# Response of the Osteoporotic Skeleton to in Vivo Loading

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $400,590

## Abstract

PROJECT SUMMARY
There is an unmet clinical need for anabolic strategies to treat the 50 million women and men in
the U.S. with severely or moderately low bone mass (osteoporosis or osteopenia, respectively).
Mechanical loading is a potent, physiological means to stimulate bone formation and increase
bone mass. However, with aging, humans and rodents have a decline in their ability to form
bone in response to exercise and other forms of mechanical loading. The basis for this decline
remains unknown. Our long-term goal is to identify key mechanisms in loading-induced bone
formation in the adult skeleton so that we may inform future strategies to increase bone mass in
osteoporosis. Our focus in this project is on the origin of osteoblasts that form bone in response
to mechanical loading, and on the Wnt signaling pathway. We propose experiments using a
physiological model of bone anabolism – murine axial tibial compression – that will extend our
scientific knowledge as follows. First, we will determine the origin of osteoblasts (in young-adult
and old mice) that form bone in response to in vivo mechanical loading. Modern lineage tracing
and histological methods will be applied to address this basic unknown. Second, we will
determine if osteoblast lineage cells in old mice are less proliferative than in young mice in
response to in vivo loading. If so, this will provide motivation to develop strategies to target this
deficit to enhance mechanoresponsiveness. Third, motivated by the finding that Wnts1 and 7b
are highly responsive to bone mechanical loading, we will determine the role of these ligands
produced by osteoblasts in loading-induced bone formation. Inducible, conditional deletion of
Wnt 1 and 7b will be accomplished in adult mice, followed by mechanical loading and
assessment of bone formation, cell proliferation and gene expression. If loss of Wnt 1 or 7b
mimics the effects of aging, it will motivate targeted treatment strategies to rescue the
mechanoresponsiveness of the aged skeleton. In summary, the decline in the anabolic
response of bone to mechanical loading is a central feature of skeletal aging. The proposed
studies will clarify the basis for this decline while addressing fundamental mechanisms that
support loading-induced bone formation.

## Key facts

- **NIH application ID:** 9896760
- **Project number:** 5R01AR047867-17
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** MATTHEW J SILVA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $400,590
- **Award type:** 5
- **Project period:** 2001-07-13 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9896760

## Citation

> US National Institutes of Health, RePORTER application 9896760, Response of the Osteoporotic Skeleton to in Vivo Loading (5R01AR047867-17). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9896760. Licensed CC0.

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