptin, helped define a direct, sympathetic pathway involving efferent neural signals from the hypothalamus to receptors on the osteoblast. Since the leptin-mediated pathway has been continuously modified to reveal a complex system involving neuromedin U, cocaineand amphetamine-related transcript and serotonin interacting within the hypothalamus and brainstem to regulate both bone formation and resorption in cancellous bone, a number of other systems have also been identified. Neuropeptide Y, acting through hypothalamic Y2 receptors, is capable of skeleton-wide modulation of osteoblast activity, with important coordination between body weight and bone mass. Cannabinoids, acting through central cannabinoid receptor 1 and bone cell cannabinoid receptor 2 receptors, modulate osteoclast activity, thereby identifying pathways active on both aspects of the bone remodeling process. This review explores the key central pathways to bone and explores the complexity of the interactions being revealed by this emergent field of research. Journal of Molecular Endocrinology (2010) 45, 175-181 Function of hypothalamusThe brain has long been appreciated as a pivotal regulator of homeostasis in peripheral tissues, including the skeleton. There is now clear evidence for crosstalk between the brain and bone through two distinct routes. The first pathway comprises welldefined hormonal signals arising from neuroendocrine neurons of the hypothalamus and subsequently processed within the pituitary. The second pathway consists of efferent neuronal discharges originating from the hypothalamus and processed through the brainstem. The hypothalamus, with its semipermeable blood-brain barrier, is thus one of the most powerful regulatory regions within the body, integrating signals not only from peripheral tissues but also from within the brain itself. These direct, neural pathways represent an emergent area of study that is identifying novel regulatory axes between the brain and the cells of bone. Moreover, this work is also providing insights into regulatory connections involving skeletal tissue, which are proving to be unexpected, thereby outlining a level of interconnectedness that has been previously unappreciated. This review examines the expanded understanding of the central, neural outputs to bone metabolism and remodeling.

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Neuromedin U and Its Receptors: Structure, Function, and Physiological Roles

Cited by 248 publications

References 123 publications

Neuromedin U is regulated by the metastasis suppressor RhoGDI2 and is a novel promoter of tumor formation, lung metastasis and cancer cachexia

Neuromedin U is regulated by the metastasis suppressor RhoGDI2 and is a novel promoter of tumor formation, lung metastasis and cancer cachexia

Chronic Psychological Stress as a Risk Factor of Osteoporosis

Hypothalamic regulation of bone

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