# Investigating the Role of Sclerostin in Calcific Aortic Valve Disease

> **NIH NIH F31** · VANDERBILT UNIVERSITY · 2020 · $45,520

## Abstract

Abstract
Recent clinical trials for Romosozumab, a monoclonal antibody targeting the protein sclerostin, have shown it to
be highly effective in reducing fracture risk in patients with osteoporosis. However, cardiovascular side effects
have been a major roadblock in FDA approval of the drug and may hinder its adoption in clinical disease
management. Although it was originally believed sclerostin was only expressed in the skeleton, recent studies
have demonstrated its expression in cardiovascular tissue, cells, and disease. Research correlating circulating
sclerostin to cardiovascular disease has been confounding. Very few studies of the mechanism of sclerostin in
cardiovascular disease have been published, and none have examined the protein’s role in aortic valve health
and disease, despite the protein being discovered in diseased valves. Calcific aortic valve disease (CAVD) is
the most common affliction of the cardiac valves and is becoming more prevalent in aging populations. It is a
notoriously difficult disease to study and treat, and is responsible for approximately 15,000 deaths per year in
North America. Pathogenesis of CAVD is characterized by gradual accumulation of fibrocalcific lesions resulting
in reduced compliance and difficulty pumping blood to systemic circulation. Without valve replacement, CAVD
can lead to death via heart failure. There is an acute need to unravel the molecular pathophysiology of this
disease in order to develop efficacious pharmaceuticals. Preliminary results from our lab indicate sclerostin is
necessary in the development of CAVD in a mouse model. Additionally, valve interstitial cells shift to a disease
phenotype when treated with the protein in vitro. We hypothesize sclerostin is a driver of CAVD through its
stimulation of the RANKL-NFκB signaling pathway leading to fibrosis and dystrophic calcification by activated
valve interstitial cells. The goal of this proposal is to better understand the role of sclerostin in CAVD and assess
its potential as a pharmacological target. This study presents two primary aims: 1) multiscale molecular
characterization of the CAVD phenotype of Sost genetic mutant mice 2) investigation of valve disease in a pre-
clinical analogue of sclerostin blocking in post-menopausal osteoporosis. This study will be the first to identify
the molecular mechanism of sclerostin in aortic valve health and disease. Intensive analysis of genetic and
pharmacological reduction of sclerostin signaling will provide insight into the side effects observed in
osteoporosis treatment as well as potential for treatment of CAVD.

## Key facts

- **NIH application ID:** 9911657
- **Project number:** 1F31HL151115-01
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Jeffery E Joll
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 1
- **Project period:** 2020-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9911657

## Citation

> US National Institutes of Health, RePORTER application 9911657, Investigating the Role of Sclerostin in Calcific Aortic Valve Disease (1F31HL151115-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9911657. Licensed CC0.

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