NGF-TrkA Signaling by Sensory Nerves Coordinates the Vascularization and Ossification of Developing Endochondral Bone

Ryan E. Tomlinson; Zhi Li; Qian Zhang; Brian C. Goh; Zhu Li; Daniel L.J. Thorek; Labchan Rajbhandari; Thomas M. Brushart; Liliana Minichiello; Fengquan Zhou; Arun Venkatesan; Thomas L. Clemens

doi:10.1016/j.celrep.2016.08.002

Cell Reports (Sep 2016)

NGF-TrkA Signaling by Sensory Nerves Coordinates the Vascularization and Ossification of Developing Endochondral Bone

Ryan E. Tomlinson,
Zhi Li,
Qian Zhang,
Brian C. Goh,
Zhu Li,
Daniel L.J. Thorek,
Labchan Rajbhandari,
Thomas M. Brushart,
Liliana Minichiello,
Fengquan Zhou,
Arun Venkatesan,
Thomas L. Clemens

Affiliations

Ryan E. Tomlinson: Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, MD 21287, USA
Zhi Li: Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, MD 21287, USA
Qian Zhang: Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, MD 21287, USA
Brian C. Goh: Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, MD 21287, USA
Zhu Li: Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, MD 21287, USA
Daniel L.J. Thorek: Department of Radiology and Radiological Sciences, Johns Hopkins University, Baltimore, MD 21287, USA
Labchan Rajbhandari: Department of Neurology, Johns Hopkins University, Baltimore, MD 21287, USA
Thomas M. Brushart: Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, MD 21287, USA
Liliana Minichiello: Department of Pharmacology, Oxford University, Oxford OX1 3QT, UK
Fengquan Zhou: Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, MD 21287, USA
Arun Venkatesan: Department of Neurology, Johns Hopkins University, Baltimore, MD 21287, USA
Thomas L. Clemens: Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, MD 21287, USA

DOI: https://doi.org/10.1016/j.celrep.2016.08.002
Journal volume & issue: Vol. 16, no. 10
pp. 2723 – 2735

Abstract

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Developing tissues dictate the amount and type of innervation they require by secreting neurotrophins, which promote neuronal survival by activating distinct tyrosine kinase receptors. Here, we show that nerve growth factor (NGF) signaling through neurotrophic tyrosine kinase receptor type 1 (TrkA) directs innervation of the developing mouse femur to promote vascularization and osteoprogenitor lineage progression. At the start of primary ossification, TrkA-positive axons were observed at perichondrial bone surfaces, coincident with NGF expression in cells adjacent to centers of incipient ossification. Inactivation of TrkA signaling during embryogenesis in TrkAF592A mice impaired innervation, delayed vascular invasion of the primary and secondary ossification centers, decreased numbers of Osx-expressing osteoprogenitors, and decreased femoral length and volume. These same phenotypic abnormalities were observed in mice following tamoxifen-induced disruption of NGF in Col2-expressing perichondrial osteochondral progenitors. We conclude that NGF serves as a skeletal neurotrophin to promote sensory innervation of developing long bones, a process critical for normal primary and secondary ossification.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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