Journal Article

Anabolic action of parathyroid hormone regulated by the β2-adrenergic receptor

Feinstein, Timothy N, Hemmi, Hiroaki, Nakamoto, Tetsuya, Kurosawa, Hisashi, Noda, Masaki, Takeda, Shu, Wehbi, Vanessa L, Hanyu, Ryo, Schipani, Ernestina, Kaneko, Kazuo, Vilardaga, Jean-Pierre, Moriya, Shuichi, Notomi, Takuya, Kronenberg, Henry M, Karsenty, Gerard, Hayata, Tadayoshi, Ezura, Yoichi, Saita, Yoshitomo, Nagao, Masashi

2012

Overview

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 β2-adrenergic receptor (β2AR), respectively. These receptors activate a common cAMP/PKA signal transduction pathway mediated through the stimulatory heterotrimeric G protein. Activation of β2AR 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 β2AR. β2AR deficiency suppressed both iPTH-induced increase in bone formation and resorption. We showed that the lack of β2AR 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 β2AR, two G protein-coupled receptors from distinct families, which control bone formation and PTH anabolism.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Absorptiometry, Photon / Anabolic Agents / Anabolic Agents - metabolism / Anabolic Agents - pharmacology / Anabolics / Animals / Biological Sciences / Bone and Bones / Bone and Bones - diagnostic imaging / Bone and Bones - drug effects / Bone and Bones - metabolism / bone density / Bone Density - drug effects / Bone formation / bone resorption / Bones / cAMP-dependent protein kinase / drug effects / Female / Femur / Femur - drug effects / Femur - metabolism / Fluoresceins / Gene Expression Regulation / Gene Expression Regulation - drug effects / genes / genetics / Hormones / Male / metabolism / Mice / Mice, Inbred C57BL / Mice, Knockout / Mice, Transgenic / nerve tissue / norepinephrine / Osteoblasts / Osteoclasts / Osteogenesis / Osteogenesis - drug effects / Osteogenesis - genetics / Osteoporosis / parathyroid hormone / Parathyroid Hormone - metabolism / Parathyroid Hormone - pharmacology / pharmacology / radiography / Receptor, Parathyroid Hormone, Type 1 / Receptor, Parathyroid Hormone, Type 1 - genetics / Receptor, Parathyroid Hormone, Type 1 - metabolism / Receptors / Receptors, Adrenergic, beta-2 / Receptors, Adrenergic, beta-2 - genetics / Receptors, Adrenergic, beta-2 - metabolism / resorption / Reverse Transcriptase Polymerase Chain Reaction / signal transduction / sympathetic nervous system / T lymphocytes / X-Ray Microtomography