# Canonical Wnt Signaling as a Novel Regulator of Chondrocyte to Osteoblast Transdifferentiation during Endochondral Bone Repair in the Mandible

> **NIH NIH F30** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $51,836

## Abstract

PROJECT SUMMARY / ABSTRACT
There are approximately 15 million bone fractures annually and the mandible sustains the majority of fractures
of the craniofacial skeleton. Importantly, prevalence of impaired healing is significant and remains an unmet
clinical need. Understanding the mechanisms that direct fracture healing is imperative to the development of
improved therapies. The mandible heals through the process of endochondral ossification, in which a cartilage
intermediate forms and is later replaced by bone. Recent work has revealed a new model of endochondral
ossification in which chondrocytes of the cartilage intermediate transdifferentiate into osteoblasts that form the
new bone at a region adjacent to the invading vasculature. The mechanisms underlying chondrocyte
transdifferentiation have not been explored, but my preliminary data, along with previously published work,
indicate that canonical Wnt signaling may be a central mediator of chondrocyte transdifferentiation. For this
project I aim to understand the role of canonical Wnt signaling during endochondral bone repair, and then test
the therapeutic effect of a novel, water-soluble molecule that strongly activates Wnt signaling. The central
hypothesis for this project is that canonical Wnt signaling regulates chondrocyte transdifferentiation by inducing
the osteogenic program and that activation of the Wnt pathway through administration of Wnt-Surrogate
accelerates mandible fracture healing by increasing the rate of conversion of chondrocytes to osteoblasts.
To determine the role of canonical Wnt signaling during endochondral fracture repair, in my first Aim, I will use
transgenic mouse strains to conditionally inhibit or activate canonical Wnt signaling in chondrocytes comprising
the fracture callus. I will assess the effects of Wnt signaling on chondrocyte transdifferentiation by measuring
the rate of cartilage to bone conversion. The effect of Wnt signaling on cellular re-programming will be
determined by measuring the expression levels and patters of chondrogenic and osteogenic genes in
chondrocytes using qPCR, in situ hybridization, immunohistochemistry, and stereology.
In the second Aim, I will test the therapeutic effect of a novel surrogate Wnt ligand to promote fracture repair.
The Garcia Laboratory (Stanford) has kindly provided us with the Wnt-Surrogate that strongly activates Wnt
signaling in vitro. To determine the osteogenic effects of Wnt-surrogate, cartilage explants will be assessed for
matrix mineralization and alkaline phosphatase activity in vitro. Additionally, mandible fracture models will be
assessed for bone mineral density and rate of healing. Design of Experiments (DOE) methodologies will be
used to optimize the dose and timing of Wnt-Surrogate administration, which will be applied to further in vivo
analysis of the effect of Wnt-Surrogate on biomechanical strength and rate of bone formation. Taken together
this study will provide improtant information regardin...

## Key facts

- **NIH application ID:** 10329923
- **Project number:** 5F30DE026359-06
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Sarah Anne Wong
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $51,836
- **Award type:** 5
- **Project period:** 2016-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10329923

## Citation

> US National Institutes of Health, RePORTER application 10329923, Canonical Wnt Signaling as a Novel Regulator of Chondrocyte to Osteoblast Transdifferentiation during Endochondral Bone Repair in the Mandible (5F30DE026359-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10329923. Licensed CC0.

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