# Notch Signaling in Endochondral Bone Development

> **NIH NIH R01** · DUKE UNIVERSITY · 2021 · $343,574

## Abstract

PROJECT SUMMARY:
 A primary function of growth plate cartilage is to support bone formation and elongation during endochondral
ossification. Growth plate chondrocytes undergo rapid proliferation and matrix synthesis followed by hypertrophic
differentiation. Hypertrophic chondrocytes secrete various factors that degrade the cartilage matrix, recruit vascular
cells and osteoblast progenitors, and promote the differentiation of osteoblasts responsible for new bone formation.
Dogma dictates that hypertrophic chondrocytes ultimately undergo apoptosis to facilitate removal of the cartilage
template that is eventual replaced by bone. Recent cartilage-specific lineage tracing studies have suggested that
terminal hypertrophic chondrocytes are capable of directly differentiating into mature osteoblasts during bone
formation and repair via a process known as transdifferentiation. However, our preliminary data suggests that at least
a subset of terminal hypertrophic chondrocytes undergo dedifferentiation to generate bone marrow mesenchymal
stem/progenitor cells (BMSCs) capable of differentiating into various mature cell types including: osteoblasts and
adipocytes. Since almost nothing is known about this process, our long-term goal is to identify the cellular and
molecular mechanism(s) that regulate hypertrophic chondrocyte dedifferentiation during endochondral bone
formation. Using a variety of sophisticated mouse genetic models and in vitro systems, we aim to: (Aim 1) identify
whether hypertrophic chondrocytes dedifferentiate to form a molecularly and functionally distinct population of
multipotent BMSCs, (Aim 2) determine whether NOTCH signaling in hypertrophic chondrocytes is necessary and/or
sufficient to promote chondrocyte dedifferentiation during endochondral bone formation, and (Aim 3) establish whether
SOX2 is an important regulator of hypertrophic chondrocyte dedifferentiation and a target of NOTCH signaling in the
regulation of this process. Completion of these aims will have broad implications in skeletal biology by elucidating
fundamental cellular and molecular mechanisms associated with the novel process of hypertrophic chondrocyte
dedifferentiation during endochondral ossification. This work will also aid our understanding of NOTCH-related skeletal
diseases, as well as, set the stage for developing novel approaches for the ex vivo generation of mesenchymal
stem/progenitors from cartilage for use in regenerative medicine or cell therapeutic applications.

## Key facts

- **NIH application ID:** 10236257
- **Project number:** 5R01AR071722-04
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Matthew J. Hilton
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $343,574
- **Award type:** 5
- **Project period:** 2018-08-15 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10236257

## Citation

> US National Institutes of Health, RePORTER application 10236257, Notch Signaling in Endochondral Bone Development (5R01AR071722-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10236257. Licensed CC0.

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