title: Anabolic action of parathyroid hormone regulated by the β2-adrenergic receptor.
abstract: Parathyroid hormone (PTH), the major calcium-regulating hormone, and norepinephrine (NE), the principal neurotransmitter of sympathetic nerves, regulate bone remodeling by activating distinct cell-surface G protein-coupled receptors in osteoblasts: the parathyroid hormone type 1 receptor (PTHR) and the β(2)-adrenergic receptor (β(2)AR), respectively. These receptors activate a common cAMP/PKA signal transduction pathway mediated through the stimulatory heterotrimeric G protein. Activation of β(2)AR via the sympathetic nervous system decreases bone formation and increases bone resorption. Conversely, daily injection of PTH (1-34), a regimen known as intermittent (i)PTH treatment, increases bone mass through the stimulation of trabecular and cortical bone formation and decreases fracture incidences in severe cases of osteoporosis. Here, we show that iPTH has no osteoanabolic activity in mice lacking the β(2)AR. β(2)AR deficiency suppressed both iPTH-induced increase in bone formation and resorption. We showed that the lack of β(2)AR blocks expression of iPTH-target genes involved in bone formation and resorption that are regulated by the cAMP/PKA pathway. These data implicate an unexpected functional interaction between PTHR and β(2)AR, two G protein-coupled receptors from distinct families, which control bone formation and PTH anabolism.
authors.affiliation: Department of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, 113-8510 Tokyo, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Hanyu
authors.forename: Vanessa L
authors.initials: VL
authors.lastname: Wehbi
authors.forename: Tadayoshi
authors.initials: T
authors.lastname: Hayata
authors.forename: Shuichi
authors.initials: S
authors.lastname: Moriya
authors.forename: Timothy N
authors.initials: TN
authors.lastname: Feinstein
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Ezura
authors.forename: Masashi
authors.initials: M
authors.lastname: Nagao
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Saita
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Hemmi
authors.forename: Takuya
authors.initials: T
authors.lastname: Notomi
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Nakamoto
authors.forename: Ernestina
authors.initials: E
authors.lastname: Schipani
authors.forename: Shu
authors.initials: S
authors.lastname: Takeda
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kaneko
authors.forename: Hisashi
authors.initials: H
authors.lastname: Kurosawa
authors.forename: Gerard
authors.initials: G
authors.lastname: Karsenty
authors.forename: Henry M
authors.initials: HM
authors.lastname: Kronenberg
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Vilardaga
authors.forename: Masaki
authors.initials: M
authors.lastname: Noda
mesh_terms: D015502:Absorptiometry, Photon; D045930:Anabolic Agents / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D015519:Bone Density / Q000187:drug effects; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005269:Femur / Q000187:drug effects / Q000378:metabolism; D005452:Fluoresceins; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics; D010281:Parathyroid Hormone / Q000378:metabolism / Q000494:pharmacology*; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000235:genetics / Q000378:metabolism*; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055114:X-Ray Microtomography
chemical_list: D045930:Anabolic Agents; D005452:Fluoresceins; D010281:Parathyroid Hormone; D044168:Receptor, Parathyroid Hormone, Type 1; D018343:Receptors, Adrenergic, beta-2; C007740:fluorexon