# Bone Marrow Inflammation and Bone Resorption

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2022 · $387,674

## Abstract

PROJECT SUMMARY/ABSTRACT
Data from our mouse model of Botulinum Toxin A (BTxA) induced muscle paralysis has revealed that
neuromuscular function, outside the axis of mechanical loading deficits, is a critical modulator of bone
homeostasis. Consistent with this thesis, we have observed that transient muscle paralysis triggers acute
inflammatory signaling within bone marrow that precedes the onset of focal RANKL-mediated
osteoclastogenesis, which is responsible for the profound cortical and trabecular bone resorption observed in
the model. However, the intercellular signaling that initiates acute bone marrow inflammation and subsequent
bone resorption has not been elucidated and therefore presents a barrier to identifying translational strategies
that would decouple neuromuscular dysfunction from bone loss. One potential initiator of this rapid response is
neurogenic inflammation, which is triggered by neuropeptide release from sensory nerves and is amplified by
mast cell mediated histamine release. We therefore pursued a series of preliminary studies to assess
activation of this pathway following muscle paralysis and found that: 1) Substance P, a classic initiator of
neurogenic inflammation, was upregulated in tibia bone marrow within 1 d of calf paralysis, 2) genes
associated with connective tissue mast cell activation were acutely elevated following muscle paralysis, and 3)
muscle paralysis induced bone resorption was significantly diminished in mast cell deficient KitW-sh/W-sh mice.
We therefore hypothesize that: Bone resorption following muscle paralysis is initiated by neuropeptide
signaling and is amplified by mast cell dependent histamine release. We will pursue this thesis via four
complementary Specific Aims (SA), each with a corresponding sub-hypothesis. First, we anticipate that
neuropeptides within bone marrow will be elevated by BTxA induced muscle paralysis prior to evidence of
mast cell activation or bone resorption (SA#1). SA#2 will then demonstrate that successful antagonism of
these neuropeptides will be required to inhibit mast cell activation and bone resorption induced by muscle
paralysis. In SA#3, we will leverage a cKit independent, connective tissue mast cell deficient mouse to
demonstrate that mast cell mediated histamine signaling is responsible for the profound osteoclastogenesis
induced by muscle paralysis. SA#4 will then provide proof of concept that treatment with histamine receptor
antagonists will significantly attenuate bone resorption caused by muscle paralysis. Each aspect of the
proposed signaling pathway (neurogenic inflammation, neuropeptide signaling, mast cell activation, paralysis
induced bone resorption) has been explored in other contexts but has not been integrated into a cellular
signaling cascade that integrates muscle, nerve, and bone physiology. Importantly, if our thesis is supported,
the broad clinical experience with histamine antagonists will enable repurposing of approved drugs toward the
goal o...

## Key facts

- **NIH application ID:** 10489795
- **Project number:** 5R01AR076353-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** TED S. GROSS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $387,674
- **Award type:** 5
- **Project period:** 2021-09-16 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10489795

## Citation

> US National Institutes of Health, RePORTER application 10489795, Bone Marrow Inflammation and Bone Resorption (5R01AR076353-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10489795. Licensed CC0.

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