A cholinergic neuroskeletal interface promotes bone formation during postnatal growth and exercise

Stephen Gadomski; Claire Fielding; Andrés  García-García; Claudia  Korn; Sadaf Ashraf; Javier  Villadiego; Raquel  del Toro; Olivia  Domingues; Jeremy N.  Skepper; Tatiana  Michel; Jacques  Zimmer; Regine  Sendtner; Scott  Dillon; Kenneth Poole; Gill  Holdsworth; Michael  Sendtner; Juan J.  Toledo-Aral; Cosimo De Bari; Andrew W.  McCaskie; Pamela G  Robey; Simón  Méndez-Ferrer

doi:10.1016/j.stem.2022.02.008

A cholinergic neuroskeletal interface promotes bone formation during postnatal growth and exercise

Stephen Gadomski, Claire Fielding , Andrés García-García, Claudia Korn, Sadaf Ashraf, Javier Villadiego, Raquel del Toro, Olivia Domingues, Jeremy N. Skepper, Tatiana Michel, Jacques Zimmer, Regine Sendtner, Scott Dillon, Kenneth Poole, Gill Holdsworth, Michael Sendtner, Juan J. Toledo-Aral, Cosimo De Bari, Andrew W. McCaskie, Pamela G RobeySimón Méndez-Ferrer^* (Corresponding Author)

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

18 Citations (Scopus)

2 Downloads (Pure)

Abstract

The autonomic nervous system is a master regulator of homeostatic processes and stress responses. Sympathetic noradrenergic nerve fibers decrease bone mass, but the role of cholinergic signaling in bone has remained largely unknown. Here, we describe that early postnatally, a subset of sympathetic nerve fibers undergoes an Interleukin-6 (IL-6)-induced cholinergic switch upon contacting the bone. A neurotrophic dependency mediated through GDNF family receptor-α2 (GFR2) and its ligand, Neurturin (NRTN), is established between sympathetic cholinergic fibers and bone-embedded osteocytes, which require cholinergic innervation for their survival and connectivity. Bone-lining osteoprogenitors amplify and propagate cholinergic signals in the bone marrow (BM). Moderate exercise augments trabecular bone partly through an IL-6-dependent expansion of sympathetic cholinergic nerve fibers. Consequently, loss of cholinergic skeletal innervation reduces osteocyte survival and function, causing osteopenia and impaired skeletal adaptation to moderate exercise. These results uncover a cholinergic neuro-osteocyte interface that regulates skeletogenesis and skeletal turnover through bone-anabolic effects.

Original language	English
Pages (from-to)	528-544.e9
Number of pages	17
Journal	Cell Stem Cell
Volume	29
Issue number	4
Early online date	10 Mar 2022
DOIs	https://doi.org/10.1016/j.stem.2022.02.008
Publication status	Published - 7 Apr 2022

Bibliographical note

Acknowledgments
We thank the Weizmann Institute of Science (Israel) for data discussion (T. Lapidot) and for providing TACE inhibitor (I. Sagi, A. Hanuna, and O. Kollet); E. Chu (NIH/NIAMS) and V. Kram (NIH/NIDCR) for assistance with μCT analysis and dynamic histomorphometry data, S. Ozanne (University of Cambridge) for treadmill and A. Horton and A. Davies (Cardiff University) for demonstrating SGC culture protocol; M. Airaksinen for Gfra2−/− mice; E. Khatib-Massalha, E. Grockowiak, Z. Fang, and other members of the S.M.-F. group for support and data discussion; A.R. Green and M. Birch (University of Cambridge), A. Pascual and J. López-Barneo (Universidad de Sevilla) for data discussion; P. Chacón-Fernández, N. Suárez-Luna, F.J. Martín, and C.O. Pintado, in memoriam, (Centro de Experimentación Animal; CEA, Universidad de Sevilla), D. Pask, T. Hamilton (University of Cambridge), the Central Biomedical Services, and Cambridge NIHR BRC Cell Phenotyping Hub for technical assistance; Genentech for providing tocilizumab; UCB Pharma for providing Scl-Ab r13c7. S.G. was supported by the NIH-OXCAM Program and the Gates Cambridge Trust. A.G.G. received fellowships from Ramón Areces and La Caixa Foundations. C.K. was supported by Marie Curie Career Integration grant H2020-MSCA-IF-2015-70841. M.S. and R.S. were supported by DFG, Se 697/7-1 and BMBF through the EnergI consortium TP6. J.V. and J.J.T.-A. were supported by Instituto de Salud Carlos III (PI12/02574), Junta de Andalucia (P12-CTS-2739), and, together with S.M.-F., by Red TerCel (ISCIII-Spanish Cell Therapy Network). S.A. and C.D.B. were supported by Versus Arthritis grant 21156. A.W.M. received funding from Versus Arthritis (21156). P.G.R. and S.G. were supported by the DIR, NIDCR, a part of the IRP, NIH, and DHHS (1ZIADE000380). K.E.S.P. acknowledges the support of the Cambridge NIHR Biomedical Research Centre. This work was supported by core support grants from MRC to the Cambridge Stem Cell Institute; National Health Service Blood and Transplant (United Kingdom), European Union’s Horizon 2020 research (ERC-2014-CoG-648765), MRC-AMED grant MR/V005421/1, and a Programme Foundation Award (C61367/A26670) from Cancer Research UK to S.M.-F. This research was funded in part by the Wellcome Trust (203151/Z/16/Z). For the purpose of Open Access, the authors have applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission.

Data Availability Statement

Microscopy data reported in this paper will be shared by the lead contact upon request.
This paper does not report original code.
Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

Keywords

cholinergic
sympathetic
osteocyte
autonomic
development
skeletal
bone
exercise
neuroskeletal
anabolic

Access to Document

10.1016/j.stem.2022.02.008Licence: CC BY

Gadomski_etal_CSC_A_Cholinergic_Neuroskeletal_VoR
ª2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Final published version, 9.3 MBLicence: CC BY

Cite this

Gadomski, S., Fielding , C., García-García, A., Korn, C., Ashraf, S., Villadiego, J., del Toro, R., Domingues, O., Skepper, J. N., Michel, T., Zimmer, J., Sendtner, R., Dillon, S., Poole, K., Holdsworth, G., Sendtner, M., Toledo-Aral, J. J., De Bari, C., McCaskie, A. W., ... Méndez-Ferrer, S. (2022). A cholinergic neuroskeletal interface promotes bone formation during postnatal growth and exercise. Cell Stem Cell, 29(4), 528-544.e9. https://doi.org/10.1016/j.stem.2022.02.008

Gadomski, S, Fielding , C, García-García, A, Korn, C, Ashraf, S, Villadiego, J, del Toro, R, Domingues, O, Skepper, JN, Michel, T, Zimmer, J, Sendtner, R, Dillon, S, Poole, K, Holdsworth, G, Sendtner, M, Toledo-Aral, JJ, De Bari, C, McCaskie, AW, Robey, PG & Méndez-Ferrer, S 2022, 'A cholinergic neuroskeletal interface promotes bone formation during postnatal growth and exercise', Cell Stem Cell, vol. 29, no. 4, pp. 528-544.e9. https://doi.org/10.1016/j.stem.2022.02.008

@article{ee4e424ffdd74b9997e3ea1b1fd83955,

title = "A cholinergic neuroskeletal interface promotes bone formation during postnatal growth and exercise",

abstract = "The autonomic nervous system is a master regulator of homeostatic processes and stress responses. Sympathetic noradrenergic nerve fibers decrease bone mass, but the role of cholinergic signaling in bone has remained largely unknown. Here, we describe that early postnatally, a subset of sympathetic nerve fibers undergoes an Interleukin-6 (IL-6)-induced cholinergic switch upon contacting the bone. A neurotrophic dependency mediated through GDNF family receptor-α2 (GFR2) and its ligand, Neurturin (NRTN), is established between sympathetic cholinergic fibers and bone-embedded osteocytes, which require cholinergic innervation for their survival and connectivity. Bone-lining osteoprogenitors amplify and propagate cholinergic signals in the bone marrow (BM). Moderate exercise augments trabecular bone partly through an IL-6-dependent expansion of sympathetic cholinergic nerve fibers. Consequently, loss of cholinergic skeletal innervation reduces osteocyte survival and function, causing osteopenia and impaired skeletal adaptation to moderate exercise. These results uncover a cholinergic neuro-osteocyte interface that regulates skeletogenesis and skeletal turnover through bone-anabolic effects.",

keywords = "cholinergic, sympathetic, osteocyte, autonomic, development, skeletal, bone, exercise, neuroskeletal, anabolic",

author = "Stephen Gadomski and Claire Fielding and Andr{\'e}s Garc{\'i}a-Garc{\'i}a and Claudia Korn and Sadaf Ashraf and Javier Villadiego and {del Toro}, Raquel and Olivia Domingues and Skepper, {Jeremy N.} and Tatiana Michel and Jacques Zimmer and Regine Sendtner and Scott Dillon and Kenneth Poole and Gill Holdsworth and Michael Sendtner and Toledo-Aral, {Juan J.} and {De Bari}, Cosimo and McCaskie, {Andrew W.} and Robey, {Pamela G} and Sim{\'o}n M{\'e}ndez-Ferrer",

note = "Acknowledgments We thank the Weizmann Institute of Science (Israel) for data discussion (T. Lapidot) and for providing TACE inhibitor (I. Sagi, A. Hanuna, and O. Kollet); E. Chu (NIH/NIAMS) and V. Kram (NIH/NIDCR) for assistance with μCT analysis and dynamic histomorphometry data, S. Ozanne (University of Cambridge) for treadmill and A. Horton and A. Davies (Cardiff University) for demonstrating SGC culture protocol; M. Airaksinen for Gfra2−/− mice; E. Khatib-Massalha, E. Grockowiak, Z. Fang, and other members of the S.M.-F. group for support and data discussion; A.R. Green and M. Birch (University of Cambridge), A. Pascual and J. L{\'o}pez-Barneo (Universidad de Sevilla) for data discussion; P. Chac{\'o}n-Fern{\'a}ndez, N. Su{\'a}rez-Luna, F.J. Mart{\'i}n, and C.O. Pintado, in memoriam, (Centro de Experimentaci{\'o}n Animal; CEA, Universidad de Sevilla), D. Pask, T. Hamilton (University of Cambridge), the Central Biomedical Services, and Cambridge NIHR BRC Cell Phenotyping Hub for technical assistance; Genentech for providing tocilizumab; UCB Pharma for providing Scl-Ab r13c7. S.G. was supported by the NIH-OXCAM Program and the Gates Cambridge Trust. A.G.G. received fellowships from Ram{\'o}n Areces and La Caixa Foundations. C.K. was supported by Marie Curie Career Integration grant H2020-MSCA-IF-2015-70841. M.S. and R.S. were supported by DFG, Se 697/7-1 and BMBF through the EnergI consortium TP6. J.V. and J.J.T.-A. were supported by Instituto de Salud Carlos III (PI12/02574), Junta de Andalucia (P12-CTS-2739), and, together with S.M.-F., by Red TerCel (ISCIII-Spanish Cell Therapy Network). S.A. and C.D.B. were supported by Versus Arthritis grant 21156. A.W.M. received funding from Versus Arthritis (21156). P.G.R. and S.G. were supported by the DIR, NIDCR, a part of the IRP, NIH, and DHHS (1ZIADE000380). K.E.S.P. acknowledges the support of the Cambridge NIHR Biomedical Research Centre. This work was supported by core support grants from MRC to the Cambridge Stem Cell Institute; National Health Service Blood and Transplant (United Kingdom), European Union{\textquoteright}s Horizon 2020 research (ERC-2014-CoG-648765), MRC-AMED grant MR/V005421/1, and a Programme Foundation Award (C61367/A26670) from Cancer Research UK to S.M.-F. This research was funded in part by the Wellcome Trust (203151/Z/16/Z). For the purpose of Open Access, the authors have applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission.",

year = "2022",

month = apr,

day = "7",

doi = "10.1016/j.stem.2022.02.008",

language = "English",

volume = "29",

pages = "528--544.e9",

journal = "Cell Stem Cell",

issn = "1934-5909",

publisher = "Cell Press",

number = "4",

}

TY - JOUR

T1 - A cholinergic neuroskeletal interface promotes bone formation during postnatal growth and exercise

AU - Gadomski, Stephen

AU - Fielding , Claire

AU - García-García, Andrés

AU - Korn, Claudia

AU - Ashraf, Sadaf

AU - Villadiego, Javier

AU - del Toro, Raquel

AU - Domingues, Olivia

AU - Skepper, Jeremy N.

AU - Michel, Tatiana

AU - Zimmer, Jacques

AU - Sendtner, Regine

AU - Dillon, Scott

AU - Poole, Kenneth

AU - Holdsworth, Gill

AU - Sendtner, Michael

AU - Toledo-Aral, Juan J.

AU - De Bari, Cosimo

AU - McCaskie, Andrew W.

AU - Robey, Pamela G

AU - Méndez-Ferrer, Simón

N1 - Acknowledgments We thank the Weizmann Institute of Science (Israel) for data discussion (T. Lapidot) and for providing TACE inhibitor (I. Sagi, A. Hanuna, and O. Kollet); E. Chu (NIH/NIAMS) and V. Kram (NIH/NIDCR) for assistance with μCT analysis and dynamic histomorphometry data, S. Ozanne (University of Cambridge) for treadmill and A. Horton and A. Davies (Cardiff University) for demonstrating SGC culture protocol; M. Airaksinen for Gfra2−/− mice; E. Khatib-Massalha, E. Grockowiak, Z. Fang, and other members of the S.M.-F. group for support and data discussion; A.R. Green and M. Birch (University of Cambridge), A. Pascual and J. López-Barneo (Universidad de Sevilla) for data discussion; P. Chacón-Fernández, N. Suárez-Luna, F.J. Martín, and C.O. Pintado, in memoriam, (Centro de Experimentación Animal; CEA, Universidad de Sevilla), D. Pask, T. Hamilton (University of Cambridge), the Central Biomedical Services, and Cambridge NIHR BRC Cell Phenotyping Hub for technical assistance; Genentech for providing tocilizumab; UCB Pharma for providing Scl-Ab r13c7. S.G. was supported by the NIH-OXCAM Program and the Gates Cambridge Trust. A.G.G. received fellowships from Ramón Areces and La Caixa Foundations. C.K. was supported by Marie Curie Career Integration grant H2020-MSCA-IF-2015-70841. M.S. and R.S. were supported by DFG, Se 697/7-1 and BMBF through the EnergI consortium TP6. J.V. and J.J.T.-A. were supported by Instituto de Salud Carlos III (PI12/02574), Junta de Andalucia (P12-CTS-2739), and, together with S.M.-F., by Red TerCel (ISCIII-Spanish Cell Therapy Network). S.A. and C.D.B. were supported by Versus Arthritis grant 21156. A.W.M. received funding from Versus Arthritis (21156). P.G.R. and S.G. were supported by the DIR, NIDCR, a part of the IRP, NIH, and DHHS (1ZIADE000380). K.E.S.P. acknowledges the support of the Cambridge NIHR Biomedical Research Centre. This work was supported by core support grants from MRC to the Cambridge Stem Cell Institute; National Health Service Blood and Transplant (United Kingdom), European Union’s Horizon 2020 research (ERC-2014-CoG-648765), MRC-AMED grant MR/V005421/1, and a Programme Foundation Award (C61367/A26670) from Cancer Research UK to S.M.-F. This research was funded in part by the Wellcome Trust (203151/Z/16/Z). For the purpose of Open Access, the authors have applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission.

PY - 2022/4/7

Y1 - 2022/4/7

N2 - The autonomic nervous system is a master regulator of homeostatic processes and stress responses. Sympathetic noradrenergic nerve fibers decrease bone mass, but the role of cholinergic signaling in bone has remained largely unknown. Here, we describe that early postnatally, a subset of sympathetic nerve fibers undergoes an Interleukin-6 (IL-6)-induced cholinergic switch upon contacting the bone. A neurotrophic dependency mediated through GDNF family receptor-α2 (GFR2) and its ligand, Neurturin (NRTN), is established between sympathetic cholinergic fibers and bone-embedded osteocytes, which require cholinergic innervation for their survival and connectivity. Bone-lining osteoprogenitors amplify and propagate cholinergic signals in the bone marrow (BM). Moderate exercise augments trabecular bone partly through an IL-6-dependent expansion of sympathetic cholinergic nerve fibers. Consequently, loss of cholinergic skeletal innervation reduces osteocyte survival and function, causing osteopenia and impaired skeletal adaptation to moderate exercise. These results uncover a cholinergic neuro-osteocyte interface that regulates skeletogenesis and skeletal turnover through bone-anabolic effects.

AB - The autonomic nervous system is a master regulator of homeostatic processes and stress responses. Sympathetic noradrenergic nerve fibers decrease bone mass, but the role of cholinergic signaling in bone has remained largely unknown. Here, we describe that early postnatally, a subset of sympathetic nerve fibers undergoes an Interleukin-6 (IL-6)-induced cholinergic switch upon contacting the bone. A neurotrophic dependency mediated through GDNF family receptor-α2 (GFR2) and its ligand, Neurturin (NRTN), is established between sympathetic cholinergic fibers and bone-embedded osteocytes, which require cholinergic innervation for their survival and connectivity. Bone-lining osteoprogenitors amplify and propagate cholinergic signals in the bone marrow (BM). Moderate exercise augments trabecular bone partly through an IL-6-dependent expansion of sympathetic cholinergic nerve fibers. Consequently, loss of cholinergic skeletal innervation reduces osteocyte survival and function, causing osteopenia and impaired skeletal adaptation to moderate exercise. These results uncover a cholinergic neuro-osteocyte interface that regulates skeletogenesis and skeletal turnover through bone-anabolic effects.

KW - cholinergic

KW - sympathetic

KW - osteocyte

KW - autonomic

KW - development

KW - skeletal

KW - bone

KW - exercise

KW - neuroskeletal

KW - anabolic

U2 - 10.1016/j.stem.2022.02.008

DO - 10.1016/j.stem.2022.02.008

M3 - Article

SN - 1934-5909

VL - 29

SP - 528-544.e9

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 4

ER -

A cholinergic neuroskeletal interface promotes bone formation during postnatal growth and exercise

Abstract

Bibliographical note

Data Availability Statement

Keywords

Access to Document

Fingerprint

Cite this