# Neuronal Regulation of Skeletal Development and Repair

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2022 · $479,373

## 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 osteogenic precursors in the sutures and
premature suture closure. These observations suggest a paradigm in which sensory nerves function in
developing bone to maintain mesenchymal stem cell 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 MSCs in microfluidic chambers suggest that
infiltrating DRG nerve fibers induce MSC proliferation, but limit differentiation in a non-contact dependent fashion.
These effects are accompanied by upregulation of osteoprogenitor mitogens (e.g. TGF) and inhibitors of MSC
differentiation (e.g. follistatin-like 1). 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 three Specific Aims. Specific Aim 1 will define the
spatiotemporal patterning of TrkA+ skeletal sensory nerves in the developing cranium, and determine their
influence on osteoprogenitor proliferation and cellular fate. Specific Aim 2 will identify key target genes in MSCs
impacted by sensory nerve signals using previously validated co-culture methods. Specific Aim 3 will identify
sensory axon-derived factors that regulate MSC proliferation and cell fate decisions. 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:** 10785405
- **Project number:** 7R01DE031028-08
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Thomas L Clemens
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $479,373
- **Award type:** 7
- **Project period:** 2023-02-20 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10785405

## Citation

> US National Institutes of Health, RePORTER application 10785405, Neuronal Regulation of Skeletal Development and Repair (7R01DE031028-08). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10785405. Licensed CC0.

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