# BLRD Research Career Scientist Award Application

> **NIH VA IK6** · RLR VA MEDICAL CENTER · 2022 · —

## 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 human diseases that result in very high bone mass. The genetic causes of these high
bone mass diseases—craniotubular hyperostosis, hyperostosis corticalis, sclerosteosis, van Buchem’s
disease—provide insight into how bone mass can be manipulated in osteoporotic patients to improve their
skeletal health and prevent fractures. Many of the high-bone-mass associated diseases are caused by
mutations in a cell signaling pathway called “Wnt.” Thus, manipulation of the Wnt pathway holds great promise
for skeletal health improvement. This pathway is particularly attractive as a therapeutic target because it can
be manipulated to increase new bone formation, rather than simply prevent further bone loss. The long term
goals of the proposed project are twofold: first, we seek to understand how the secreted inhibitors of Wnt
signaling function as a coordinated unit (i.e., a milieu), by adjusting their expression levels when other
members of the unit are adjusted (e.g., inhibited or deleted). Those adjustments in expression in the members
of the milieu represent prime targeting opportunities to enact large changes in anabolic action in bone, as our
supporting data suggest. We also seek to understand how this Wnt inhibitor milieu controls the anabolic action
of mechanical loading—a potent anabolic stimulus that has lasting benefits to the skeleton. We seek to
understand whether certain members of the inhibitory milieu function as “homing signals” to ensure that new
bone is added where it is needed most – to the high strain regions of the bone, and that it is not added where it
is not needed – to the low strain regions of the bone. Again, our data suggest that the Wnt inhibitory milieu
plays a significant role in this process. Our second goal of the application is to conduct functional studies
targeting the Wnt inhibitor milieu, that have direct applicability to future therapeutic approaches in patients.
Bone wasting conditions such as mechanical disuse (e.g., bedrest, paralysis) and glucocorticoid therapy (a
drug used for treating inflammation and immunosuppression) are common among veterans. Based on
measurements we and others have made regarding the changes in expression of Wnt inhibitors following
disuse and glucocorticoid exposure, we hypothesize that the “compensatory milieu” of four Wnt inhibitors–Sost,
Dkk1, sFrp4, and Wise—coordinate via unknown mechanisms to prevent anabolic action in the presence of
disuse glucocorticoid therapy. We propose to target the entire milieu in different combinations, to determine
wheth...

## Key facts

- **NIH application ID:** 10485574
- **Project number:** 2IK6BX003783-06
- **Recipient organization:** RLR VA MEDICAL CENTER
- **Principal Investigator:** ALEXANDER G ROBLING
- **Activity code:** IK6 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2017-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10485574

## Citation

> US National Institutes of Health, RePORTER application 10485574, BLRD Research Career Scientist Award Application (2IK6BX003783-06). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10485574. Licensed CC0.

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