title: NGF-TrkA Signaling by Sensory Nerves Coordinates the Vascularization and Ossification of Developing Endochondral Bone.
abstract: 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 TrkA(F592A) 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.
authors: Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, MD 21287, USA.
authors: Ryan E
authors: RE
authors: Tomlinson
authors: Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, MD 21287, USA.
authors: Zhi
authors: Z
authors: Li
authors: Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, MD 21287, USA.
authors: Qian
authors: Q
authors: Zhang
authors: Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, MD 21287, USA.
authors: Brian C
authors: BC
authors: Goh
authors: Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, MD 21287, USA.
authors: Zhu
authors: Z
authors: Li
authors: Department of Radiology and Radiological Sciences, Johns Hopkins University, Baltimore, MD 21287, USA; Department of Oncology, Johns Hopkins University, Baltimore, MD 21287, USA.
authors: Daniel L J
authors: DLJ
authors: Thorek
authors: Department of Neurology, Johns Hopkins University, Baltimore, MD 21287, USA.
authors: Labchan
authors: L
authors: Rajbhandari
authors: Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, MD 21287, USA.
authors: Thomas M
authors: TM
authors: Brushart
authors: Department of Pharmacology, Oxford University, Oxford OX1 3QT, UK.
authors: Liliana
authors: L
authors: Minichiello
authors: Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, MD 21287, USA.
authors: Fengquan
authors: F
authors: Zhou
authors: Department of Neurology, Johns Hopkins University, Baltimore, MD 21287, USA.
authors: Arun
authors: A
authors: Venkatesan
authors: Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, MD 21287, USA; Baltimore Veterans Administration Medical Center, Baltimore, MD 21201, USA. Electronic address: tclemen5@jhmi.edu.
authors: Thomas L
authors: TL
authors: Clemens
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D004622:Embryo, Mammalian / Q000294:innervation; D005269:Femur / Q000098:blood supply* / Q000254:growth & development / Q000294:innervation*; D006614:Hindlimb / Q000294:innervation; D051379:Mice; D018919:Neovascularization, Physiologic; D020932:Nerve Growth Factor / Q000378:metabolism*; D010012:Osteogenesis; D020917:Receptor, trkA / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D020932:Nerve Growth Factor; D020917:Receptor, trkA
keywords: endochondral bone; nerve growth factor; neurotrophic tyrosine kinase receptor type 1; sensory nerves