PMID- 31638597
OWN - NLM
STAT- MEDLINE
DCOM- 20200622
LR  - 20240422
IS  - 1558-8238 (Electronic)
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 129
IP  - 12
DP  - 2019 Dec 2
TI  - Fracture repair requires TrkA signaling by skeletal sensory nerves.
PG  - 5137-5150
LID - 128428 [pii]
LID - 10.1172/JCI128428 [doi]
AB  - Bone is richly innervated by nerve growth factor-responsive (NGF-responsive) 
      tropomyosin receptor kinase A-expressing (TrKa-expressing) sensory nerve fibers, 
      which are required for osteochondral progenitor expansion during mammalian 
      skeletal development. Aside from pain sensation, little is known regarding the 
      role of sensory innervation in bone repair. Here, we characterized the 
      reinnervation of tissue following experimental ulnar stress fracture and assessed 
      the impact of loss of TrkA signaling in this process. Sequential histological 
      data obtained in reporter mice subjected to fracture demonstrated a marked 
      upregulation of NGF expression in periosteal stromal progenitors and 
      fracture-associated macrophages. Sprouting and arborization of CGRP+TrkA+ sensory 
      nerve fibers within the reactive periosteum in NGF-enriched cellular domains were 
      evident at time points preceding periosteal vascularization, ossification, and 
      mineralization. Temporal inhibition of TrkA catalytic activity by administration 
      of 1NMPP1 to TrkAF592A mice significantly reduced the numbers of sensory fibers, 
      blunted revascularization, and delayed ossification of the fracture callus. We 
      observed similar deficiencies in nerve regrowth and fracture healing in a mouse 
      model of peripheral neuropathy induced by paclitaxel treatment. Together, our 
      studies demonstrate an essential role of TrkA signaling for stress fracture 
      repair and implicate skeletal sensory nerves as an important upstream mediator of 
      this repair process.
FAU - Li, Zhu
AU  - Li Z
AD  - Department of Orthopaedics, Johns Hopkins University, Baltimore, Maryland, USA.
AD  - Baltimore Veterans Administration Medical Center, Baltimore, Maryland, USA.
FAU - Meyers, Carolyn A
AU  - Meyers CA
AD  - Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.
FAU - Chang, Leslie
AU  - Chang L
AD  - Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.
FAU - Lee, Seungyong
AU  - Lee S
AD  - Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.
FAU - Li, Zhi
AU  - Li Z
AD  - Department of Orthopaedics, Johns Hopkins University, Baltimore, Maryland, USA.
FAU - Tomlinson, Ryan
AU  - Tomlinson R
AD  - Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
FAU - Hoke, Ahmet
AU  - Hoke A
AD  - Department of Neuroscience, Johns Hopkins University, Baltimore, Maryland, USA.
FAU - Clemens, Thomas L
AU  - Clemens TL
AD  - Department of Orthopaedics, Johns Hopkins University, Baltimore, Maryland, USA.
AD  - Baltimore Veterans Administration Medical Center, Baltimore, Maryland, USA.
FAU - James, Aaron W
AU  - James AW
AD  - Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.
LA  - eng
GR  - K08 AR068316/AR/NIAMS NIH HHS/United States
GR  - IK6 BX004984/BX/BLRD VA/United States
GR  - R21 DE027922/DE/NIDCR NIH HHS/United States
GR  - T32 AR067708/AR/NIAMS NIH HHS/United States
GR  - R01 AR070773/AR/NIAMS NIH HHS/United States
GR  - R01 AR068934/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 9061-61-4 (Nerve Growth Factor)
RN  - EC 2.7.10.1 (Receptor, trkA)
SB  - IM
MH  - Animals
MH  - Disease Models, Animal
MH  - *Fracture Healing
MH  - Fractures, Bone/*metabolism
MH  - Fractures, Stress
MH  - Ganglia, Spinal/metabolism
MH  - Genes, Reporter
MH  - Imaging, Three-Dimensional
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Nerve Growth Factor/metabolism
MH  - Osteogenesis
MH  - Periosteum/metabolism
MH  - Receptor, trkA/*metabolism
MH  - Sensory Receptor Cells/*metabolism
MH  - Signal Transduction
MH  - Stem Cells
MH  - Transgenes
MH  - X-Ray Microtomography
PMC - PMC6877307
OTO - NOTNLM
OT  - Bone Biology
OT  - Bone disease
COIS- Conflict of interest: The James laboratory receives research support from 
      Musculoskeletal Transplant Foundation (MTF) Biologics.
EDAT- 2019/10/23 06:00
MHDA- 2020/06/23 06:00
PMCR- 2020/03/02
CRDT- 2019/10/23 06:00
PHST- 2019/02/27 00:00 [received]
PHST- 2019/08/20 00:00 [accepted]
PHST- 2019/10/23 06:00 [pubmed]
PHST- 2020/06/23 06:00 [medline]
PHST- 2019/10/23 06:00 [entrez]
PHST- 2020/03/02 00:00 [pmc-release]
AID - 128428 [pii]
AID - 10.1172/JCI128428 [doi]
PST - ppublish
SO  - J Clin Invest. 2019 Dec 2;129(12):5137-5150. doi: 10.1172/JCI128428.