# Harnessing the anabolic potential of Wnt signaling to improve bone health

> **NIH VA I01** · RLR VA MEDICAL CENTER · 2021 · —

## Abstract

Osteoporosis (porous bone disease) is a disease of the skeleton that can have debilitating
effects on many US veterans. An estimated 44 million Americans, or 55 percent of the people
50 years of age and older, are currently at risk for osteoporotic fracture. Improved treatment
options for the disease require a greater understanding of the cellular events and signaling
pathways that control bone metabolism. The proposed research capitalizes on a recently
identified secreted inhibitor of Wnt glycoproteins. The long-term goal of the proposed project is
to investigate whether targeting a new, secreted inhibitor of Wnt signaling—Notum--can improve
bone properties and reduce fracture susceptibility. In the first aim we propose to determine the
cell type in which Notum inhibition exerts its effects on bone homeostasis, by crossing
conditional Notum mutant mice to different Cre drivers that are active during different stages of
the mesenchymal cell lineage. We will also look the gene expression changes induced by
Notum inhibition to see if the canonical Wnt pathway, the noncanonical Wnt pathway, the
Hedgehog pathway, or some other pathway, is primarily affected. We will also identify
downstream nodes in the pathways altered by Notum inhibition, to see if there are more readily
targetable effectors of the HBM phenotype induced by Notum inhibition. I the second aim, we
will conduct functional studies targeting Notum, which has direct applicability to future
therapeutic approaches in patients. Glucocorticoids are widely used among the veteran
population for numerous conditions, including organ transplant, rheumatoid arthritis,
inflammatory bowel disease, and others, but side effects are not trivial, and bone wasting is a
major concern among glucocorticoid-treated patients. Likewise, mechanical disuse is a major
problem among veterans, which results from long term bedrest, paralysis, and other
complications. We will inhibit Notum in these preclinical models to determine whether Notum
inhibition represents a viable strategy for preserving bone mass and function during two relevant
bone wasting conditions. In this renewal Merit application, we address these questions in order
to identify new ways to improve bone health among the veteran population, and among the
public in general.

## Key facts

- **NIH application ID:** 10013686
- **Project number:** 2I01BX001478-09
- **Recipient organization:** RLR VA MEDICAL CENTER
- **Principal Investigator:** ALEXANDER G ROBLING
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2012-01-01 → 2024-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10013686

## Citation

> US National Institutes of Health, RePORTER application 10013686, Harnessing the anabolic potential of Wnt signaling to improve bone health (2I01BX001478-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10013686. Licensed CC0.

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