# NGF-TrkA Signaling in Load-Induced Bone Formation

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2020 · $343,200

## Abstract

Project Summary/Abstract
Nearly all of the sensory nerves that innervate bone express neurotrophic tyrosine kinase receptor type 1 (TrkA),
the high affinity receptor for nerve growth factor (NGF). In mature bone, these specialized sensory nerves blanket
the periosteum in a dense mesh-like network, occupying a preferential location for biomechanical signaling.
However, the mechanism by which NGF is regulated in the osteoblast and the signals transmitted to bone by
sensory nerves remain unknown. Our main objective in this project is to determine the upstream mediators and
downstream effectors of NGF-TrkA signaling during strain adaptive bone remodeling. Our central hypothesis is
that activation of NF-κB signaling in mature osteoblasts is required for the expression of NGF in response to
mechanical load, which in turn activates TrKA sensory nerves to provide osteogenic cues that support load-
induced bone formation. In Specific Aim 1, we will determine the regulation of NGF expression in osteoblasts
using in vitro pulsatile fluid flow and in vivo forelimb axial compression of conditional knockout mice. In Specific
Aim 2, we will identify nerve-derived signals that promote load-induced bone formation by analyzing mRNA and
protein from loaded limbs in mouse models of diminished NGF-TrkA signaling, with validation using an in vitro
microfluidic platform. In Specific Aim 3, we will assess a potential therapeutic application of this signaling pathway
to increase bone accrual following osteogenic mechanical loading without hyperalgesia. In total, the results from
this study will define the upstream mediators and downstream effectors of NGF-TrkA signaling during strain
adaptive bone remodeling and provide a potential therapeutic tool for leveraging this system to improve skeletal
health. Moreover, the proposed studies are highly aligned with the NIAMS Long-Range Plan, and our
interdisciplinary team is uniquely positioned to advance these specific aims.

## Key facts

- **NIH application ID:** 9894734
- **Project number:** 5R01AR074953-02
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Ryan Tomlinson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $343,200
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9894734

## Citation

> US National Institutes of Health, RePORTER application 9894734, NGF-TrkA Signaling in Load-Induced Bone Formation (5R01AR074953-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9894734. Licensed CC0.

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