# Neurobehavioral phenotypes of mouse models of Osteogenesis Imperfecta

> **NIH NIH R21** · BOSTON CHILDREN'S HOSPITAL · 2022 · $231,304

## Abstract

Osteogenesis Imperfecta (OI), which affects nearly 20,000 US citizens, is a genetically heterogeneous
disorder that causes skeletal fragility. Patients with OI live with significant chronic pain, which also affects their
level of activity and quality of life. Bisphosphonates are currently used off-label in children with OI to improve
bone mass and reduce skeletal deformity. Yet, despite improvements in bone mass, double-blind placebo-
control trials have not found reduced fracture rates in OI patients who have received bisphosphonates. A
suggested explanation for this apparent lack of efficacy is that bisphosphonate-induced increases in bone
mass also reduce pain and as a consequence increase patient activity. Thus, it is the increased activity that
paradoxically causes bisphosphonate-treated OI patients to fracture at the same rate as untreated patients.
However, the ability to robustly assess pain and activity in OI patients is limited by several factors. OI patients
have a range of clinical severity that is influenced by their specific mutation, genetic background, age, and
environment. In addition, non-physiological factors such as cognitive, behavioral, and spiritual components
affect how OI patients self-report pain, activity, and quality of life.
 We found that the automated Holeboard assay reveals significant differences in activity and exploratory
behavior between the Jrt mouse model of moderate OI and wild-type littermates, independent of fracture. We
now want to determine if therapies that increase bone mass, such as promoting bone anabolism by enhancing
Wnt signaling and preventing catabolism by inhibiting osteoclast activity, improve activity and increase
exploratory behavior in the Jrt mice, and we want to extend our studies to AGA2 mice, a more severe model of
OI. We will also determine if the opioid analgesic Buprenorphine-SR increases activity and behavior in mouse
models of OI, independent of fracture or increasing bone mass. Even though mice are not humans, peripheral
and central pain perception pathways are highly conserved between these species. Moreover, cohorts of mice
with the same mutation on a fixed genetic background can be housed and handled similarly, evaluated at the
same age, time of day, and in a consistent order and spacing between tests.
 Successful completion of these experiments will inform us whether therapies that affect bone mass and
bone properties provide additional benefits, such as increased activity and reduced anxiety. If these additional
benefits occur in OI mice, they are likely to occur in OI patients as well.

## Key facts

- **NIH application ID:** 10416072
- **Project number:** 5R21AR077292-02
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Matthew L Warman
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $231,304
- **Award type:** 5
- **Project period:** 2021-06-02 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10416072

## Citation

> US National Institutes of Health, RePORTER application 10416072, Neurobehavioral phenotypes of mouse models of Osteogenesis Imperfecta (5R21AR077292-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10416072. Licensed CC0.

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