In this new project we will explore the role of sensory nerves in bone. In contrast to increasing body of work on to the role of angiogenesis in bone development, few studies have investigated the role of nerves in bone despite a wealth of circumstantial evidence implicating the importance of innervation in skeletal development and repair. This knowledge gap is in part due the difficulty of identifying nerve fibers in calcified tissue and the lack of tractable model systems for study skeletal innervation. To overcome these limitations, our laboratory has validated mouse models for visualizing and disrupting functional signaling of sensory nerves that innervate the skeleton. Using these models we demonstrate that tropomyosin receptor kinase A (TrkA) expressing sensory neurons emanating from the dorsal root ganglion project axons to nerve growth factor (NGF) expressing perichondral cells of developing limbs coincident with incipient mineralization of adjacent cartilage. Elimination of TrkA kinase activity in these sensory nerves during embryogenesis retards axonal ingrowth and attenuates nascent bone mineralization. Disruption of TrkA signaling during embryogenesis reduces postnatal bone acquisition and retards the regeneration of adult bone in response to experimental fracture. These observations, and other studies described below, provide direct evidence for the requirement of TrkA sensory nerves in bone development, acquisition and repair. The studies outlined in this proposal will explore the mechanisms through which sensory nerves function to promote osteogenesis. Our approach will test the hypothesis that nerve growth factor (NGF) produced in the developing and injured limb mesenchyme activates TrkA sensory neurons to promote their survival and guide their axons to primary ossification centers to initiate osteoblast differentiation. This hypothesis will be tested in a setting of bone development (Aim 1) and in response to an established model of experimental bone repair (Aim 2). We believe that our project will yield new insights into the role of sensory nerves in healthy humans and will ultimately inform on the neuropathological manifestations associated with certain bone disorders.

Public Health Relevance

Anyone who has broken a bone knows of the existence and function of sensory nerves in bone, however, little is known about how nerves innervate the skeleton and what purpose beyond pain these nerves perform. In this project, we will use several novel approaches to characterize the timing of innervation and the consequence of blocking nerve action on bone development and repair. Our results are expected to yield new insights into the role of sensory nerves in bone.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR068934-03
Application #
9275906
Study Section
Special Emphasis Panel (ZRG1-MOSS-U (90)S)
Program Officer
Wang, Fei
Project Start
2015-06-01
Project End
2020-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
3
Fiscal Year
2017
Total Cost
$356,400
Indirect Cost
$136,400
Name
Johns Hopkins University
Department
Orthopedics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Tomlinson, Ryan E; Li, Zhi; Li, Zhu et al. (2017) NGF-TrkA signaling in sensory nerves is required for skeletal adaptation to mechanical loads in mice. Proc Natl Acad Sci U S A 114:E3632-E3641
Tomlinson, Ryan E; Li, Zhi; Zhang, Qian et al. (2016) NGF-TrkA Signaling by Sensory Nerves Coordinates the Vascularization and Ossification of Developing Endochondral Bone. Cell Rep 16:2723-2735