# The LRP5 Pathway and Osteoblast Function In Osteogenesis Imperfecta

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2020 · $626,530

## Abstract

Osteogenesis Imperfecta (OI) is a genetic disorder characterized by low bone mass that predisposes
children and adults to skeletal fracture. Most patients with OI have a mutation in one of the two genes that
encode type 1 collagen. Current medical therapies for patients with OI are limited, acting by preventing bone
turnover to increase bone mass and do not decrease fracture rate in all patients. Our previous work has shown
that enhancing bone anabolism via the low density lipoprotein receptor related-protein 5 (LRP5) signaling
pathway, either through a genetic mutation that increases signaling or administration of an antibody that binds
an inhibitor of the pathway, leads to significant increases in bone mass and bone strength in several mouse
models of OI caused by dominant type 1 collagen mutations. In addition, we have shown that osteoblasts from
mice with OI have ER swelling that improves with increased LRP5 signaling, suggesting that protein trafficking
is improved. This is important as therapies (Sclerostin antibody) are available that increase LRP5 signaling and
our data suggest they will be have dual beneficial effects in patients with OI, both increasing bone matrix
production and improving osteoblast function. In the present application, we propose to utilize two different
mouse models of dominant OI 1) To identify the molecular mechanisms by which an Lrp5 HBM mutation
improves protein trafficking of type I collagen in dominant forms of OI, 2) To determine the effect of
treatment with Sclerostin antibody on osteoblast development and function in OI and 3) To determine if
increased LRP5 signaling is required during osteoblast development to improve osteoblast function in
dominant forms of OI. The successful completion of these aims will allow for greater understanding of the
mechanisms by which increased LRP5 signaling both increases collagen production and improves osteoblast
function. Together the results will show that therapies targeting LRP5 signaling, unlike other currently available
treatments, not only increase collagen production but also treat the specific osteoblast dysfunction seen in OI,
which may lead to better outcomes for patients.

## Key facts

- **NIH application ID:** 9950844
- **Project number:** 5R01AR071342-03
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** CHRISTINA MARIE JACOBSEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $626,530
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9950844

## Citation

> US National Institutes of Health, RePORTER application 9950844, The LRP5 Pathway and Osteoblast Function In Osteogenesis Imperfecta (5R01AR071342-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9950844. Licensed CC0.

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