Central control of bone remodeling by neuromedin U

Sato, Shingo; Hanada, Reiko; Kimura, Ayako; Abe, Tomomi; Μatsumoto, Takahiro; Iwasaki, Makiko; Inose, Hiroyuki; Ida, Takanori; Mieda, Michihiro; Takeuchi, Yasuhiro; Fukumoto, Seiji; Fujita, Toshiro; Kato, Shigeaki; Kangawa, Kenji; Kojima, Masayasu; Shinomiya, Kenichi; Takeda, Satoshi

doi:10.1038/nm1640

Cited by 178 publications

(122 citation statements)

References 25 publications

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“…BFR was analyzed by the calcein doublelabeling method (30). Calcein (Sigma) was dissolved in calcein buffer (0.15 M NaCl, 2% NaHCO 3) and injected twice at 0.125 mg/g body weight on days 1 and 4, and then mice were killed on day 6. Unstained 4-m sections were used for BFR measurements.…”

Section: Methodsmentioning

confidence: 99%

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Dissociation of the neuronal regulation of bone mass and energy metabolism by leptin in vivo

Yadav

Suda

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

128

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The leptin regulation of bone remodeling, which has been documented through studies of loss-of-function mutations of this hormone or of its receptor in mice and humans, still raised several unanswered questions. For instance, it has been assumed but not formally demonstrated that this regulation occurs through neuronal means. Likewise, it has not been possible until now to dissociate the influence leptin exerts on appetite and energy expenditure from this function. We show here through mouse genetic studies that a deletion of the leptin receptor in neurons results in an increase in bone formation and bone resorption, resulting in a high bone mass as seen in leptin-deficient mice. In contrast, the same deletion in osteoblasts only does not influence bone remodeling. Furthermore, through the use of l/l mice, a model of gain of function in leptin signaling harboring a Y985L substitution in the leptin receptor, we show that leptin signaling inhibits bone mass accrual by up-regulating sympathetic activity independently of any change in appetite or energy expenditure. This work establishes that in vivo leptin regulates bone mass accrual by acting through neuronal means and provides a direct demonstration that this function of leptin can occur independently of its regulation of energy metabolism.bone remodeling ͉ energy expenditure ͉ osteoblasts ͉ osteoclasts I n the last 10 years, significant advances in our understanding of bone remodeling have come from the study of its endocrine regulation by leptin (1). Remarkably, many studies uncovered that the regulation of either arm of bone remodeling, bone formation and bone resorption, involves molecules not classically associated with bone physiology (1-4). For instance, it has been proposed that leptin regulation of bone mass occurs after its binding to its receptor presumably on hypothalamic neurons. This results in an activation of the sympathetic tone that then acts on osteoblasts to decrease bone formation and to increase osteoclast differentiation (4-8). In addition, leptin via another mediator, CART (cocaine and amphetamine-regulated transcript), inhibits bone resorption (4, 9). Thus, leptin, through the combined actions of these two mediators, prevents bone mass accrual (1).Several questions surround leptin regulation of bone mass accrual. First, there has been no evidence to date that in vivo leptin regulates bone mass through neuronal means rather than through a direct effect on osteoblasts as initially proposed (10, 11). Another lingering point has been to rule out that leptin regulation of bone mass is merely a secondary consequence of regulation of energy metabolism by this hormone.Leptin mediates its functions after its binding to a single receptor [LRb, the long form (b) of the leptin receptor, encoded by the Lepr gene] that is linked to the Jak2 tyrosine kinase (12-18). Leptin binding activates Jak2, resulting in the tyrosine phosphorylation of several residues on LRb, each of which possesses unique functions. Phosphorylated Tyr-1077 and Tyr-1138 on LRb rec...

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Section: Methodsmentioning

confidence: 99%

“…Remarkably, many studies uncovered that the regulation of either arm of bone remodeling, bone formation and bone resorption, involves molecules not classically associated with bone physiology (1)(2)(3)(4). For instance, it has been proposed that leptin regulation of bone mass occurs after its binding to its receptor presumably on hypothalamic neurons.…”

mentioning

confidence: 99%

Dissociation of the neuronal regulation of bone mass and energy metabolism by leptin in vivo

Yadav

Suda

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

128

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“…The sympathetic nervous system has been found to modulate bone through ␤2-adrenergic receptors (Adrb2) with leptin and neuromedin U, playing key roles in the central control of sympathetic nervous system activity (4,5,59,60). In mice, increased tone of the sympathetic nervous system has been suggested to be responsible for reduced bone formation in a mouse model of immobilization through activation of Adrb2 expressed in bone marrow cell-derived osteoblasts (61).…”

Section: Effects Of Reloading By Es-induced Muscle Contraction Are Inmentioning

confidence: 99%

The Central Nervous System (CNS)-independent Anti-bone-resorptive Activity of Muscle Contraction and the Underlying Molecular and Cellular Signatures

Qin

Sun

Cao

et al. 2013

Journal of Biological Chemistry

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Background: Mechanisms by which muscle regulates bone are poorly understood. Results: Electrically stimulated muscle contraction reversed elevations in bone resorption and increased Wnt signaling in bone-derived cells after spinal cord transection. Conclusion: Muscle contraction reduced resorption of unloaded bone independently of the CNS, through mechanical effects and, potentially, nonmechanical signals (e.g. myokines). Significance: The study provides new insights regarding muscle-bone interactions.

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“…However, it has also been shown to regulate bone mass. NMU null mice display increased bone formation and bone mass via a central, hypothalamic pathway (Sato et al 2007). NMU2 receptor is expressed in the paraventricular nucleus, and central infusion of NMU rescued the high bone mass of NMU null mice.…”

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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Central control of bone remodeling by neuromedin U

Cited by 178 publications

References 25 publications

Dissociation of the neuronal regulation of bone mass and energy metabolism by leptin in vivo

Dissociation of the neuronal regulation of bone mass and energy metabolism by leptin in vivo

The Central Nervous System (CNS)-independent Anti-bone-resorptive Activity of Muscle Contraction and the Underlying Molecular and Cellular Signatures

Hypothalamic regulation of bone

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