# Influence of Genetic Background on Bone Anabolic Response to Mechanical Loading

> **NIH NIH R21** · WASHINGTON UNIVERSITY · 2022 · $214,408

## Abstract

SUMMARY
Osteoporosis is a heritable disease of low bone mass and increased fracture risk. Drugs are available to
treat low bone mass, yet they carry risks and have limited indications. Thus, there remains a need for new
approaches to prevent and treat osteoporosis. Mechanical loading can build and maintain bone mass in
humans, and is a potent bone anabolic stimulus in animals. Studies of skeletal loading in mice provide a
powerful platform to study bone anabolism at the gene, cell and tissue levels. Yet studies to date have been
limited by a lack of genetic diversity – most murine bone loading studies have been done using inbred
C57Bl/6 (B6) mice, and the few done with multiple strains used mice with limited genetic diversity. Thus,
little is known about the contribution of genetic background to bone's anabolic response to mechanical
loading. Our goal is to test the overall hypothesis that the response of bone to mechanical loading is
heritable (i.e., depends on genetic background). We will test this using mice from eight genetically diverse
inbred mouse strains, including five common laboratory strains and three wild-derived strains. These strains
account for 89% of the variation in the mouse genome. In Aim 1, we will apply strain-matched tibial loading
to young-adult mice of the eight inbred strains, and determine cortical bone formation responses. We will
include female and male mice, to allow assessment of genotype and sex main effects, and sex-genotype
interactions. We will then perform RNA-seq analysis on mouse strains identified as low and high responders
in order to explore the transcriptomic differences that may drive the differential loading responses. Skeletal
loading drives fluid flow in the osteocyte lacunocanalicular network (LCN), and it is widely believed that
osteocytes transduce this fluid flow stimulus and regulate the anabolic response to loading. Changes to the
LCN occur with osteoporosis and aging, and may alter the osteocyte micromechanical environment, and in
turn the anabolic response to loading. In Aim 2, we propose to characterize LCN morphology in bones from
the eight inbred strains, and test whether these traits vary between strains. We will use sub-micron
resolution X-ray microscopy and confocal imaging to characterize the osteocyte LCN. We will then explore
whether inter-strain variations in LCN morphology are associated with variations in anabolic response to
loading between strains (from Aim 1). This proposal is appropriate as an R21 Exploratory/ Developmental
grant. Aim 1 is developmental; it will establish whether bone's anabolic response to loading is heritable. If
so, it will provide rationale for large-scale future studies using genetically diverse mice to discover genes
that influence bone's response to loading. Aim 2 will assess the heritability of osteocyte LCN morphology,
which may likewise motivate future studies to identify causal genes. It will also explore a fundamental
question in bone mechanobiology...

## Key facts

- **NIH application ID:** 10373527
- **Project number:** 1R21AR079052-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** MATTHEW J SILVA
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $214,408
- **Award type:** 1
- **Project period:** 2022-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10373527

## Citation

> US National Institutes of Health, RePORTER application 10373527, Influence of Genetic Background on Bone Anabolic Response to Mechanical Loading (1R21AR079052-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10373527. Licensed CC0.

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