# Switch of Osteogenesis in Vascular Calcification

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $390,000

## Abstract

SUMMARY
Therapeutic advances in vascular calcification may have far-reaching public benefits. Vascular calcification is a
frequent complication of diabetes mellitus associated with the increase of morbidity and mortality. Although the
precise mechanism has not been determined, vascular calcification is known to be an active process involving
ectopic bone formation, in which osteogenic differentiation occurs in the cells transdifferentiated from other
lineages. Previous studies have shown that vascular endothelial cells switch cell fate to differentiate into
osteoblastic-like cells in vascular calcification. However, it is unknown if reversing this switch by inducing
osteoblastic-endothelial transdifferentiation ameliorates vascular calcification. Advanced investigations have
shown that the small molecules are able to reprogram and modulate cell fates, and also shown that
endothelial-like cells can be transdifferentiated from other lineages. In present proposal, we take advantage of
a small molecule identified by using high throughput technology, aiming to induce osteoblastic-endothelial
transdifferentiation and investigate the effects on vascular calcification in diabetes mellitus. In preliminary data,
we use a high throughput model to identify that GSK3 inhibitor SB216763 converts osteoblasts into
endothelial-like cells. We show that SB216763 or limiting GSK3ß modulates protein levels of SMAD1 and ß-
catenin and their transcriptional activity to switch the osteoblastic fate for endothelial differentiation.
Furthermore, SB216763 treatment reduces EC-origin osteogenic differentiation and decreases calcification in
aorta of matrix Gla protein null mouse, an established model of vascular calcification. The treatment of
SB216763 also decreases arterial calcification in diabetic Ins2Akita/+ mice without affecting other tissues.
Therefore, we hypothesize that GSK3 inhibition induces osteoblastic-endothelial transdifferentiation to
ameliorate vascular calcification in diabetes mellitus. In specific Aim 1, we will elucidate the mechanism
underlying osteoblastic-endothelial transdifferentiation induced by GSK3 inhibition. In specific Aim 2, we will
determine if GSK3 inhibition ameliorates vascular calcification in diabetic mouse model. If successful, it will
build osteoblastic-endothelial transdifferentiation as a new concept, and GSK3 inhibitor SB216763 may
emerge as a new therapeutic approach to treat calcification in acquired vascular diseases.

## Key facts

- **NIH application ID:** 9964524
- **Project number:** 5R01HL139675-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Yucheng Yao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $390,000
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9964524

## Citation

> US National Institutes of Health, RePORTER application 9964524, Switch of Osteogenesis in Vascular Calcification (5R01HL139675-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9964524. Licensed CC0.

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