# Lrp4 signaling in bone metabolism and mechanotransduction

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2021 · $607,734

## Abstract

The search for molecular targets/pathways that can be manipulated to improve bone properties is a highly
active area of investigation. Recently, particular interest has been expressed in targeting biomolecules that can
augment mechanical signaling in bone; the next generation of osteoporosis drugs is likely to work in
conjunction with physical activity/loading in order to disproportionately direct new bone formation to skeletal
areas that need it most (i.e., those regions that endure the greatest strains and are at the greatest risk of
failure). The WNT signaling pathway has emerged as a key regulator of bone mass and strength, but also of
bone cell mechanotransduction. Recent work by Professor Wim van Hul in Antwerp and by Novartis Pharma in
Basel identified an accessory protein—LRP4—that regulates the activity of SOST, which is a secreted inhibitor
of the WNT co-receptors LRP5/LRP6. Specific missense mutations in LRP4 cause high bone mass (HBM)
phenotypes by eliminating SOST-mediated inhibition of LRP5/LRP6. The goal of the present application is to
understand precisely how LRP4, LRP5, and LRP6 function to regulate bone metabolism and
mechanotransduction, which ultimately will reveal new approaches for preventing or treating bone disorders—a
primary mission of NIAMS/NIH. Among the key questions we addressed are: (1) Is the principal role of LRP4
in bone to bind SOST? (2) Does LRP4 directly present SOST to LRP5/LRP6 or simply increase local
concentration of this inhibitor? (3) Does LRP4 function throughout osteoprogenitor differentiation, or does it
have stage-specific roles? (4) Does LRP4 regulate LRP5 and LRP6 equally, or is LRP4 more important for one
of these two WNT co-receptors? (5) Will bone-specific deletion/inhibition of LRP4 prevent the bone-wasting
effects of mechanical disuse? (6) Does LRP4 coordinate the deposition of new bone to high-strain surfaces
during mechanical loading? (7) Do LRP5 and LRP6 differ in terms of when (early vs. late in differentiation) and
where (cortical vs. trabecular envelopes) they are active? (8) Which upstream and downstream mechanical
signaling pathways will be identified in specific bone cell subtypes using single-cell transcriptomics of loaded
and unloaded bone? We will use cutting-edge, novel, mouse models (CRISPR-based Lrp4 and Lrp6
knockins), single-cell transcriptomic approaches (Drop-seq and 10XGenomics), live cell microscopic
techniques (FRET/FLIM), mechanotransduction models (strain mapping in ulnar loading and tail suspension),
and radiographic/histologic/biochemical approaches to reveal the underlying biology and therapeutic potential
of LRP4, LRP5, and LRP6 manipulation in bone tissue. The project is a continuation of the close collaboration
between the Robling (Indiana Univ.) and Warman (Harvard Univ.) labs, an extremely fruitful partnership for
more than 12 yrs. We have assembled a unique combination of expertise, resources, biological models/tools,
and technical innovation to elucidate the ...

## Key facts

- **NIH application ID:** 10247070
- **Project number:** 5R01AR053237-15
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** ALEXANDER G ROBLING
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $607,734
- **Award type:** 5
- **Project period:** 2005-09-30 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247070

## Citation

> US National Institutes of Health, RePORTER application 10247070, Lrp4 signaling in bone metabolism and mechanotransduction (5R01AR053237-15). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10247070. Licensed CC0.

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