# Discoidin Domain Receptor 2, β1 Integrins and ECM Control of Bone Formation

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $469,994

## Abstract

Discoidin domain receptor 2 (DDR2) is a non-integrin collagen receptor having important but poorly understood
skeletal functions. Inactivating mutations in DDR2 cause spondylo-meta-epiphyseal dysplasia (SMED-short
limb type), a human disorder with severe craniofacial and skeletal abnormalities. Ddr2-deficient mice have a
similar phenotype including abnormal skull shape, delayed suture fusion and defective cartilage
growth/orientation in synchondroses at the base of the skull, shortened long bone growth plates and reduced
trabecular and cortical bone mass. Preliminary studies where Ddr2 was selectively inactivated in skeletal
progenitors indicate distinct functions in cells of the bone lineage. Studies will test the following hypothesis:
DDR2 is an important regulator of bone formation that functions in bone lineage cells to sense the collagenous ECM niche
and thereby stimulate SPC lineage commitment and differentiation; on activation by fibrillar collagens, DDR2
synergistically interacts with β1 integrins to stimulate osteoblast differentiation. Aims are:
1. Establish the distribution, fates and gene expression profile of Ddr2-positive cells during craniofacial and
skeletal development. Hypothesis: During development, Ddr2 is expressed in SPCs as well as more mature bone cells.
Studies will: a) establish the time course and pattern of Ddr2 expression during skeletal development, b) define
the lineage of Ddr2-expressing cells, c) Define the molecular signature of Ddr2-expressing cells and their
progeny using single-cell RNAseq.
2. Define the cellular sites of action of DDR2 in the craniofacial and appendicular skeleton. Hypothesis: Ddr2
functions in both SPCs and committed chondrogenic and osteogenic cells to stimulate bone formation. It is not known
which skeletal cells require DDR2 for normal function; skeletal SCs, differentiated cells or both. a) To define
cellular functions of DDR2, a targeted deletion approach will be used to inactivate Ddr2 in Gli+
craniofacial/skeletal progenitors, chondrocytes and osteoblasts. b) To determine if Ddr2 controls the
differentiation of SPCs, the effect of Ddr2 deficiency on the lineage of Gli1+ SPCs will be examined.
3. Examine the mechanistic basis for interactions between DDR2 and collagen-binding β1 integrins.
Hypothesis: DDR2 and β1 integrins synergistically interact to stimulate cellular activity. Collagen-binding β1 integrins
and DDR2 synergistically interact. The mechanistic basis for this synergy will be established using in vitro and
in vivo approaches as follows: a. Examine interactions between DDR2 and integrin signaling during osteoblast
differentiation. b. Use a genetic approach to detect Ddr2 and β1 integrin interactions in vivo.
 Proposed studies will elucidate the skeletal functions of DDR2 and its interactions with β1 integrins. This is
a highly significant but understudied area with important implications for understanding the role of cell-
collagen interactions in bone diseases including SM...

## Key facts

- **NIH application ID:** 10795682
- **Project number:** 5R01DE029465-04
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Renny Theodore Franceschi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $469,994
- **Award type:** 5
- **Project period:** 2021-03-12 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10795682

## Citation

> US National Institutes of Health, RePORTER application 10795682, Discoidin Domain Receptor 2, β1 Integrins and ECM Control of Bone Formation (5R01DE029465-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10795682. Licensed CC0.

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