# Response of the Osteoporotic Skeleton to Mechanical Loading

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $543,441

## Abstract

PROJECT SUMMARY
Wnt signaling and mechanical loading are key regulators of skeletal health. Wnt signaling
initiates when a Wnt ligand binds to frizzled (FZD) and LRP5/6 co-receptors. Several Wnt
pathway factors (Lrp5, Sost) have known roles in bone’s anabolic response to loading. In the
past funding period, we focused on the Wnt ligands (‘Wnts’), which have been relatively
understudied. We discovered that Wnt ligand secretion by Osx+ bone cells
(osteoblasts/osteocytes) is essential for the anabolic response to skeletal loading, and that
Wnt1 upregulation in particular is required. But with aging, loading induces less Wnt1
upregulation and less bone formation. We now shift focus to intervention, and to test the overall
hypothesis that molecules that mimic Wnts can rescue the loss of bone mass and
mechanoresponsiveness that are hallmarks of aging. The ability to test this hypothesis is
enabled by the recent development of Wnt surrogates – antibody-based molecules that function
like Wnt ligands by directly binding FZD and LRP5/6. In contrast to sclerostin antibody-based
treatments that work by “inhibiting the inhibitor”, Wnt surrogates directly activate Wnt signaling.
Our pilot data show that a novel tetravalent molecule that targets several FZD receptors and
LRP5 potently increases bone formation, bone mass and strength in young-adult mice. We
propose to test whether this LRP5-binding Wnt surrogate is effective in increasing bone mass in
two mouse models of osteoporosis – aging and Wnt1 conditional deletion (which models the
early-onset osteoporosis that afflicts people with WNT1 mutations). We also will evaluate the
possible synergy between Wnt surrogate treatment and mechanical loading, and test whether
the surrogate rescues the impaired response to loading seen in aged mice and in Wnt1 mutant
mice. Next, because LRP5 and LRP6 are each required for skeletal health, we will take
advantage of the modularity of the Wnt surrogate platform to compare cell and bone responses
to LRP5-binding and LRP6-binding surrogates. Finally, we will test whether the LRP6-binding
surrogate can rescue osteoporosis in mice with conditional deletion of Lrp5, which models
human osteoporosis-pseudoglioma (OPPG) syndrome. Development of Wnt surrogates
addresses a need for new, targeted anabolic therapies that can be used for a personalized
approach to the treatment of osteoporosis.

## Key facts

- **NIH application ID:** 10824328
- **Project number:** 5R01AR047867-20
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** MATTHEW J SILVA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $543,441
- **Award type:** 5
- **Project period:** 2001-07-13 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10824328

## Citation

> US National Institutes of Health, RePORTER application 10824328, Response of the Osteoporotic Skeleton to Mechanical Loading (5R01AR047867-20). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10824328. Licensed CC0.

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