Orexin Regulates Bone Remodeling via a Dominant Positive Central Action and a Subordinate Negative Peripheral Action

Wei, Wei; Motoike, Toshiyuki; Krzeszinski, Jing Y.; Jin, Zixue; Xie, Xian Jin; Dechow, Paul C.; Yanagisawa, Masashi; Wan, Yihong

doi:10.1016/j.cmet.2014.03.016

Cited by 33 publications

(41 citation statements)

References 56 publications

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“…Through gene knockout studies, Wei et al. showed that orexins function peripherally through orexin receptor 1 in the bone to suppress bone formation and enhance bone resorption, and centrally through orexin receptor 2 in the brain to enhance bone formation . Another group also confirmed orexin's inhibitory activity, functioning through OX1R, using calvarial rat OB proliferation .…”

Section: Peptides From Nervous Systemmentioning

confidence: 99%

Short Anabolic Peptides for Bone Growth

Amso

Cornish²,

Brimble

2016

Medicinal Research Reviews

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Loss of bone occurs in the age-related skeletal disorder, osteoporosis, leading to bone fragility and increased incidence of fractures, which are associated with enormous costs and substantial morbidity and mortality. Recent data indicate that osteoporotic fractures are more common than other diseases, which usually attract public attention (e.g., heart attack and breast cancer). The prevention and treatment of this skeletal disorder are therefore of paramount importance. Majority of osteoporosis medications restore skeletal balance by reducing osteoclastic activity, thereby reducing bone resorption. These agents, however, do not regenerate damaged bone tissue, leaving limited options for patients once bone loss has occurred. Recently, attention has turned to bone-anabolic agents. Such agents have the ability to increase bone mass and strength, potentially reversing structural damage. To date, only one bone-anabolic drug is available in the market. The discovery of more novel, cost-effective bone anabolic agents is therefore a priority to treat those suffering from this disabling condition. Short peptides offer an important alternative for the development of novel bone-anabolic agents given their high target binding specificity, which translates into potent activity with limited side effects. This review summarizes attempts in the identification of bone-anabolic peptides, and their development for promoting bone growth.

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Section: Peptides From Nervous Systemmentioning

confidence: 99%

Short Anabolic Peptides for Bone Growth

Amso

Cornish²,

Brimble

2016

Medicinal Research Reviews

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“…The unexplained loss of these orexin neurons is the most common cause for human narcolepsy. The orexin neurons spread projections throughout the whole brain and regulate a variety of important physiological processes such as sleep/wake cycle, reproduction, brown fat and bone development, feeding, and energy metabolism (7)(8)(9)(10).…”

mentioning

confidence: 99%

Orexin/Hypocretin Activates mTOR Complex 1 (mTORC1) via an Erk/Akt-independent and Calcium-stimulated Lysosome v-ATPase Pathway

Wang

Liu

Kakizaki

et al. 2014

Journal of Biological Chemistry

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Background: Narcolepsy is caused by deficiency of neuropeptide orexin/hypocretin, of which downstream signaling pathways are unclear. Results: Orexin activates the mTOR pathway in the mouse brain and multiple cell lines expressing OX1R or OX2R. Conclusion: Orexin activates mTOR complex 1 (mTORC1) via calcium-stimulated lysosome v-ATPase pathway. Significance: mTORC1 may play a key role in the functions of orexin in physiology and metabolism.

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“…In this study we Central molecules and neuropeptides can play important roles in the regulation of bone metabolism (31). Leptin inhibits bone formation through the sympathetic nervous system (14) and orexin is a critical regulator of skeletal homeostasis and exerts dual regulation of bone mass (16). Specific neuronal subtypes and circuits can also exert influence on the regulation of bone mass (32), such as AGRP neurons in the arcuate nucleus that regulate bone mass through the sympathetic nervous system (33).…”

Section: Anxiety-related Disorders Central Molecules and Neural Circmentioning

confidence: 99%

“…Bone metabolism is a dynamic physiological process that is finely regulated by the brain (12); central signals from the brain exert important influences on bone metabolism (13)(14)(15). For example, leptin signaling in the hypothalamus inhibits bone formation through the sympathetic nervous system (14) and orexin, which is produced in the hypothalamus, is a critical regulator of skeletal homeostasis and exerts regulation of bone mass (16). The hypothalamus is an important neural control center relaying information from higher centers in the forebrain to regulate body metabolism (17).…”

Section: Introductionmentioning

confidence: 99%

Identification of a Central Neural Circuit that Regulates Anxiety-induced Bone Loss

Yang

Liu

Chen

et al. 2019

Preprint

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# These authors contributed equally to this work. One Sentence Summary: Identification of a new GABAergic neural circuit from forebrain to hypothalamus used for regulation of anxiety-induced bone loss. Abstract:The homeostasis of bone metabolism is finely regulated by the central nervous system and recent studies have suggested that mood disorders, such as anxiety, are closely related to bone metabolic abnormalities; however, our understanding of central neural circuits regulating bone metabolism is still largely limited. In this study, we first demonstrate that confined isolation of human participants under normal gravity resulted in decreased bone density and elevated anxiety levels. We then used an established mouse model to dissect the neural circuitry regulating anxiety-induced bone loss. Combining electrophysiological, optogenetic and chemogenetic approaches, we demonstrate that GABAergic neural circuitry in ventromedial hypothalamus (VMH) modulates anxiety-induced bone loss; importantly, the GABAergic input in VMHdm arose from a specific group of somatostatin neurons in the bed nucleus of the stria terminalis (BNST), which is both indispensable for anxiety-induced bone loss and able to trigger bone loss in the absence of stressors. VGLUT2 neurons in Nucleus tractus solitaries (NTS) and peripheral sympathetic system were employed by this BNST-VMH neural circuit to regulate anxiety-induced bone loss. Overall, we uncovered new GABAergic neural circuitry from the forebrain to hypothalamus, used in the regulation of anxiety-induced bone loss, and revealed a population of somatostatin neurons in BNST not previously implicated in bone mass regulation.These findings thus identify the underlying central neural mechanism of psychiatric disorders, such as anxiety, that influences bone metabolism at the circuit level.

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Orexin Regulates Bone Remodeling via a Dominant Positive Central Action and a Subordinate Negative Peripheral Action

Cited by 33 publications

References 56 publications

Short Anabolic Peptides for Bone Growth

Short Anabolic Peptides for Bone Growth

Orexin/Hypocretin Activates mTOR Complex 1 (mTORC1) via an Erk/Akt-independent and Calcium-stimulated Lysosome v-ATPase Pathway

Identification of a Central Neural Circuit that Regulates Anxiety-induced Bone Loss

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