# Utilizing Bioenergetics to Wake Osteocytes and Lower Thresholds for New Bone Formation

> **NIH NIH R21** · CITY COLLEGE OF NEW YORK · 2020 · $172,700

## Abstract

The goal of this project is to develop an innovative method for mechanically enhancing bone formation by
lowering the mechanical threshold signal required for that formation by osteoblasts. Current clinical methods
utilize approaches that do not necessarily target new formation where most needed and the drugs are subject to
off-target effects. Bone has a principally mechanical function. Thus, adaptation to mechanical loading
strengthens the skeleton in a site and magnitude appropriate manner, at least in healthy people. Those at risk
for osteoporosis often cannot generate, without injury, the high impacts or resistive-type loads required to form
adequate new bone formation. Thus, this work envisions applications to populations at risk for fracture, to
allow for safe, lower levels of impact-type loading. Mechanical loads are detected by osteocyte cells via fluid
flow through small tunnels buried within the bone matrix. The osteocytes are mechanical sensors and signal for
new bone formation upon stimulation with mechanical loads. The first signals are immediate, regular,
intermittent cytoplasmic calcium ion (Ca2+) spikes. The spikes are triggered by oscillatory fluid shear stress
(OFSS) that induces channels in the osteocyte membrane to open to extracellular Ca2+ resulting in the spikes.
The channels open upon stimulation with ATP, the energy molecule of the body. These signaling events are fast
and very few are required to result in eventual new bone formation. However, the magnitude of formation
response appears dependent on the number of osteocytes that exhibit spiking. That number depends on the
magnitude of the loads induced and the concentration of ATP in the osteocyte microenvironment. ATP is
produced by the osteocytes through the breakdown of glucose. Established in vitro and in vivo models will be
used to test whether a drug administered immediately prior to a bout of controlled loads can lower the
osteocyte threshold for response to mechanical loads and result in greater bone formation. Specific Aim 1
tests the hypothesis that increased number of osteocytes are stimulated to exhibit Ca2+ spikes and downstream
responses (β-catenin nuclear translocation and expression of Wnt targets) when OFSS is applied with the drug
in the medium. We will quantify the responding osteocytes at multiple levels of OFSS and multiple
concentrations of the drug. Specific Aim 2 tests the hypothesis that the drug lowers the mechanical
threshold for a bone formation response to a single bout of controlled in vivo loading. The primary outcomes
will be the bone formation rate parameters for mineral apposition and mineralizing surface. In vivo, controlled
mechanical loads will be applied to the mouse tibia that have demonstrated nearly linear increases in bone
formation response with increase in mechanical load magnitude. If this concept is proven then the immediate
impact of this work would be to address the unmet need to provide new bone formation where most
mechan...

## Key facts

- **NIH application ID:** 10020174
- **Project number:** 5R21AR074670-02
- **Recipient organization:** CITY COLLEGE OF NEW YORK
- **Principal Investigator:** James Christopher Fritton
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $172,700
- **Award type:** 5
- **Project period:** 2019-09-17 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10020174

## Citation

> US National Institutes of Health, RePORTER application 10020174, Utilizing Bioenergetics to Wake Osteocytes and Lower Thresholds for New Bone Formation (5R21AR074670-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10020174. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*