# Neuronal Regulation of Skeletal Development and Repair

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $484,215

## Abstract

ABSTRACT
This is a renewal application of a program investigating the role of sensory nerves in bone. Our studies
during the first funding period demonstrate that NGF-dependent TrkA signaling by sensory nerves is the
primary driver of angiogenesis and osteogenesis in the developing femur and skull. In these avascular
settings, acute up-regulation of NGF in mesenchymal lineage cell domains is followed by nociceptive fiber
ingrowth, which subsequently home to locations of proliferating mesenchymal cells. Blockade of sensory
nerve ingrowth, either by inhibition of TrkA signaling or disruption of NGF, retards vascularization and
disrupts femoral and calvarial bone formation. Histological data in the calvaria model revealed that loss
of sensory nerve fibers is associated with reduced numbers of proliferating mesenchymal progenitor cells
(MPCs) in the sutures and premature suture closure. These observations suggest a paradigm in which
sensory nerves function in developing bone to maintain MPC plasticity, a concept well established in
models of limb regeneration and supported by recent studies in developing mouse femur. Our preliminary
findings directly examining the interaction of sensory nerve axons with MPCs in microfluidic chambers
suggest that infiltrating DRG nerve fibers induce MPC proliferation, but limit differentiation in a non-contact
dependent fashion. These effects appear to be mediated by neural derived FSTL1, which induces MPC
proliferation and impairs BMP-induced osteogenic differentiation. Together, this data support the premise
that TrkA+ sensory nerves function in developing bone to maintain stem cells in a proliferative,
undifferentiated state by delivering soluble factors that activate mitogenic and anti-differentiation
signaling pathways.
This conceptual model will be explored in studies divided into two Specific Aims. Specific Aim 1 will define the
spatiotemporal patterning of TrkA+ skeletal sensory nerves in the developing cranium, determine their
influence on MPC proliferation and cellular fate, and further elucidate signaling pathways associated with
impaired innervation. Specific Aim 2 will identify sensory axon-derived factors that regulate MPC proliferation
and cell fate decisions, and definitively identifying FSTL1 as a neural-derived factor which impacts MPC
cellular behavior. Our results should provide new insights into the fundamental roles sensory nerves play in
skeletal morphogenesis, homeostasis and repair, and provide critical insight into the neuropathological
manifestations associated with bone disorders in humans.

## Key facts

- **NIH application ID:** 10378304
- **Project number:** 2R01DE031028-06A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Thomas L Clemens
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $484,215
- **Award type:** 2
- **Project period:** 2021-09-07 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10378304

## Citation

> US National Institutes of Health, RePORTER application 10378304, Neuronal Regulation of Skeletal Development and Repair (2R01DE031028-06A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10378304. Licensed CC0.

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