Skeletal parasympathetic innervation communicates central IL-1 signals regulating bone mass accrual

Alon Bajayo, Arik Bar, Adam Denes, Marilyn Bachar, Vardit Kram, Malka Attar-Namdar, Alberta Zallone, K. Kovács, Raz Yirmiya, Itai Bab

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

Bone mass accrual is a major determinant of skeletal mass, governed by bone remodeling, which consists of bone resorption by osteoclasts and bone formation by osteoblasts. Bone mass accrual is inhibited by sympathetic signaling centrally regulated through activation of receptors for serotonin, leptin, and ACh. However, skeletal activity of the parasympathetic nervous system (PSNS) has not been reported at the bone level. Here we report skeletal immune-positive fibers for the PSNS marker vesicular ACh transporter (VAChT). Pseudorabies virus inoculated into the distal femoral metaphysis is identifiable in the sacral intermediolateral cell column and central autonomic nucleus, demonstrating PSNS femoral innervation originating in the spinal cord. The PSNS neurotransmitter ACh targets nicotinic (nAChRs), but not muscarinic receptors in bone cells, affecting mainly osteoclasts. nAChR agonists up-regulate osteoclast apoptosis and restrain bone resorption. Mice deficient of the α2nAChR subunit have increased bone resorption and low bone mass. Silencing of the IL-1 receptor signaling in the central nervous system by brain-specific overexpression of the human IL-1 receptor antagonist (hIL1raAst +/+ mice) leads to very low skeletal VAChT expression and ACh levels. These mice also exhibit increased bone resorption and low bone mass. In WT but not in hIL1raAst+/+ mice, the cholinergic ACh esterase inhibitor pyridostigmine increases ACh levels and bone mass apparently by inhibiting bone resorption. Taken together, these results identify a previously unexplored key central IL-1-parasympathetic-bone axis that antagonizes the skeletal sympathetic tone, thus potently favoring bone mass accrual.

Original languageEnglish
Pages (from-to)15455-15460
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number38
DOIs
Publication statusPublished - Sep 18 2012

Fingerprint

Interleukin-1
Bone and Bones
Parasympathetic Nervous System
Bone Resorption
Osteoclasts
Interleukin-1 Receptors
Thigh
Pyridostigmine Bromide
Suid Herpesvirus 1
Leptin Receptors
Bone Remodeling
Serotonin Receptors
Cholinergic Receptors
Muscarinic Receptors
Esterases
Osteoblasts
Osteogenesis
Cholinergic Agents
Neurotransmitter Agents
Spinal Cord

Keywords

  • Autonomic nervous system
  • Postnatal skeletal development

ASJC Scopus subject areas

  • General

Cite this

Skeletal parasympathetic innervation communicates central IL-1 signals regulating bone mass accrual. / Bajayo, Alon; Bar, Arik; Denes, Adam; Bachar, Marilyn; Kram, Vardit; Attar-Namdar, Malka; Zallone, Alberta; Kovács, K.; Yirmiya, Raz; Bab, Itai.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 38, 18.09.2012, p. 15455-15460.

Research output: Contribution to journalArticle

Bajayo, Alon ; Bar, Arik ; Denes, Adam ; Bachar, Marilyn ; Kram, Vardit ; Attar-Namdar, Malka ; Zallone, Alberta ; Kovács, K. ; Yirmiya, Raz ; Bab, Itai. / Skeletal parasympathetic innervation communicates central IL-1 signals regulating bone mass accrual. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 38. pp. 15455-15460.
@article{df4951be180e4b2eb8be6ae10ed8129b,
title = "Skeletal parasympathetic innervation communicates central IL-1 signals regulating bone mass accrual",
abstract = "Bone mass accrual is a major determinant of skeletal mass, governed by bone remodeling, which consists of bone resorption by osteoclasts and bone formation by osteoblasts. Bone mass accrual is inhibited by sympathetic signaling centrally regulated through activation of receptors for serotonin, leptin, and ACh. However, skeletal activity of the parasympathetic nervous system (PSNS) has not been reported at the bone level. Here we report skeletal immune-positive fibers for the PSNS marker vesicular ACh transporter (VAChT). Pseudorabies virus inoculated into the distal femoral metaphysis is identifiable in the sacral intermediolateral cell column and central autonomic nucleus, demonstrating PSNS femoral innervation originating in the spinal cord. The PSNS neurotransmitter ACh targets nicotinic (nAChRs), but not muscarinic receptors in bone cells, affecting mainly osteoclasts. nAChR agonists up-regulate osteoclast apoptosis and restrain bone resorption. Mice deficient of the α2nAChR subunit have increased bone resorption and low bone mass. Silencing of the IL-1 receptor signaling in the central nervous system by brain-specific overexpression of the human IL-1 receptor antagonist (hIL1raAst +/+ mice) leads to very low skeletal VAChT expression and ACh levels. These mice also exhibit increased bone resorption and low bone mass. In WT but not in hIL1raAst+/+ mice, the cholinergic ACh esterase inhibitor pyridostigmine increases ACh levels and bone mass apparently by inhibiting bone resorption. Taken together, these results identify a previously unexplored key central IL-1-parasympathetic-bone axis that antagonizes the skeletal sympathetic tone, thus potently favoring bone mass accrual.",
keywords = "Autonomic nervous system, Postnatal skeletal development",
author = "Alon Bajayo and Arik Bar and Adam Denes and Marilyn Bachar and Vardit Kram and Malka Attar-Namdar and Alberta Zallone and K. Kov{\'a}cs and Raz Yirmiya and Itai Bab",
year = "2012",
month = "9",
day = "18",
doi = "10.1073/pnas.1206061109",
language = "English",
volume = "109",
pages = "15455--15460",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "38",

}

TY - JOUR

T1 - Skeletal parasympathetic innervation communicates central IL-1 signals regulating bone mass accrual

AU - Bajayo, Alon

AU - Bar, Arik

AU - Denes, Adam

AU - Bachar, Marilyn

AU - Kram, Vardit

AU - Attar-Namdar, Malka

AU - Zallone, Alberta

AU - Kovács, K.

AU - Yirmiya, Raz

AU - Bab, Itai

PY - 2012/9/18

Y1 - 2012/9/18

N2 - Bone mass accrual is a major determinant of skeletal mass, governed by bone remodeling, which consists of bone resorption by osteoclasts and bone formation by osteoblasts. Bone mass accrual is inhibited by sympathetic signaling centrally regulated through activation of receptors for serotonin, leptin, and ACh. However, skeletal activity of the parasympathetic nervous system (PSNS) has not been reported at the bone level. Here we report skeletal immune-positive fibers for the PSNS marker vesicular ACh transporter (VAChT). Pseudorabies virus inoculated into the distal femoral metaphysis is identifiable in the sacral intermediolateral cell column and central autonomic nucleus, demonstrating PSNS femoral innervation originating in the spinal cord. The PSNS neurotransmitter ACh targets nicotinic (nAChRs), but not muscarinic receptors in bone cells, affecting mainly osteoclasts. nAChR agonists up-regulate osteoclast apoptosis and restrain bone resorption. Mice deficient of the α2nAChR subunit have increased bone resorption and low bone mass. Silencing of the IL-1 receptor signaling in the central nervous system by brain-specific overexpression of the human IL-1 receptor antagonist (hIL1raAst +/+ mice) leads to very low skeletal VAChT expression and ACh levels. These mice also exhibit increased bone resorption and low bone mass. In WT but not in hIL1raAst+/+ mice, the cholinergic ACh esterase inhibitor pyridostigmine increases ACh levels and bone mass apparently by inhibiting bone resorption. Taken together, these results identify a previously unexplored key central IL-1-parasympathetic-bone axis that antagonizes the skeletal sympathetic tone, thus potently favoring bone mass accrual.

AB - Bone mass accrual is a major determinant of skeletal mass, governed by bone remodeling, which consists of bone resorption by osteoclasts and bone formation by osteoblasts. Bone mass accrual is inhibited by sympathetic signaling centrally regulated through activation of receptors for serotonin, leptin, and ACh. However, skeletal activity of the parasympathetic nervous system (PSNS) has not been reported at the bone level. Here we report skeletal immune-positive fibers for the PSNS marker vesicular ACh transporter (VAChT). Pseudorabies virus inoculated into the distal femoral metaphysis is identifiable in the sacral intermediolateral cell column and central autonomic nucleus, demonstrating PSNS femoral innervation originating in the spinal cord. The PSNS neurotransmitter ACh targets nicotinic (nAChRs), but not muscarinic receptors in bone cells, affecting mainly osteoclasts. nAChR agonists up-regulate osteoclast apoptosis and restrain bone resorption. Mice deficient of the α2nAChR subunit have increased bone resorption and low bone mass. Silencing of the IL-1 receptor signaling in the central nervous system by brain-specific overexpression of the human IL-1 receptor antagonist (hIL1raAst +/+ mice) leads to very low skeletal VAChT expression and ACh levels. These mice also exhibit increased bone resorption and low bone mass. In WT but not in hIL1raAst+/+ mice, the cholinergic ACh esterase inhibitor pyridostigmine increases ACh levels and bone mass apparently by inhibiting bone resorption. Taken together, these results identify a previously unexplored key central IL-1-parasympathetic-bone axis that antagonizes the skeletal sympathetic tone, thus potently favoring bone mass accrual.

KW - Autonomic nervous system

KW - Postnatal skeletal development

UR - http://www.scopus.com/inward/record.url?scp=84866542685&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84866542685&partnerID=8YFLogxK

U2 - 10.1073/pnas.1206061109

DO - 10.1073/pnas.1206061109

M3 - Article

VL - 109

SP - 15455

EP - 15460

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 38

ER -