# "Establishing Pathways for Endothelial Support of Bone Formation with SLIT3"

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $369,171

## Abstract

Project Summary/Abstract
Recent work establishes that skeletal blood vessels are not just mere channels for blood, but
instead play an active role in supporting bone formation. However, it is unknown which types of
blood vessels provide this support, how these blood vessels alter the production of bone
forming cells from their stem cell progenitors, or how this coupling between blood vessels and
bone forming cells is tied to the overall physiologic demand for bone formation. Progress in this
area has been impeded by most of the growth factors for blood vessels in bone also having
direct effects on bone forming cells, preventing their use to study interactions between blood
vessels and bone forming cells. We have recently identified a new growth factor for skeletal
blood vessels, SLIT3. SLIT3 is produced by bone forming cells and increases bone formation
not by targeting bone forming cells themselves, but instead by promoting outgrowth of blood
vessels that in turn support bone formation. Thus, SLIT3 presents an attractive tool to study
which blood vessels in bone influence bone formation and how these blood vessels shape the
production of bone forming cells. Furthermore, recent advances in understanding skeletal stem
cells from ourselves and others identify that bone contains multiple populations of stem cells
giving rise to bone forming cells, with each of these stem cells having a different anatomic
location and function. It is unlikely that a single type of blood vessel is able to support all of
these different of skeletal stem cell populations, and we accordingly hypothesize that different
types of skeletal blood vessels each support different types of skeletal stem cells. Here, SLIT3
to both address this hypothesis and establish fundamental paradigms for how endothelial cells
support bone formation. In Aim 1, we will study how SLIT3-mediated outgrowth of skeletal blood
vessels is driven by signals known to promote bone formation, determining if this SLIT3-driven
blood vessel outgrowth is needed for the bone formation response to these signals and also
which subsets of bone forming cells are the key producers of SLIT3 needed for these
responses. In Aim 2, we will determine which specific bone forming cells are supported by each
blood vessel type induced by SLIT3. In Aim 3, we will determine how SLIT3-induced blood
vessels shape the differentiation of bone forming cells. Overall, this work will provide a
foundation for the development of drugs targeting skeletal blood vessels as a new approach to
treat osteoporosis and other skeletal disorders.
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## Key facts

- **NIH application ID:** 10347187
- **Project number:** 5R01AR075585-03
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Matthew Blake Greenblatt
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $369,171
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10347187

## Citation

> US National Institutes of Health, RePORTER application 10347187, "Establishing Pathways for Endothelial Support of Bone Formation with SLIT3" (5R01AR075585-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10347187. Licensed CC0.

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