# Project 1: The role of WNT1 signaling in osteogenesis imperfecta

> **NIH NIH P01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $429,614

## Abstract

Project 1 Project Summary
 Osteogenesis imperfecta (OI) is one of the most common skeletal dysplasias. Most cases are caused
by either qualitative or quantitative defects in type I collagen. We previously identified the pathogenic
mechanism of recessively inherited OI caused by CRTAP and P3H1 mutations, components of a collagen
prolyl 3-hydroxylation complex. We also identified mutations in the signaling molecules PEDF, IFITM5, and
WNT1 causing recessive OI. Importantly, our WNT1 finding identified the first specific WNT ligand involved in a
human skeletal dysplasia. Surprisingly, WNT1 is best known for its functions in neural crest and cerebellar
development, while its essential function in bone was a surprise. Hence, there are many unanswered
questions regarding WNT1-related OI: 1) What are the tissue-specific requirements of WNT1 in bone? 2)
Which signaling pathways mediate WNT1 function in bone? 3) Can therapeutics that target Wnt signaling show
differential efficacy in distinct OI types? 4) What other Wnt-signaling pathway genes contribute to OI and/or low
bone mass? The goals of Project 1 are to understand the functions of WNT1 in bone development and
homeostasis; to identify the pathogenic mechanisms by which mutations in WNT1 lead to OI; to test the
potential of anti-sclerostin antibody treatment for WNT1-related vs. other types of OI; and to identify novel
genes in the WNT and collagen modification pathway leading to OI. Our preliminary data show that Wnt1
mutant mice (swaying) exhibit spontaneous fractures and reduced bone mass. Moreover, overexpression of
Wnt1 increases osteoblast differentiation and activates mTORC1 signaling in vitro. We hypothesize that Wnt1
expressed in osteocytes contributes to bone homeostasis by regulating mTORC1 signaling in osteoblasts. We
will test this hypothesis by accomplishing the following specific aims: Aim 1. What are the tissue and cell-
specific contributions of Wnt1 to skeletal development and homeostasis? Aim 2. What are the downstream
signaling pathways that mediate Wnt1 functions in skeletal development and homeostasis? Aim 3. What are
the effects of Wnt-targeted therapies in different forms of OI? Aim 4. Are there rare forms of OI that identify
new and essential components of collagen processing and/or Wnt signaling in bone?

## Key facts

- **NIH application ID:** 9974353
- **Project number:** 5P01HD070394-10
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Brendan Lee
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $429,614
- **Award type:** 5
- **Project period:** — → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9974353

## Citation

> US National Institutes of Health, RePORTER application 9974353, Project 1: The role of WNT1 signaling in osteogenesis imperfecta (5P01HD070394-10). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9974353. Licensed CC0.

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