title: Orexin regulates bone remodeling via a dominant positive central action and a subordinate negative peripheral action.
abstract: Orexin neuropeptides promote arousal, appetite, reward, and energy expenditure. However, whether orexin affects bone mass accrual is unknown. Here, we show that orexin functions centrally through orexin receptor 2 (OX2R) in the brain to enhance bone formation. OX2R null mice exhibit low bone mass owing to elevated circulating leptin, whereas central administration of an OX2R-selective agonist augments bone mass. Conversely, orexin also functions peripherally through orexin receptor 1 (OX1R) in the bone to suppress bone formation. OX1R null mice exhibit high bone mass owing to a differentiation shift from marrow adipocyte to osteoblast that results from higher osseous ghrelin expression. The central action is dominant because bone mass is reduced in orexin null and OX1R2R double null mice but enhanced in orexin-overexpressing transgenic mice. These findings reveal orexin as a critical rheostat of skeletal homeostasis that exerts a yin-yang dual regulation and highlight orexin as a therapeutic target for osteoporosis.
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.affiliation: Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba 305-8575, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Motoike
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Jing Y
authors.initials: JY
authors.lastname: Krzeszinski
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Zixue
authors.initials: Z
authors.lastname: Jin
authors.affiliation: Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Xian-Jin
authors.initials: XJ
authors.lastname: Xie
authors.affiliation: Department of Biomedical Sciences, Baylor College of Dentistry, Texas A&M University Health Sciences Center, Dallas, TX 75246, USA.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Dechow
authors.affiliation: Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba 305-8575, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Yanagisawa
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: yihong.wan@utsouthwestern.edu.
authors.forename: Yihong
authors.initials: Y
authors.lastname: Wan
mesh_terms: D000818:Animals; D015519:Bone Density / Q000235:genetics / Q000502:physiology*; D016723:Bone Remodeling / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D054439:Ghrelin / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D020738:Leptin / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D009479:Neuropeptides / Q000378:metabolism*; D064446:Orexin Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D000068797:Orexins; D010012:Osteogenesis / Q000502:physiology*; D034622:RNA Interference; D034741:RNA, Small Interfering
chemical_list: C501103:Cd200r1 protein, mouse; D054439:Ghrelin; D047908:Intracellular Signaling Peptides and Proteins; D020738:Leptin; D009479:Neuropeptides; D064446:Orexin Receptors; D000068797:Orexins; D034741:RNA, Small Interfering